Fever in infections correlates with inflammation, macrophage infiltration into the affected organ, macrophage activation, and release of cytokines involved in immune response, hematopoiesis, and homeostatic processes. Angiotensin-converting enzyme 2 (ACE2) is the canonical cell surface receptor for SARS-CoV-2. ACE2 together with angiotensin receptor types 1 and 2 and ACE2 are components of the renin–angiotensin system (RAS). Exacerbated production of cytokines, mainly IL-6, points to macrophages as key to understand differential COVID-19 severity. SARS-CoV-2 may modulate macrophage-mediated inflammation events by altering the balance between angiotensin II, which activates angiotensin receptor types 1 and 2, and angiotensin 1–7 and alamandine, which activate MAS proto-oncogene and MAS-related D receptors, respectively. In addition to macrophages, lung cells express RAS components; also, some lung cells are able to produce IL-6. Addressing how SARS-CoV-2 unbalances RAS functionality via ACE2 will help design therapies to attenuate a COVID-19–related cytokine storm.

A mammalian naive organism exposed to a new pathogen can activate two different branches of the immune system: the innate and the adaptive immunity. The innate immunity is involved in the activation of nonspecific processes such as inflammation, whereas the adaptive immunity is related with Ag-specific processes such as, among other, Ab production or immunological memory. The most serious consequences of COVID-19 infection come from an acute respiratory distress syndrome that is aggravated by exacerbated inflammation (1). Immune cells of the white lineage infiltrate the affected tissue to become macrophages that are subsequently activated to produce and release a variety of cytokines. The plasma levels of one of them, IL-6, directly correlates with COVID-19 severity. Often, the macrophage response is limited and does not aggravate viral infections. However, for unknown reasons, some COVID-19 patients develop the so-called cytokine storm, which correlates with symptom aggravation, and the outcome can be fatal (24). Patients (n = 30) in the critical care unit of one of the main hospitals in Barcelona were assessed for plasma/serum levels of four cytokines (IL-6, IL-1β, IL-8, and TNF-α). IL-6 levels led to high interindividual variability, whereas IL-1β levels were within the reference value range. There was not any common trend in IL-8 or TNF-α values, which were either normal or increased. In summary, the most noticeable finding in the cytokine storm was the level of IL-6, which in some patients, may be high enough to lose the dynamic range of measurement (i.e., two orders of magnitude increase or even higher) (Refs. 5, 6, and T. Herold, V. Jurinovic, C. Arnreich, J.C. Hellmuth, M. von Bergwelt-Baildon, M. Klein, and T. Weinberger, manuscript posted on medRxiv, M.J. Cummings, M.R. Baldwin, D. Abrams, S.D. Jacobson, B.J. Meyer, E.M. Balough, J.G. Aaron, J. Claassen, L.E. Rabbani, J. Hastie, B.R. Hochman, J. Salazar-Schicchi, N.H. Yip, D. Brodie, and M.R. O’Donnell, manuscript posted on medRxiv, and J. Gong, H. Dong, S.Q. Xia, Y.Z. Huang, D. Wang, Y. Zhao, W. Liu, S. Tu, M. Zhang, Q. Wang, and F. Lu, manuscript posted on medRxiv). The marked increase in IL-6 levels has prompted the design of a clinical assay using tocilizumab, a monoclonal anti–IL-6 Ab (7, 8). More promising, and already used in COVID-19 patients treated in Spanish hospitals, corticoids may attenuate IL-6 production. It is known that the production of the cytokine is inhibited by glucocorticoids in a wide range of cell types (9). In critical illnesses, the α isoform of the glucocorticoid receptor (or nuclear receptor subfamily 3, group C, member 1 [NR3C1]) arises as a key regulator of homeostatic processes (see Ref. 10 for review).

The link between the renin–angiotensin system (RAS) and coronaviruses was serendipitously discovered. The angiotensin-converting enzyme (ACE) 2 was identified as the receptor for viruses of the SARS family, SARS-CoV-2 being no exception (1115). Importantly (see below), ACE2 has peptidase activity; it is one of the newest members of the RAS, which has been widely studied in relationship with the control of blood pressure. Among its components, there are ACE1, which produces angiotensin II (Ang II), and ACE2, which converts Ang II to angiotensin 1–7 (Ang1–7), Ang II receptors (Ang II receptor type 1 [AT1R] and Ang II receptor type 2 [AT2R]), and the Ang1–7 receptor. The latter was first identified as a product of an oncogene and because of resemblance to the mitochondrial assembly gene from Saccharomyces cerevisiae was named as Mas-related proto-oncogene (16). The receptor whose endogenous agonist is Ang1–7 is now known as Mas receptor (MasR). All these angiotensin-related receptors belong to the superfamily of G-protein–coupled receptors (GPRCRs). It should be finally noted that a novel family of receptors has been named as Mas-related GPCRs (Mrgprs) that, interestingly, also respond to Ang1–7 (1719) but whose endogenous agonist is alamandine, another new RAS member. The relationships between RAS members is shown in Fig. 1.

FIGURE 1.

Components of RAS.

FIGURE 1.

Components of RAS.

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The intense multidisciplinary research on HIV-1 infection led to the discovery of one of the main anchoring molecules, the chemokine CXCR4 GPCR, and of other cell surface proteins acting as virus coreceptors. A relevant HIV-1 coreceptor was identified as dipeptidyl peptidase IV (DPPIV), also known as CD26. In human lymphocytes, the link between CXCR4 and CD26 was proven using different approaches (20). Identified in bats but also occurring in primates, CD26 acts as a receptor for Middle East respiratory syndrome (MERS) coronavirus (21, 22). Using the online Search Tool for the Retrieval of Interacting Genes/Proteins (STRING), ACE2 is directly connected with CD26/DPPIV (Fig. 2A). By default, ACE2 is connected to Ang II, which, in turn, is connected to its cognate receptors, AT1R and AT2R (Fig. 2A). Interestingly, the appearance of a GPCR related to DPPIV is required to force the system to include chemokine receptors in the search for connections (Fig. 2B). In contrast, with these easy-to-find connections, there are almost no papers linking SARS viruses to GPCRs. In sharp contrast, there are several articles devoted to the link between HIV-1 and GPCRs. This fact probably derives from the exhaustive research on HIV-1 and the AIDS it produces, which was more deadly than coronavirus infections. A physiological substrate of CD26 is the stromal-derived factor 1 (SDF-1), alternatively known as CXCL12, which is the endogenous agonist of the CXCR4 chemokine receptor (Fig. 3). On the one hand, SDF-1 is protective against viral entry into cells, and CD26/DPPIV catalytic activity reduces the concentration of this protective factor (20, 23). On the other hand, CXCR4 is a factor in HIV-1 viral entry (2430). Unfortunately, SARS-CoV-2 arrived, and no background on GPCRs and the viral proteins and/or viral entry into the cells exists. Therefore, there is a need to put the focus on the blind point of COVID-19 related research: involved GPCRs, how GPCR functionality is affected by coronaviruses, and whether GPCRs may or not favor SARS entry into cells. Obviously, it is also needed to know how the viral cycle affects the functionality of GPCRs that are directly involved in viral targeting, membrane fusion, and/or viral entrance into cells.

FIGURE 2.

Interaction graph analysis for ACE2 and DPPIV/CD26 restricted to human using STRING. (A) First shell of interactions between ACE2 and other proteins. (B) First shell of interactions between DPPIV (DPP4 in STRING database) and other proteins. Network nodes represent proteins and edges protein–protein associations. The colors of the edges represent different sources of evidence. Known interactions: cyan, from curated databases; magenta, experimentally determined. Predicted interaction: green, gene neighborhood; red, gene fusions; blue, gene co-occurrence. Other: yellow, text mining; black, coexpression; lilac, protein homology. AGT, angiotensinogen; AGTR1, type-1 Ang II receptor; AGTR2, type-2 Ang II receptor; CXCL12, stromal cell-derived factor 1; DPP4, dipeptidyl peptidase 4; MEP1A, meprin A subunit α; MEP1B, meprin A subunit β; MME, neprilysin; PRCP, lysosomal Pro-X carboxypeptidase; REN, renin; XPNPEP2, Xaa-Pro aminopeptidase 2.

FIGURE 2.

Interaction graph analysis for ACE2 and DPPIV/CD26 restricted to human using STRING. (A) First shell of interactions between ACE2 and other proteins. (B) First shell of interactions between DPPIV (DPP4 in STRING database) and other proteins. Network nodes represent proteins and edges protein–protein associations. The colors of the edges represent different sources of evidence. Known interactions: cyan, from curated databases; magenta, experimentally determined. Predicted interaction: green, gene neighborhood; red, gene fusions; blue, gene co-occurrence. Other: yellow, text mining; black, coexpression; lilac, protein homology. AGT, angiotensinogen; AGTR1, type-1 Ang II receptor; AGTR2, type-2 Ang II receptor; CXCL12, stromal cell-derived factor 1; DPP4, dipeptidyl peptidase 4; MEP1A, meprin A subunit α; MEP1B, meprin A subunit β; MME, neprilysin; PRCP, lysosomal Pro-X carboxypeptidase; REN, renin; XPNPEP2, Xaa-Pro aminopeptidase 2.

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FIGURE 3.

Analogies between HIV-1 and SARS receptors and coreceptors Nonconfirmed interactions are represented as a question mark (?).

FIGURE 3.

Analogies between HIV-1 and SARS receptors and coreceptors Nonconfirmed interactions are represented as a question mark (?).

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Extensive research is available related to the receptor of SDF-1, the CXCR4 chemokine receptor, and HIV-1. A search in PubMed on SDF-1 and HIV-1 leads to ∼500 articles and 40 reviews, the most recent (review) in May 2020 (31). The number of articles for HIV-1 and CXCR4 are ∼8 times higher, and the last review appeared in May 2020 (25). Interestingly, the formyl peptide GPCR binds with high-affinity peptides derived from proteins of HIV-1, SARS, and Ebola viruses (32, 33). However, the physiological and/or pharmacological relevance of such findings reported in 2006 is unclear. With the exception of the results related with the formyl peptide receptor, there are few or no articles devoted to studying links between GPCRs and the SARS family of coronaviruses.

The RAS is widely distributed in the mammalian body, and data in the CNS have provided evidence of a relevant role in immune function modulation. All receptors related to both Ang and Ang1–7 are expressed in microglia and contribute to the regulation of cell activation. There is interest in knowing whether the neurologic alterations observed in some COVID-19 patients are somehow mediated by the RAS system expressed in neurons and/or microglia (3448). However, our focus in this review is RAS in macrophages, which release IL-6 when activated and also express RAS components. RAS has been for years under scrutiny from assuming that Ang II was proinflammatory and a potential profibrotic agent (49). It becomes evident that proinflammation and profibrotic actions depend on an exquisite balance within RAS, whose activity changes depending on the differential cell surface expression of its protein components (enzymes and receptors).

Activated macrophages appear in two main phenotypic variants, the proinflammatory or M1 and the anti-inflammatory or M2. From a pharmacological point of view, it is of interest to know how to skew macrophages to the M2 phenotype and whether it is possible that, at some stage of activation, M1 macrophages could be converted into M2 macrophages. Such polarization depends on inhibiting the anti-inflammatory pathway to reinforce the proinflammatory or vice versa. As pointed out in an excellent review in this topic (50), this cross-feedback regulation is due to activation/deactivation of transcription factors: PPARγ, IRF4, and STAT to promote M2 skewing and AP1, NF-κB, STAT1, and IRF5 to promote M1 skewing.

Unlike in renal cells, the RAS Ang1–7-MasR branch has been better characterized in macrophages than the Ang II–AT1R–AT2R branch. Although the expression pattern and the role of Ang II receptors in macrophages are not fully elucidated yet, the general idea is that Ang II is proinflammatory and that inhibitors of ACE1 or antagonists of Ang II receptors could be beneficial for patient with inflammatory diseases coursing with inflammation (51). Unfortunately, the system is more complex, as the two Ang II receptors usually have opposite functional activities. The present review complements another review (1) that appeared recently and tackles the issue of whether ACE2 expression is beneficial or not in SARS-CoV-2 infection (52).

In principle, Ang II has opposite effects depending on the receptor that is activated (Fig. 4). Activation of AT1R by agonists exacerbates inflammation via enhancement of expression of proinflammatory cytokines. In contrast, activation of the AT2R in macrophages regulates the activity of inducible NO synthase and negatively modulates the production of TNF-α, NF-κB, IL-6, and IL-1β (53, 54). The AT2R also mediates the production of IL-10 by the activated macrophage (55), thus attenuating the inflammatory response. In physiological scenarios, it is assumed that inflammation occurs with preponderance of AT1R-mediated signaling but that time passing leads to the downregulation of this receptor and to the upregulation of those RAS receptors whose function is to be anti-inflammatory and/or to mitigate inflammation (Fig. 4, left). There is a variety of ways by which RAS disbalances.

FIGURE 4.

Altered ACE2 function because of SARS viral infection leads to proinflammatory outcomes via RAS deregulation. Images produced using Servier Medical Art (http://www.servier.com).

FIGURE 4.

Altered ACE2 function because of SARS viral infection leads to proinflammatory outcomes via RAS deregulation. Images produced using Servier Medical Art (http://www.servier.com).

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The burden of SARS-CoV-2 infections is much higher in men than in women. In April, it was reported that 2.4 times more men than women died of COVID-19 (56). As the ACE2 gene is in the X chromosome, it is tempting to speculate that gender differences in symptoms and mortality are due to decreased (overall) expression of ACE2 in men. Currently, there are no data to support the benefit of having more or less ACE2 expression. Also, one of the two X chromosomes in women is inactive. Surely 20–30% of genes escape inactivation, and the ACE2 gene seems to be one of them (57), but it is also true that ACE2 expression is greatly affected by sex hormones (58). ACE2 polymorphisms have been described (59), and therefore, males express one protein, whereas females may express two isoforms. If a given isoform represents a higher vulnerability to infection, men would be more exposed because the second isoform in women could exert a compensatory/protective effect. In summary, ACE2 expression may be different in men and women, but it cannot yet be confirmed that differential expression of equal or polymorphic ACE2 correlates with symptom’s severity and with mortality.

A hypothesis based on evidence from SARS research is virus-induced local reduction of ACE2 activity by either reducing its catalytic activity, downregulation, or shedding. In any of those circumstances, Ang II accumulates, Ang1–7 is reduced, and inflammation is prolonged and/or exacerbated (Fig. 4, right).

It is not known whether the two angiotensin receptors interact in macrophages as they do in microglia, where they are upregulated upon activation and where the AT2R counteracts the proinflammatory effects mediated by the AT1R (37, 60). Activation of the AT2R, which is usually upregulated in diseases with inflammatory component, reduces the action of M1 macrophages and, accordingly, the synthesis of TNF-α and IL-6 (61). In summary, more effort is needed to assess the expression of AT1R and AT2R in resting and activated macrophages and to define the role of each receptor when macrophages activate in response to different pathogens.

The first evidence linking Ang1–7 to the regulation of cytokine release by LPS-activated macrophages came from studies using ACE2 knockout mice whose macrophages, upon activation, showed altered expression of adhesion molecules and of cytokines (IL-6 included) (62). When ACE2 is overexpressed, there is a marked reduction of Ang II–induced MCP-1 production, which is seemingly mediated by Ang1–7 (63). Those results led us to propose that the Ang1–7-MasR branch of RAS was relevant for regulating macrophage activation (64). The anti-inflammatory action of Ang1–7 was later confirmed in LPS-treated peritoneal macrophages (65) and in a polymicrobial sepsis rat model (66). Very recent results in an endotoxemia rat model show systemic anti-inflammatory action of Ang1–7 that is mediated by the MasR (67).

MasR activation poses a brake in macrophage activation. In fact, genetic ablation of the receptor leads to increased infiltration of macrophages in a variety of tissues and to increased expression of proinflammatory genes (68). Already, in 2012, upregulation of MasR in LPS-treated cells and regulation by Ang1–7 of TNF-α and of IL-6 production by activated macrophages were reported (65). The effect of the most recently identified member of the angiotensin family, alamandine (Fig. 1), and of Ang1–7 depends on the activated macrophage phenotype. In an in vitro model using macrophages activated using different protocols and in subsets of infiltrating lung macrophages isolated after inducing pleurisy in mice, activation of either MasR or Mrgprs is ineffective on resting cells but reduces inflammation because there were fewer cells producing IL-1β and TNF-α (i.e., fewer cells with the M1 proinflammatory phenotype). In contrast, receptor activation by Ang1–7 or alamandine leads to an anti-inflammatory reprograming of activated macrophages (69).

Based on the involvement of RAS in macrophage biology, alterations induced by SARS-CoV-2 may lead to aberrant macrophage activation. The details of the likely mechanisms operating in macrophages responding to the viral infection are schematized in Fig. 5. First of all, SARS-CoV-2 influences the homeostatic function of its receptor. This issue has not been fully addressed, but even if the SARS-CoV-2 is not affecting peptidase activity, it has been shown that 1) the virus needs ACE2 for entering into cells (70), and 2) there is a coronavirus-induced shedding of ACE2 mediated by transmembrane serine protease 2 (TMPRSS2) and/or disintegrin and metalloproteinase domain-containing protein 17 (ADAM17) (71, 72). About 30 y ago, a selective reduction in cell surface expression of CD26 in cells targeted by HIV-1 was discovered (73). Analogously, ∼15 y ago, it was shown that coronavirus infection markedly reduces cell surface ACE2 expression (74, 75).

FIGURE 5.

Possible scenarios involving RAS under SARS-CoV-2 infection. *1) the potential interaction between ACE2 and the AT2R or the MasR should be investigated, and 2) there is the possibility of cointernalization of SARS-CoV-2/ACE2 together with ACE2-interacting proteins.

FIGURE 5.

Possible scenarios involving RAS under SARS-CoV-2 infection. *1) the potential interaction between ACE2 and the AT2R or the MasR should be investigated, and 2) there is the possibility of cointernalization of SARS-CoV-2/ACE2 together with ACE2-interacting proteins.

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A decrease in ACE2 in the cell surface leads to RAS disbalance because of an increase in Ang II and a decrease in Ang1–7/alamandine extracellular concentrations. This unbalance of RAS leading to increasing the concentration of the proinflammatory peptide while decreasing the concentration of the anti-inflammatory peptide would exacerbate inflammation and proinflammatory IL production (Fig. 4).

Other scenarios remain speculative, as there are a number of unknowns to fully understand macrophage-associated pathology and propose effective therapies. For instance, it is not known whether ACE2 may interact with the AT2R, or even with MasR or with Mrgprs. SARS viruses are surrounded by membrane proteins of the host; are ACE2 and angiotensin receptors among them? Downregulation of ACE2 would result in a similar outcome as enzyme inhibition. If the AT1R is identified as coreceptor, is it disappearing from the cell surface together with ACE2 and/or SARS-CoV-2? This possibility would lead to the preponderance of the action of AT2R, which, in general terms, is anti-inflammatory; therefore, it is not occurring or only occurs in those patients who do not develop the cytokine storm. Overall, it would be informative to investigate whether ACE2 interacts with other RAS components, thus leading to the possibility that receptors of the RAS are coreceptors for the virus. Also needed is to investigate how the virus itself and/or the spike protein of the virus affect the expression and function of all components of RAS in macrophages and targeted lung cells. As in the case of CD26, ACE2 may have catalytically independent function in those cells; indeed, CD26 in lymphocytes acts as a costimulatory molecule of relevance in immune and endocrine responses (76). In addition, the noncatalytic function of CD26 is altered by HIV-1 viral particles and by the envelope HIV-1 gp120 glycoprotein (77). This action is mechanistically dependent on the expression of the main HIV-1 receptor, CD4, and of CXCR4 (78). Already, in 2008, a role of the C-terminal domain of ACE2 in infections by SARS-CoV was identified (79) but was not investigated further. In summary, it would be important to know how SARS-CoV-2 affects the expression and function of protein RAS components, including the possible heteromers that, hopefully because of COVID-19–related research pressure, may now be discovered (labeled with * in Fig. 5).

Inhibiting ACE2 and altering the RAS balance in macrophages surely lead to the increase in proinflammatory cytokines but probably not to the extent of triggering a cytokine storm. Then, other mechanism may operate in cases with serious symptoms, very abnormal IL-6 levels, and increased death risk. It should be noted the title of a recent preprint: “Level of IL-6 predicts respiratory failure in hospitalized symptomatic COVID-19 patients” (T. Herold, V. Jurinovic, C. Arnreich, J.C. Hellmuth, M. von Bergwelt-Baildon, M. Klein, and T. Weinberger, manuscript posted on medRxiv). A recent metanalysis confirms that elevated IL-6 is one of the common findings in fatal outcomes (5). It is then reasonable to hypothesize that in the most serious cases, cells of the patient’s lungs may be able to release IL-6, thus engaging a harmful, vicious cycle.

The most serious COVID-19 cases course with pneumonia, and ACE2 is heavily expressed in the lung (80). The air-exposed internal surface of the lungs is composed of a variety of cells: ciliated, secretory, pneumocyte, basal, stromal, endothelial, and epithelial. The most abundant (i.e., epithelial and endothelial) are capable of producing IL-6 and express almost every RAS component. ACE2 is expressed in type II pneumocytes and in most respiratory-related epithelial cells, with the notable exception of those in the upper respiratory tract, including nasal and oral mucosa (80). In addition, ACE2 is located in the apical side of polarized cells (81) (i.e., readily available to SARS-CoV-2). How expression of RAS components is affected by SARS-CoV-2 in pneumocytes and lung epithelial or endothelial cells has not been tested yet.

Epithelial cells may produce IL-6. The first article on this issue reported production and secretion of IL-6 by stimulated epithelial cells of the human retinal pigment (82). As demonstrated in a variety of experimental models, endothelial cells may produce IL-6 (8385). Furthermore, IL-6 and TNF-α produced by macrophages may lead to endothelial dysfunction (86).

From a multicenter validation study in critically ill patients because of sepsis, which also occurs in some COVID-19 patients (87), it is known that markers of endothelium activation are predictive of final outcome and that soluble FLT-1 (sFLT-1) may be a sepsis biomarker (88). The sFLT-1 is a marker of preeclamptic hypertension in which RAS is dysbalanced, and there is an increase in the expression in platelets of the heteromer formed by the AT1R and the bradykinin B2 receptor (89). Interestingly, the B2 receptor may interact directly with the AT2R (90). In addition, it has been recently hypothesized that dysregulated bradykinin signaling is behind respiratory complications because of COVID-19 (91), whereas it is known the direct link between bradykinin, platelets, and coagulopathy (92), which is another complication in COVID-19 patients. In fact, some patients not only present a cytokine storm, but signs of disseminated intravascular coagulation, which increased serum levels of fibrin degradation products, such as the d-dimer (93, 94). IL-6 may negatively impact on coagulation control mechanisms (8).

Also known is that human coronavirus spike proteins downregulate ACE2 (95) and that ACE2 expression is protective against lung failure (in a murine model) (74). After COVID-19 infection, sequalae include lung fibrosis that can be mediated by altered RAS. Ang II reportedly upregulates the AT1R, downregulates the AT2R (AT1R/AT2R ratio going from 0.4 to 1.4), and increases the activity of a profibrotic enzyme, hyaluronidase (96).

The interindividual response to COVID-19 depends on the viral load, the rate of viral replication, which varies from individual to individual, and the differential expression of the RAS component in the attacked cells (lung cells exposed to the inspired air) and in infiltrating macrophages. However, it cannot be ruled out that opportunistic infections take over and influence disease outcome. Bacterial infection can lead to the production of ILs by cells of the nonimmune system. In fact, bacterial LPS endotoxin can induce IL-6 synthesis by a variety of cells as diverse as osteoblasts (97) and endothelial cells (98). Existing data cannot test the hypothesis that pneumonia is caused by more than one pathogen, but it maintains that possibility. If this were the case, RAS would also have a relevant role.

It should be noted that acute respiratory distress syndrome animal models can be achieved by sepsis induction; therefore, superinfection may be also impacting in the respiratory problems in patients, requiring mechanical ventilation (99). Potential pathogens include, but are not limited to, Mycoplasma and Chlamydia, which, in parallel to pneumonia induction, lead to increases in serum of IL-6 levels (100104), with features such as IL-17–mediated effects that are common in patients infected with MERS-CoV or SARS-CoV viruses (105, 106). Even pneumonia induced by Escherichia coli courses with elevated IL-6 concentration in serum, Gram-positive bacteria, leading to lower IL-6 and TNF-α levels than Gram-negative bacteria (107, 108). The very informative report on the findings in interstitial pneumonia versus nonspecific interstitial pneumonia/fibrosis is recommended, which includes the sources of IL-6 upon analysis of lung biopsy specimens (109). The imbalance of RAS in idiopathic pneumonia, the involvement in fibrosis postpneumonia, and the therapeutic possibilities by targeting some of the components are reviewed elsewhere (110).

MERS viruses attach to DPPIV/CD26 peptidase in targeted cells. SARS viruses attach to and alter ACE2 peptidase function with local downregulation and reduction of the catalytic activity, thus altering the Ang II/Ang1–7 and Ang II/alamandine ratios. Such RAS disbalance may lead to serious consequences in cases of inflammation. SARS-CoV-2 not only alters RAS in targeted cells but in macrophages infiltrating the affected tissue(s). The evidence points to a reduction of ACE2 function, by inhibition, downregulation, and/or shedding caused by viral proteins. Further alterations in the function of RAS proteins are likely to occur after coronavirus attack. The link between an altered RAS and cytokine storm and pulmonary fibrosis also needs to be addressed in detail. Such knowledge would likely open new perspectives to combat infection and guide the appropriate management of disease aggravation and of comorbidities.

Abbreviations used in this article:

     
  • ACE

    angiotensin-converting enzyme

  •  
  • Ang II

    angiotensin II

  •  
  • Ang1–7

    angiotensin 1–7

  •  
  • AT1R

    Ang II receptor type 1

  •  
  • AT2R

    Ang II receptor type 2

  •  
  • DPPIV

    dipeptidyl peptidase IV

  •  
  • GPCR

    G-protein–coupled receptor

  •  
  • MasR

    Mas receptor

  •  
  • MERS

    Middle East respiratory syndrome

  •  
  • Mrgpr

    Mas-related GPCR

  •  
  • RAS

    renin–angiotensin system

  •  
  • SDF-1

    stromal-derived factor 1

  •  
  • STRING

    Search Tool for the Retrieval of Interacting Genes/Proteins.

1
Merad
,
M.
,
J. C.
Martin
.
2020
.
Pathological inflammation in patients with COVID-19: a key role for monocytes and macrophages. [Published erratum appears in 2020 Nat. Rev. Immunol. 20: 448.]
Nat. Rev. Immunol.
20
:
355
362
.
2
Chen
,
J.
,
K.
Subbarao
.
2007
.
The immunobiology of SARS*.
Annu. Rev. Immunol.
25
:
443
472
.
3
Chen
,
N.
,
M.
Zhou
,
X.
Dong
,
J.
Qu
,
F.
Gong
,
Y.
Han
,
Y.
Qiu
,
J.
Wang
,
Y.
Liu
,
Y.
Wei
, et al
.
2020
.
Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study.
Lancet
395
:
507
513
.
4
Zhou
,
F.
,
T.
Yu
,
R.
Du
,
G.
Fan
,
Y.
Liu
,
Z.
Liu
,
J.
Xiang
,
Y.
Wang
,
B.
Song
,
X.
Gu
, et al
.
2020
.
Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. [Published erratum appears in 2020 Lancet 395: 1038.]
Lancet
395
:
1054
1062
.
5
Henry
,
B. M.
,
M. H. S.
de Oliveira
,
S.
Benoit
,
M.
Plebani
,
G.
Lippi
.
2020
.
Hematologic, biochemical and immune biomarker abnormalities associated with severe illness and mortality in coronavirus disease 2019 (COVID-19): a meta-analysis.
Clin. Chem. Lab. Med.
58
:
1021
1028
.
6
Liu
,
T.
,
J.
Zhang
,
Y.
Yang
,
H.
Ma
,
Z.
Li
,
J.
Zhang
,
J.
Cheng
,
X.
Zhang
,
Y.
Zhao
,
Z.
Xia
, et al
.
2020
.
The role of interleukin-6 in monitoring severe case of coronavirus disease 2019.
EMBO Mol. Med.
DOI: 10.15252/emmm.202012421.
7
Chen
,
X.
,
B.
Zhao
,
Y.
Qu
,
Y.
Chen
,
J.
Xiong
,
Y.
Feng
,
D.
Men
,
Q.
Huang
,
Y.
Liu
,
B.
Yang
, et al
.
2020
.
Detectable serum SARS-CoV-2 viral load (RNAaemia) is closely correlated with drastically elevated interleukin 6 (IL-6) level in critically ill COVID-19 patients.
Clin. Infect. Dis.
DOI: 10.1093/cid/ciaa449.
8
Tanaka
,
T.
,
M.
Narazaki
,
T.
Kishimoto
.
2016
.
Immunotherapeutic implications of IL-6 blockade for cytokine storm.
Immunotherapy
8
:
959
970
.
9
Waage
,
A.
,
G.
Slupphaug
,
R.
Shalaby
.
1990
.
Glucocorticoids inhibit the production of IL6 from monocytes, endothelial cells and fibroblasts.
Eur. J. Immunol.
20
:
2439
2443
.
10
Meduri
,
G. U.
,
G. P.
Chrousos
.
2020
.
General adaptation in critical illness: glucocorticoid receptor-alpha master regulator of homeostatic corrections.
Front. Endocrinol. (Lausanne)
11
:
161
.
11
Clarke
,
N. E.
,
A. J.
Turner
.
2012
.
Angiotensin-converting enzyme 2: the first decade.
Int. J. Hypertens.
2012
: 307315.
12
Wan
,
Y.
,
J.
Shang
,
R.
Graham
,
R. S.
Baric
,
F.
Li
.
2020
.
Receptor recognition by the novel coronavirus from Wuhan: an analysis based on decade-long structural studies of SARS coronavirus.
J. Virol.
94
: e00127-20.
13
Shang
,
J.
,
G.
Ye
,
K.
Shi
,
Y.
Wan
,
C.
Luo
,
H.
Aihara
,
Q.
Geng
,
A.
Auerbach
,
F.
Li
.
2020
.
Structural basis of receptor recognition by SARS-CoV-2.
Nature
581
:
221
224
.
14
Kuhn
,
J. H.
,
W.
Li
,
H.
Choe
,
M.
Farzan
.
2004
.
Angiotensin-converting enzyme 2: a functional receptor for SARS coronavirus.
Cell. Mol. Life Sci.
61
:
2738
2743
.
15
Li
,
W.
,
M. J.
Moore
,
N.
Vasilieva
,
J.
Sui
,
S. K.
Wong
,
M. A.
Berne
,
M.
Somasundaran
,
J. L.
Sullivan
,
K.
Luzuriaga
,
T. C.
Greenough
, et al
.
2003
.
Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus.
Nature
426
:
450
454
.
16
Bader
,
M.
,
N.
Alenina
,
D.
Young
,
R. A. S.
Santos
,
R. M.
Touyz
.
2018
.
The meaning of mas.
Hypertension
72
:
1072
1075
.
17
Souza
,
L. L.
,
J.
Duchene
,
M.
Todiras
,
L. C. P.
Azevedo
,
C. M.
Costa-Neto
,
N.
Alenina
,
R. A.
Santos
,
M.
Bader
.
2014
.
Receptor MAS protects mice against hypothermia and mortality induced by endotoxemia.
Shock
41
:
331
336
.
18
Santos
,
R. A. S.
,
A. C.
Simoes e Silva
,
C.
Maric
,
D. M. R.
Silva
,
R. P.
Machado
,
I.
de Buhr
,
S.
Heringer-Walther
,
S. V. B.
Pinheiro
,
M. T.
Lopes
,
M.
Bader
, et al
.
2003
.
Angiotensin-(1-7) is an endogenous ligand for the G protein-coupled receptor Mas.
Proc. Natl. Acad. Sci. USA
100
:
8258
8263
.
19
Villela
,
D.
,
J.
Leonhardt
,
N.
Patel
,
J.
Joseph
,
S.
Kirsch
,
A.
Hallberg
,
T.
Unger
,
M.
Bader
,
R. A.
Santos
,
C.
Sumners
,
U. M.
Steckelings
.
2015
.
Angiotensin type 2 receptor (AT2R) and receptor Mas: a complex liaison.
Clin. Sci. (Lond.)
128
:
227
234
.
20
Herrera
,
C.
,
C.
Morimoto
,
J.
Blanco
,
J.
Mallol
,
F.
Arenzana
,
C.
Lluis
,
R.
Franco
.
2001
.
Comodulation of CXCR4 and CD26 in human lymphocytes.
J. Biol. Chem.
276
:
19532
19539
.
21
van Doremalen
,
N.
,
V. J.
Munster
.
2015
.
Animal models of middle east respiratory syndrome coronavirus infection.
Antiviral Res.
122
:
28
38
.
22
Munster
,
V. J.
,
D. R.
Adney
,
N.
van Doremalen
,
V. R.
Brown
,
K. L.
Miazgowicz
,
S.
Milne-Price
,
T.
Bushmaker
,
R.
Rosenke
,
D.
Scott
,
A.
Hawkinson
, et al
.
2016
.
Replication and shedding of MERS-CoV in Jamaican fruit bats (Artibeus jamaicensis).
Sci. Rep.
6
:
21878
.
23
Shioda
,
T.
,
H.
Kato
,
Y.
Ohnishi
,
K.
Tashiro
,
M.
Ikegawa
,
E. E.
Nakayama
,
H.
Hu
,
A.
Kato
,
Y.
Sakai
,
H.
Liu
, et al
.
1998
.
Anti-HIV-1 and chemotactic activities of human stromal cell-derived factor 1alpha (SDF-1alpha) and SDF-1beta are abolished by CD26/dipeptidyl peptidase IV-mediated cleavage.
Proc. Natl. Acad. Sci. USA
95
:
6331
6336
.
24
Berger
,
E. A.
,
P. M.
Murphy
,
J. M.
Farber
.
1999
.
Chemokine receptors as HIV-1 coreceptors: roles in viral entry, tropism, and disease.
Annu. Rev. Immunol.
17
:
657
700
.
25
Wang
,
Q.
,
A.
Finzi
,
J.
Sodroski
.
2020
.
The conformational states of the HIV-1 envelope glycoproteins.
Trends Microbiol.
DOI: 10.1016/j.tim.2020.03.007.
26
Cammack
,
N.
1999
.
Human immunodeficiency virus type 1 entry and chemokine receptors: a new therapeutic target.
Antivir. Chem. Chemother.
10
:
53
62
.
27
Hoxie
,
J. A.
,
C. C.
LaBranche
,
M. J.
Endres
,
J. D.
Turner
,
J. F.
Berson
,
R. W.
Doms
,
T. J.
Matthews
.
1998
.
CD4-independent utilization of the CXCR4 chemokine receptor by HIV-1 and HIV-2.
J. Reprod. Immunol.
41
:
197
211
.
28
Clapham
,
P. R.
,
J. D.
Reeves
,
G.
Simmons
,
N.
Dejucq
,
S.
Hibbitts
,
A.
McKnight
.
1999
.
HIV coreceptors, cell tropism and inhibition by chemokine receptor ligands.
Mol. Membr. Biol.
16
:
49
55
.
29
Choe
,
H.
1998
.
Chemokine receptors in HIV-1 and SIV infection.
Arch. Pharm. Res.
21
:
634
639
.
30
Howard
,
O. M.
,
T.
Korte
,
N. I.
Tarasova
,
M.
Grimm
,
J. A.
Turpin
,
W. G.
Rice
,
C. J.
Michejda
,
R.
Blumenthal
,
J. J.
Oppenheim
.
1998
.
Small molecule inhibitor of HIV-1 cell fusion blocks chemokine receptor-mediated function.
J. Leukoc. Biol.
64
:
6
13
.
31
Fang
,
X.
,
Q.
Meng
,
H.
Zhang
,
B.
Liang
,
S.
Zhu
,
J.
Wang
,
C.
Zhang
,
L. S.
Huang
,
X.
Zhang
,
R. T.
Schooley
, et al
.
2020
.
Design, synthesis, and biological characterization of a new class of symmetrical polyamine-based small molecule CXCR4 antagonists.
Eur. J. Med. Chem.
200
: 112410.
32
Mills
,
J. S.
2006
.
Peptides derived from HIV-1, HIV-2, Ebola virus, SARS coronavirus and coronavirus 229E exhibit high affinity binding to the formyl peptide receptor.
Biochim. Biophys. Acta
1762
:
693
703
.
33
Braun
,
M. C.
,
J. M.
Wang
,
E.
Lahey
,
R. L.
Rabin
,
B. L.
Kelsall
.
2001
.
Activation of the formyl peptide receptor by the HIV-derived peptide T-20 suppresses interleukin-12 p70 production by human monocytes.
Blood
97
:
3531
3536
.
34
Labandeira-Garcia
,
J. L.
,
A. I.
Rodríguez-Perez
,
P.
Garrido-Gil
,
J.
Rodriguez-Pallares
,
J. L.
Lanciego
,
M. J.
Guerra
.
2017
.
Brain renin-angiotensin system and microglial polarization: implications for aging and neurodegeneration.
Front. Aging Neurosci.
9
:
129
.
35
Garrido-Gil
,
P.
,
A. I.
Rodriguez-Perez
,
A.
Dominguez-Meijide
,
M. J.
Guerra
,
J. L.
Labandeira-Garcia
.
2018
.
Bidirectional neural interaction between central dopaminergic and gut lesions in Parkinson’s disease models.
Mol. Neurobiol.
55
:
7297
7316
.
36
Valenzuela
,
R.
,
M. A.
Costa-Besada
,
J.
Iglesias-Gonzalez
,
E.
Perez-Costas
,
B.
Villar-Cheda
,
P.
Garrido-Gil
,
M.
Melendez-Ferro
,
R.
Soto-Otero
,
J. L.
Lanciego
,
D.
Henrion
, et al
.
2016
.
Mitochondrial angiotensin receptors in dopaminergic neurons. Role in cell protection and aging-related vulnerability to neurodegeneration.
Cell Death Dis.
7
: e2427.
37
Rodriguez-Perez
,
A. I.
,
P.
Garrido-Gil
,
M. A.
Pedrosa
,
M.
Garcia-Garrote
,
R.
Valenzuela
,
G.
Navarro
,
R.
Franco
,
J. L.
Labandeira-Garcia
.
2020
.
Angiotensin type 2 receptors: role in aging and neuroinflammation in the substantia nigra.
Brain Behav. Immun.
87
:
256
271
.
38
Dominguez-Meijide
,
A.
,
A. I.
Rodriguez-Perez
,
C.
Diaz-Ruiz
,
M. J.
Guerra
,
J. L.
Labandeira-Garcia
.
2017
.
Dopamine modulates astroglial and microglial activity via glial renin-angiotensin system in cultures.
Brain Behav. Immun.
62
:
277
290
.
39
Garcia-Garrote
,
M.
,
A.
Perez-Villalba
,
P.
Garrido-Gil
,
G.
Belenguer
,
J. A.
Parga
,
F.
Perez-Sanchez
,
J. L.
Labandeira-Garcia
,
I.
Fariñas
,
J.
Rodriguez-Pallares
.
2019
.
Interaction between angiotensin type 1, type 2, and Mas receptors to regulate adult neurogenesis in the brain ventricular-subventricular zone.
Cells
8
:
1551
.
40
Rivas-Santisteban
,
R.
,
A.
Rodriguez-Perez
,
A.
Muñoz
,
I.
Reyes-Resina
,
J.
Labandeira-García
,
G.
Navarro
,
R.
Franco
.
2020
.
Angiotensin AT1 and AT2 receptor heteromer expression in the hemilesioned rat model of Parkinson’s disease that increases with levodopa-induced dyskinesia. J. Neuroinflammation. In press.
41
Valenzuela
,
R.
,
P.
Barroso-Chinea
,
B.
Villar-Cheda
,
B.
Joglar
,
A.
Muñoz
,
J. L.
Lanciego
,
J. L.
Labandeira-Garcia
.
2010
.
Location of prorenin receptors in primate substantia nigra: effects on dopaminergic cell death.
J. Neuropathol. Exp. Neurol.
69
:
1130
1142
.
42
Joglar
,
B.
,
J.
Rodriguez-Pallares
,
A. I.
Rodriguez-Perez
,
P.
Rey
,
M. J.
Guerra
,
J. L.
Labandeira-Garcia
.
2009
.
The inflammatory response in the MPTP model of Parkinson’s disease is mediated by brain angiotensin: relevance to progression of the disease.
J. Neurochem.
109
:
656
669
.
43
Rodriguez-Pallares
,
J.
,
P.
Rey
,
J. A.
Parga
,
A.
Muñoz
,
M. J.
Guerra
,
J. L.
Labandeira-Garcia
.
2008
.
Brain angiotensin enhances dopaminergic cell death via microglial activation and NADPH-derived ROS.
Neurobiol. Dis.
31
:
58
73
.
44
Villar-Cheda
,
B.
,
R.
Valenzuela
,
A. I.
Rodriguez-Perez
,
M. J.
Guerra
,
J. L.
Labandeira-Garcia
.
2012
.
Aging-related changes in the nigral angiotensin system enhances proinflammatory and pro-oxidative markers and 6-OHDA-induced dopaminergic degeneration.
Neurobiol. Aging
DOI: 10.1016/j.neurobiolaging.2010.08.006.
45
Garrido-Gil
,
P.
,
R.
Valenzuela
,
B.
Villar-Cheda
,
J. L.
Lanciego
,
J. L.
Labandeira-Garcia
.
2013
.
Expression of angiotensinogen and receptors for angiotensin and prorenin in the monkey and human substantia nigra: an intracellular renin-angiotensin system in the nigra.
Brain Struct. Funct.
218
:
373
388
.
46
Garrido-Gil
,
P.
,
A. I.
Rodriguez-Perez
,
P.
Fernandez-Rodriguez
,
J. L.
Lanciego
,
J. L.
Labandeira-Garcia
.
2017
.
Expression of angiotensinogen and receptors for angiotensin and prorenin in the rat and monkey striatal neurons and glial cells.
Brain Struct. Funct.
222
:
2559
2571
.
47
Rodriguez-Perez
,
A. I.
,
D.
Sucunza
,
M. A.
Pedrosa
,
P.
Garrido-Gil
,
J.
Kulisevsky
,
J. L.
Lanciego
,
J. L.
Labandeira-Garcia
.
2018
.
Angiotensin type 1 receptor antagonists protect against alpha-synuclein-induced neuroinflammation and dopaminergic neuron death.
Neurotherapeutics
15
:
1063
1081
.
48
Martínez-Pinilla
,
E.
,
A. I. I.
Rodríguez-Pérez
,
G.
Navarro
,
D.
Aguinaga
,
E.
Moreno
,
J. L. L.
Lanciego
,
J. L. L.
Labandeira-García
,
R.
Franco
.
2015
.
Dopamine D2 and angiotensin II type 1 receptors form functional heteromers in rat striatum.
Biochem. Pharmacol.
96
:
131
142
.
49
Benigni
,
A.
,
P.
Cassis
,
G.
Remuzzi
.
2010
.
Angiotensin II revisited: new roles in inflammation, immunology and aging.
EMBO Mol. Med.
2
:
247
257
.
50
Liu
,
Y.-C.
,
X.-B.
Zou
,
Y.-F.
Chai
,
Y.-M.
Yao
.
2014
.
Macrophage polarization in inflammatory diseases.
Int. J. Biol. Sci.
10
:
520
529
.
51
Dagenais
,
N. J.
,
F.
Jamali
.
2005
.
Protective effects of angiotensin II interruption: evidence for antiinflammatory actions.
Pharmacotherapy
25
:
1213
1229
.
52
Banu
,
N.
,
S. S.
Panikar
,
L. R.
Leal
,
A. R.
Leal
.
2020
.
Protective role of ACE2 and its downregulation in SARS-CoV-2 infection leading to macrophage activation syndrome: therapeutic implications.
Life Sci.
256
: 117905.
53
Isaksson
,
R.
,
A.
Casselbrant
,
E.
Elebring
,
M.
Hallberg
,
M.
Larhed
,
L.
Fändriks
.
2020
.
Direct stimulation of angiotensin II type 2 receptor reduces nitric oxide production in lipopolysaccharide treated mouse macrophages.
Eur. J. Pharmacol.
868
: 172855.
54
Menk
,
M.
,
J. A.
Graw
,
C.
von Haefen
,
M.
Sifringer
,
D.
Schwaiberger
,
T.
Unger
,
U.
Steckelings
,
C. D.
Spies
.
2015
.
Stimulation of the angiotensin II AT2 receptor is anti-inflammatory in human lipopolysaccharide-activated monocytic cells.
Inflammation
38
:
1690
1699
.
55
Dhande
,
I.
,
W.
Ma
,
T.
Hussain
.
2015
.
Angiotensin AT2 receptor stimulation is anti-inflammatory in lipopolysaccharide-activated THP-1 macrophages via increased interleukin-10 production.
Hypertens. Res.
38
:
21
29
.
56
Jin
,
J. M.
,
P.
Bai
,
W.
He
,
F.
Wu
,
X. F.
Liu
,
D. M.
Han
,
S.
Liu
,
J. K.
Yang
.
2020
.
Gender differences in patients with COVID-19: focus on severity and mortality.
Front. Public Health
8
:
152
.
57
Tukiainen
,
T.
,
A. C.
Villani
,
A.
Yen
,
M. A.
Rivas
,
J. L.
Marshall
,
R.
Satija
,
M.
Aguirre
,
L.
Gauthier
,
M.
Fleharty
,
A.
Kirby
, et al
GTEx Consortium
; 
Laboratory, Data Analysis &Coordinating Center (LDACC)—Analysis Working Group
; 
Statistical Methods groups—Analysis Working Group
; 
Enhancing GTEx (eGTEx) groups
; 
NIH Common Fund
; 
NIH/NCI
; 
NIH/NHGRI
; 
NIH/NIMH
; 
NIH/NIDA
; 
Biospecimen Collection Source Site—NDRI
; 
Biospecimen Collection Source Site—RPCI
; 
Biospecimen Core Resource—VARI
; 
Brain Bank Repository—University of Miami Brain Endowment Bank
; 
Leidos Biomedical—Project Management
; 
ELSI Study
; 
Genome Browser Data Integration &Visualization—EBI
; 
Genome Browser Data Integration &Visualization—UCSC Genomics Institute, University of California Santa Cruz
.
2017
.
Landscape of X chromosome inactivation across human tissues. [Published erratum appears in 2018 Nature 555: 274.]
Nature
550
:
244
248
.
58
Liu
,
J.
,
H.
Ji
,
W.
Zheng
,
X.
Wu
,
J. J.
Zhu
,
A. P.
Arnold
,
K.
Sandberg
.
2010
.
Sex differences in renal angiotensin converting enzyme 2 (ACE2) activity are 17β-oestradiol-dependent and sex chromosome-independent.
Biol. Sex Differ.
1
:
6
.
59
Li
,
Q.
,
Z.
Cao
,
P.
Rahman
.
2020
.
Genetic variability of human angiotensin-converting enzyme 2 (hACE2) among various ethnic populations.
Mol. Genet. Genomic Med.
DOI: 10.1002/mgg3.1344.
60
Navarro
,
G.
,
D.
Borroto-Escuela
,
E.
Angelats
,
I.
Etayo
,
I.
Reyes-Resina
,
M.
Pulido-Salgado
,
A. I.
Rodríguez-Pérez
,
E. I.
Canela
,
J.
Saura
,
J. L.
Lanciego
, et al
.
2018
.
Receptor-heteromer mediated regulation of endocannabinoid signaling in activated microglia. Role of CB 1 and CB 2 receptors and relevance for Alzheimer’s disease and levodopa-induced dyskinesia.
Brain Behav. Immun.
67
:
139
151
.
61
Sampson
,
A. K.
,
J. C.
Irvine
,
W. A.
Shihata
,
D.
Dragoljevic
,
N.
Lumsden
,
O.
Huet
,
T.
Barnes
,
T.
Unger
,
U. M.
Steckelings
,
G. L.
Jennings
, et al
.
2016
.
Compound 21, a selective agonist of angiotensin AT2 receptors, prevents endothelial inflammation and leukocyte adhesion in vitro and in vivo.
Br. J. Pharmacol.
173
:
729
740
.
62
Thomas
,
M. C.
,
R. J.
Pickering
,
D.
Tsorotes
,
A.
Koitka
,
K.
Sheehy
,
S.
Bernardi
,
B.
Toffoli
,
T. P.
Nguyen-Huu
,
G. A.
Head
,
Y.
Fu
, et al
.
2010
.
Genetic Ace2 deficiency accentuates vascular inflammation and atherosclerosis in the ApoE knockout mouse.
Circ. Res.
107
:
888
897
.
63
Guo
,
Y. J.
,
W. H.
Li
,
R.
Wu
,
Q.
Xie
,
L. Q.
Cui
.
2008
.
ACE2 overexpression inhibits angiotensin II-induced monocyte chemoattractant protein-1 expression in macrophages.
Arch. Med. Res.
39
:
149
154
.
64
Simões e Silva
,
A. C.
,
K. D.
Silveira
,
A. J.
Ferreira
,
M. M.
Teixeira
.
2013
.
ACE2, angiotensin-(1-7) and Mas receptor axis in inflammation and fibrosis.
Br. J. Pharmacol.
169
:
477
492
.
65
Souza
,
L. L.
,
C. M.
Costa-Neto
.
2012
.
Angiotensin-(1-7) decreases LPS-induced inflammatory response in macrophages.
J. Cell. Physiol.
227
:
2117
2122
.
66
Tsai
,
H. J.
,
M. H.
Liao
,
C. C.
Shih
,
S. M.
Ka
,
C. M.
Tsao
,
C. C.
Wu
.
2018
.
Angiotensin-(1-7) attenuates organ injury and mortality in rats with polymicrobial sepsis.
Crit. Care
22
:
269
.
67
Passaglia
,
P.
,
F.
de Lima Faim
,
M. E.
Batalhão
,
L. M.
Bendhack
,
J.
Antunes-Rodrigues
,
L.
Ulloa
,
A.
Kanashiro
,
E. C.
Carnio
.
2020
.
Central angiotensin-(1-7) attenuates systemic inflammation via activation of sympathetic signaling in endotoxemic rats.
Brain Behav. Immun.
DOI: 10.1016/j.bbi.2020.04.059.
68
Hammer
,
A.
,
G.
Yang
,
J.
Friedrich
,
A.
Kovacs
,
D. H.
Lee
,
K.
Grave
,
S.
Jörg
,
N.
Alenina
,
J.
Grosch
,
J.
Winkler
, et al
.
2016
.
Role of the receptor Mas in macrophage-mediated inflammation in vivo.
Proc. Natl. Acad. Sci. USA
113
:
14109
14114
.
69
de Carvalho Santuchi
,
M.
,
M. F.
Dutra
,
J. P.
Vago
,
K. M.
Lima
,
I.
Galvão
,
F. P.
de Souza-Neto
,
M.
Morais E Silva
,
A. C.
Oliveira
,
F. C. B.
de Oliveira
,
R.
Gonçalves
, et al
.
2019
.
Angiotensin-(1-7) and alamandine promote anti-inflammatory response in macrophages in vitro and in vivo.
Mediators Inflamm.
2019
: 2401081.
70
Hoffmann
,
M.
,
H.
Kleine-Weber
,
S.
Schroeder
,
N.
Krüger
,
T.
Herrler
,
S.
Erichsen
,
T. S.
Schiergens
,
G.
Herrler
,
N. H.
Wu
,
A.
Nitsche
, et al
.
2020
.
SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor.
Cell
181
:
271
280.e8
.
71
Lambert
,
D. W.
,
M.
Yarski
,
F. J.
Warner
,
P.
Thornhill
,
E. T.
Parkin
,
A. I.
Smith
,
N. M.
Hooper
,
A. J.
Turner
.
2005
.
Tumor necrosis factor-α convertase (ADAM17) mediates regulated ectodomain shedding of the severe-acute respiratory syndrome-coronavirus (SARS-CoV) receptor, angiotensin-converting enzyme-2 (ACE2).
J. Biol. Chem.
280
:
30113
30119
.
72
Heurich
,
A.
,
H.
Hofmann-Winkler
,
S.
Gierer
,
T.
Liepold
,
O.
Jahn
,
S.
Pöhlmann
.
2014
.
TMPRSS2 and ADAM17 cleave ACE2 differentially and only proteolysis by TMPRSS2 augments entry driven by the severe acute respiratory syndrome coronavirus spike protein.
J. Virol.
88
:
1293
1307
.
73
Blazquez
,
M. V.
,
J. A.
Madueño
,
R.
Gonzalez
,
R.
Jurado
,
W. W.
Bachovchin
,
J.
Peña
,
E.
Muñoz
.
1992
.
Selective decrease of CD26 expression in T cells from HIV-1-infected individuals.
J. Immunol.
149
:
3073
3077
.
74
Imai
,
Y.
,
K.
Kuba
,
S.
Rao
,
Y.
Huan
,
F.
Guo
,
B.
Guan
,
P.
Yang
,
R.
Sarao
,
T.
Wada
,
H.
Leong-Poi
, et al
.
2005
.
Angiotensin-converting enzyme 2 protects from severe acute lung failure.
Nature
436
:
112
116
.
75
Kuba
,
K.
,
Y.
Imai
,
T.
Ohto-Nakanishi
,
J. M.
Penninger
.
2010
.
Trilogy of ACE2: a peptidase in the renin-angiotensin system, a SARS receptor, and a partner for amino acid transporters.
Pharmacol. Ther.
128
:
119
128
.
76
De Meester
,
I.
,
S.
Korom
,
J.
Van Damme
,
S.
Scharpé
.
1999
.
CD26, let it cut or cut it down.
Immunol. Today
20
:
367
375
.
77
Valenzuela
,
A.
,
J.
Blanco
,
C.
Callebaut
,
E.
Jacotot
,
C.
Lluis
,
A. G.
Hovanessian
,
R.
Franco
.
1997
.
Adenosine deaminase binding to human CD26 is inhibited by HIV-1 envelope glycoprotein gp120 and viral particles.
J. Immunol.
158
:
3721
3729
.
78
Blanco
,
J.
,
A.
Valenzuela
,
C.
Herrera
,
C.
Lluís
,
A. G.
Hovanessian
,
R.
Franco
.
2000
.
The HIV-1 gp120 inhibits the binding of adenosine deaminase to CD26 by a mechanism modulated by CD4 and CXCR4 expression.
FEBS Lett.
477
:
123
128
.
79
Haga
,
S.
,
N.
Yamamoto
,
C.
Nakai-Murakami
,
Y.
Osawa
,
K.
Tokunaga
,
T.
Sata
,
N.
Yamamoto
,
T.
Sasazuki
,
Y.
Ishizaka
.
2008
.
Modulation of TNF-alpha-converting enzyme by the spike protein of SARS-CoV and ACE2 induces TNF-alpha production and facilitates viral entry.
Proc. Natl. Acad. Sci. USA
105
:
7809
7814
.
80
Hamming
,
I.
,
W.
Timens
,
M. L. C.
Bulthuis
,
A. T.
Lely
,
G. J.
Navis
,
H.
van Goor
.
2004
.
Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis.
J. Pathol.
203
:
631
637
.
81
Warner
,
F. J.
,
R. A.
Lew
,
A. I.
Smith
,
D. W.
Lambert
,
N. M.
Hooper
,
A. J.
Turner
.
2005
.
Angiotensin-converting enzyme 2 (ACE2), but not ACE, is preferentially localized to the apical surface of polarized kidney cells.
J. Biol. Chem.
280
:
39353
39362
.
82
Elner
,
V. M.
,
W.
Scales
,
S. G.
Elner
,
J.
Danforth
,
S. L.
Kunkel
,
R. M.
Strieter
.
1992
.
Interleukin-6 (IL-6) gene expression and secretion by cytokine-stimulated human retinal pigment epithelial cells.
Exp. Eye Res.
54
:
361
368
.
83
Lee
,
Y. W.
,
W. H.
Lee
,
P. H.
Kim
.
2010
.
Oxidative mechanisms of IL-4-induced IL-6 expression in vascular endothelium.
Cytokine
49
:
73
79
.
84
Willenberg
,
H. S.
,
I.
Ansurudeen
,
K.
Schebesta
,
M.
Haase
,
B.
Wess
,
S.
Schinner
,
A.
Raffel
,
M.
Schott
,
W. A.
Scherbaum
.
2008
.
The endothelium secretes interleukin-6 (IL-6) and induces IL-6 and aldosterone generation by adrenocortical cells.
Exp. Clin. Endocrinol. Diabetes
116
(
Suppl. 1
):
S70
S74
.
85
Sawa
,
Y.
,
T.
Ueki
,
M.
Hata
,
K.
Iwasawa
,
E.
Tsuruga
,
H.
Kojima
,
H.
Ishikawa
,
S.
Yoshida
.
2008
.
LPS-induced IL-6, IL-8, VCAM-1, and ICAM-1 expression in human lymphatic endothelium.
J. Histochem. Cytochem.
56
:
97
109
.
86
Lee
,
J.
,
S.
Lee
,
H.
Zhang
,
M. A.
Hill
,
C.
Zhang
,
Y.
Park
.
2017
.
Interaction of IL-6 and TNF-α contributes to endothelial dysfunction in type 2 diabetic mouse hearts.
PLoS One
12
: e0187189.
87
Ren
,
D.
,
C.
Ren
,
R. Q.
Yao
,
Y. W.
Feng
,
Y. M.
Yao
.
2020
.
Clinical features and development of sepsis in patients infected with SARS-CoV-2: a retrospective analysis of 150 cases outside Wuhan, China.
Intensive Care Med.
DOI: 10.1007/s00134-020-06084-5.
88
Skibsted
,
S.
,
A. E.
Jones
,
M. A.
Puskarich
,
R.
Arnold
,
R.
Sherwin
,
S.
Trzeciak
,
P.
Schuetz
,
W. C.
Aird
,
N. I.
Shapiro
.
2013
.
Biomarkers of endothelial cell activation in early sepsis.
Shock
39
:
427
432
.
89
AbdAlla
,
S.
,
H.
Lother
,
A.
el Massiery
,
U.
Quitterer
.
2001
.
Increased AT(1) receptor heterodimers in preeclampsia mediate enhanced angiotensin II responsiveness.
Nat. Med.
7
:
1003
1009
.
90
Abadir
,
P. M.
,
A.
Periasamy
,
R. M.
Carey
,
H. M.
Siragy
.
2006
.
Angiotensin II type 2 receptor-bradykinin B2 receptor functional heterodimerization.
Hypertension
48
:
316
322
.
91
Roche
,
J. A.
,
R.
Roche
.
2020
.
A hypothesized role for dysregulated bradykinin signaling in COVID-19 respiratory complications.
FASEB J.
34
:
7265
7269
.
92
Rochaesilva
,
M.
1964
.
Chemical mediators of the acute inflammatory reaction.
Ann. N. Y. Acad. Sci.
116
:
899
911
.
93
Tang
,
N.
,
D.
Li
,
X.
Wang
,
Z.
Sun
.
2020
.
Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia.
J. Thromb. Haemost.
18
:
844
847
.
94
Lillicrap
,
D.
2020
.
Disseminated intravascular coagulation in patients with 2019-nCoV pneumonia.
J. Thromb. Haemost.
18
:
786
787
.
95
Glowacka
,
I.
,
S.
Bertram
,
P.
Herzog
,
S.
Pfefferle
,
I.
Steffen
,
M. O.
Muench
,
G.
Simmons
,
H.
Hofmann
,
T.
Kuri
,
F.
Weber
, et al
.
2010
.
Differential downregulation of ACE2 by the spike proteins of severe acute respiratory syndrome coronavirus and human coronavirus NL63.
J. Virol.
84
:
1198
1205
.
96
Bai
,
F.
,
X. F.
Pang
,
L. H.
Zhang
,
N. P.
Wang
,
R. J.
McKallip
,
R. E.
Garner
,
Z. Q.
Zhao
.
2016
.
Angiotensin II AT1 receptor alters ACE2 activity, eNOS expression and CD44-hyaluronan interaction in rats with hypertension and myocardial fibrosis.
Life Sci.
153
:
141
152
.
97
Kondo
,
A.
,
Y.
Koshihara
,
A.
Togari
.
2001
.
Signal transduction system for interleukin-6 synthesis stimulated by lipopolysaccharide in human osteoblasts.
J. Interferon Cytokine Res.
21
:
943
950
.
98
Modat
,
G.
,
J.
Dornand
,
N.
Bernad
,
D.
Junquero
,
A.
Mary
,
A.
Muller
,
C.
Bonne
.
1990
.
LPS-stimulated bovine aortic endothelial cells produce IL-1 and IL-6 like activities.
Agents Actions
30
:
403
411
.
99
Nagase
,
T.
,
N.
Uozumi
,
S.
Ishii
,
K.
Kume
,
T.
Izumi
,
Y.
Ouchi
,
T.
Shimizu
.
2000
.
Acute lung injury by sepsis and acid aspiration: a key role for cytosolic phospholipase A2.
Nat. Immunol.
1
:
42
46
.
100
Qiao
,
H. M.
,
H. X.
Pang
,
Y. F.
Zhang
,
H. J.
Cheng
,
L.
Liu
,
J. R.
Lu
.
2012
.
Changes of IL-6,IL-10 and TNF-α in children with Mycoplasma pneumoniae pneumonia.
J. Clin. Pediatr.
1
:
59
61
.
101
Zhang
,
Y.
,
Y.
Zhou
,
S.
Li
,
D.
Yang
,
X.
Wu
,
Z.
Chen
.
2016
.
The clinical characteristics and predictors of refractory Mycoplasma pneumoniae pneumonia in children.
PLoS One
11
: e0156465.
102
Kragsbjerg
,
P.
,
T.
Vikerfors
,
H.
Holmberg
.
1998
.
Cytokine responses in patients with Pneumonia caused by chlamydia or mycoplasma.
Respiration
65
:
299
303
.
103
Kurai
,
D.
,
K.
Nakagaki
,
H.
Wada
,
T.
Saraya
,
S.
Kamiya
,
Y.
Fujioka
,
K.
Nakata
,
H.
Takizawa
,
H.
Goto
.
2013
.
Mycoplasma pneumoniae extract induces an IL-17-associated inflammatory reaction in murine lung: implication for mycoplasmal pneumonia.
Inflammation
36
:
285
293
.
104
Zhao
,
J.
,
W.
Zhang
,
L.
Shen
,
X.
Yang
,
Y.
Liu
,
Z.
Gai
.
2017
.
Association of the ACE, GSTM1, IL-6, NOS3, and CYP1A1 polymorphisms with susceptibility of mycoplasma pneumoniae pneumonia in Chinese children.
Medicine (Baltimore)
96
:
e6642
.
105
Faure
,
E.
,
J.
Poissy
,
A.
Goffard
,
C.
Fournier
,
E.
Kipnis
,
M.
Titecat
,
P.
Bortolotti
,
L.
Martinez
,
S.
Dubucquoi
,
R.
Dessein
, et al
.
2014
.
Distinct immune response in two MERS-CoV-infected patients: can we go from bench to bedside?
PLoS One
9
: e88716.
106
Josset
,
L.
,
V. D.
Menachery
,
L. E.
Gralinski
,
S.
Agnihothram
,
P.
Sova
,
V. S.
Carter
,
B. L.
Yount
,
R. L.
Graham
,
R. S.
Baric
,
M. G.
Katze
.
2013
.
Cell host response to infection with novel human coronavirus EMC predicts potential antivirals and important differences with SARS coronavirus.
MBio
4
: e00165-13.
107
Kragsbjerg
,
P.
,
B.
Söderquist
,
H.
Holmberg
,
T.
Vikerfors
,
D.
Danielsson
.
1998
.
Production of tumor necrosis factor-α and interleukin-6 in whole blood stimulated by live Gram-negative and Gram-positive bacteria.
Clin. Microbiol. Infect.
4
:
129
134
.
108
Quinton
,
L. J.
,
M. R.
Jones
,
B. E.
Robson
,
B. T.
Simms
,
J. A.
Whitsett
,
J. P.
Mizgerd
.
2008
.
Alveolar epithelial STAT3, IL-6 family cytokines, and host defense during Escherichia coli pneumonia.
Am. J. Respir. Cell Mol. Biol.
38
:
699
706
.
109
Park
,
C. S.
,
S. W.
Chung
,
S. Y.
Ki
,
G. I.
Lim
,
S. T.
Uh
,
Y. H.
Kim
,
D. I.
Choi
,
J. S.
Park
,
D. W.
Lee
,
M.
Kitaichi
.
2000
.
Increased levels of interleukin-6 are associated with lymphocytosis in bronchoalveolar lavage fluids of idiopathic nonspecific interstitial pneumonia.
Am. J. Respir. Crit. Care Med.
162
:
1162
1168
.
110
Thannickal
,
V. J.
,
K. R.
Flaherty
,
F. J.
Martinez
,
J. P.
Lynch
III
.
2004
.
Idiopathic pulmonary fibrosis: emerging concepts on pharmacotherapy.
Expert Opin. Pharmacother.
5
:
1671
1686
.

The authors have no financial conflicts of interest.