Mucosal surfaces function as selectively permeable barriers between the host and the outside world. Given their close proximity to microbial Ags, mucosal surfaces have evolved sophisticated mechanisms for maintaining homeostasis and preventing excessive acute inflammatory reactions. The role attributed to epithelial cells was historically limited to serving as a selective barrier; in recent years, numerous findings implicate an active role of the epithelium with proresolving mediators in the maintenance of immunological equilibrium. In this brief review, we highlight new evidence that the epithelium actively contributes to coordination and resolution of inflammation, principally through the generation of anti-inflammatory and proresolution lipid mediators. These autacoids, derived from ω-6 and ω-3 polyunsaturated fatty acids, are implicated in the initiation, progression, and resolution of acute inflammation and display specific, epithelial-directed actions focused on mucosal homeostasis. We also summarize present knowledge of mechanisms for resolution via regulation of epithelial-derived antimicrobial peptides in response to proresolving lipid mediators.

The resolution of ongoing inflammation was historically considered a passive act of the healing process with dilution of proinflammatory chemical mediators (1) and occurred independent of active biochemical pathways (1, 2). This view has changed in fundamental ways in the past decade. It is now appreciated that uncontrolled inflammation is a unifying component in many diseases, and new evidence indicates that inflammatory resolution is a biosynthetically active process (3). These new findings implicate a tissue decision process wherein acute inflammation, chronic inflammation, or inflammatory resolution hold the answers as to what endogenous mechanisms control the magnitude and duration of the acute response, particularly as they relate to the cardinal signs of inflammation (2, 4). It has now become evident that the resolution program of acute inflammation particularly within mucosal surfaces remains to be uncovered, and that a complete understanding of these critical pathways will undoubtedly direct new therapeutic opportunities.

Inflammation at mucosal surfaces provides a unique setting for which to define resolution pathways. By their nature, mucosal surfaces interact with the environment and thereby the microbial world in which we live. Important in this regard, the microbiota of each mucosal surface is unique. It is estimated, for example, that the skin harbors 182 different bacterial species, whereas the large intestine may support as many as 1220 different bacterial phylotypes (5). Given this diversity of microbiota, it is not surprising that humans have evolved unique mechanisms to counteract regular microbial challenges. Along these same lines, the timely resolution of ongoing local inflammation has evolved to these ever-changing challenges. We are only now beginning to appreciate the unique features and importance of these responses.

In this brief review, we highlight recent discoveries that impact the active resolution of mucosal inflammation. Given their founding role in active resolution mechanisms, we have focused on the unique contributions of specialized proresolving mediators (SPMs), namely, the resolvins, lipid-derived mediators that are agonist dependent, temporally distinct, and functionally carry novel potent mucosa-directed signals (2).

Resolution of inflammation and return to tissue homeostasis is an exceptionally well-coordinated process. SPMs generated during the resolution phase of ongoing inflammation actively stimulate restoration of tissue homeostasis (3). The first resolvin, known today as resolvin E1 (RvE1), was identified in 1999 as a potent and active initiator of resolution (4). Inordinate, unrestricted, acute inflammation is now acknowledged as an instigating factor, which, when unchecked, contributes to numerous chronic disease states, including cardiovascular disease, metabolic disorders, and cancer. As such, an understanding of the pharmacology of anti-inflammation and endogenous proresolution has been a significant venture (2).

As a basic feature, cyclooxygenase-2 (COX-2) contributes fundamentally to both inflammation and resolution (6, 7). COX-2 expression is rapidly induced at sites of inflammation and is a key enzyme in the generation of PGs, via its oxygenase and peroxidase activities (7). In brief, after liberation of the ω-6 fatty acid arachidonic acid (AA) from cell membranes via phospholipase A2, the oxygenase function of COX-2 catalyzes AA to PGG2 and subsequently to PGH2 via the peroxidase activity of the enzyme. Nonsteroidal anti-inflammatory drugs lower the amplitude of inflammation and delay resolution (6, 8). Acetylsalicylic acid (ASA, aspirin), stands apart in that it inhibits proinflammatory signals and accelerates resolution (9). ASA irreversibly acetylates COX-2 on serine 516, rendering it incapable of converting AA to PGG2. In its acetylated state, ASA produces 15R-H(P)ETE and its peroxidase activity remains intact, resulting in formation of 15R-hydroxyeicosatetraenoate. Aside from ASA’s anti-inflammatory action of inhibiting PG synthesis, 15R-hydroxyeicosatetraenoate is a precursor for proresolution 15-epi-lipoxins (10). Such aspirin-triggered lipoxins (ATLs) are more resistant to metabolic inactivation than lipoxins (11) and also assert anti-inflammatory and proresolving activities in a wide range of inflammatory diseases (7, 8). In addition to the arachidonate-derived lipoxins and ATLs, bioactive SPMs are also biosynthesized from the ω-3 polyunsaturated fatty acids (PUFAs). Both eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are precursors in the biosynthesis of both aspirin-triggered forms of the E- and D-series resolvins. Of importance, lipoxygenases can initiate the biosynthesis of resolvins (both E- and d-series), as well as protectins and maresins, without ASA treatment (3) (see Fig. 1). These are the main pathways for SPM biosynthesis in the absence of ASA treatment. Other nonsteroidal anti-inflammatory drugs (i.e., indomethacin) can both block the biosynthesis of the aspirin-triggered forms of SPM and lead to enhanced formation of SPMs via the lipoxygenase routes involved in the biosynthesis of specific SPMs. The biosynthesis of SPM has recently been reviewed in detail and those interested should see Ref. 12.

FIGURE 1.

“Class switching” in the lipid metabolome promotes resolution. Enzymes COX-1 and COX-2 convert AA to PGG2 by cyclooxygenation, and subsequently to PGH2 by peroxidation. In turn, PGH2 is metabolized to PGs and thromboxanes via specific synthases (top panel). ASA-mediated acetylation of COX enzymes inhibits the cyclooxygenation in COX-1, but COX-2 retains activity (see Refs. 4 and 87 for further details). Proresolving SPMs are produced via acetylated COX-2 with substrates AA and the ω substrates EPA and DHA (bottom panel). Lipoxygenases in human, mouse, and fish tissues can also initiate the biosynthesis of 17S-containing resolvins and protectins de novo.

FIGURE 1.

“Class switching” in the lipid metabolome promotes resolution. Enzymes COX-1 and COX-2 convert AA to PGG2 by cyclooxygenation, and subsequently to PGH2 by peroxidation. In turn, PGH2 is metabolized to PGs and thromboxanes via specific synthases (top panel). ASA-mediated acetylation of COX enzymes inhibits the cyclooxygenation in COX-1, but COX-2 retains activity (see Refs. 4 and 87 for further details). Proresolving SPMs are produced via acetylated COX-2 with substrates AA and the ω substrates EPA and DHA (bottom panel). Lipoxygenases in human, mouse, and fish tissues can also initiate the biosynthesis of 17S-containing resolvins and protectins de novo.

Close modal

Resolution of acute, self-limited inflammation is distinct, by definition, from anti-inflammatory process (3). Proresolving mediators restrict further infiltration of polymorphonuclear leukocyte (PMN, neutrophil) to sites of acute inflammation and promote resolution via enhancing clearance of apoptotic cells by macrophages (3). Importantly, proresolving mediators stimulate antimicrobial activities of epithelia (13, 14), aiding a return to tissue homeostasis. These are particularly relevant in the eye, lung, and oral epithelial surfaces. For example, RvE1 reduces ocular herpes simplex-induced inflammation (15); protectin D1 reduces ocular epithelial injury (16); resolvin D1 (RvD1), RvE1, and protectin D1 each reduce airway inflammation (1720); and RvE1 reduces oral inflammation of the periodontium (21) and stimulates the clearance of apoptotic cell from mucosal surfaces (22). The protective role of RvE1 in periodontal disease has been attributed to both diminished inflammation and curtailed osteoclast-dependent destruction of bone (23). In the gastrointestinal tract, RvE1 is protective in murine models of colitis (13, 2426). Moreover, RvE1 and RvD1 have been recently implicated in the alleviation of inflammatory pain (27). Thus, the potential therapeutic benefits of SPMs are far-reaching.

Much recent attention has been paid to understanding the innate mechanisms involved in the resolution of inflammation at mucosal sites. The best understood are the families of lipid mediators termed the resolvins and the maresins (2). Resolvins have been studied in most detail and are ω-3 PUFA-derived lipid mediators central to activation of the inflammatory resolution program (2, 3). The discovery of resolvins was permitted by using an unbiased systems approach to acute contained self-limited/naturally resolving inflammatory exudates using liquid chromatography-mass spectrometry-mass spectrometry–based lipidemics and earlier knowledge that ω-3 PUFAs are beneficial to a number of cardiovascular and immunoregulatory responses (9). Ensuing studies revealed the existence of novel families of lipid mediators, derived from either EPA (C20:5, 18-series resolvins), as well as DHA (C22:6, 17-series resolvins), which potently and stereoselectively initiate and enhance the resolution mechanisms in acute inflammation.

To date, an array of SPMs has been identified with potent proresolution activities; their mechanisms of action are equally diverse. ATL (15-epi-lipoxin) binds to the lipoxin A4 (LXA4) receptor (ALX/FPR2; Formyl Peptide Receptor 2), eliciting antagonistic activities on PMN chemotaxis (28). RvE1 binds to and interacts with ChemR23 receptor, resulting in ERK and AKT phosphorylation and subsequent signal transduction via ribosomal protein S6 to enhance macrophage phagocytosis (29). RvE1 also binds to the LTB4 receptor BLT1 on neutrophils, where it acts as a partial agonist (30). Aside from signal transduction directly affecting leukocyte function, modulation of gene expression in response to SPM has revealed key insight to their mechanism of resolution. LXA4 and RvE1 induce CCR5 expression on the surface of apoptotic PMN and T cells, resulting in sequestration of CCL3/CCL5 in murine peritonitis, facilitating resolution (31). RvE1 and RvD1 both attenuate PMN transmigration across endothelia (32, 33). Furthermore, RvE1 accelerates the clearance apically adherent PMN from epithelia by enhancing antiadhesive CD55 expression (22). Likewise, ATL induces the expression of an antimicrobial peptide, bactericidal-permeability enhancing, in epithelial cells (14). Also, resolvin D2 (7S,8R,17S-trihydroxy-4Z,9E,11E,13Z,15E,19Z-docosahexaenoic acid) enhances phagocyte killing of microbes, improving survival in cecal ligation puncture-initiated sepsis (34), and RvD1 modulates macrophage responses to LPS-TLR4 signaling, resulting in decreased proinflammatory cytokine release, whereas maintaining IL-10 expression (35).

More recently, RvE1 was discovered to upregulate the expression of intestinal alkaline phosphatase (ALPI), a marker of differentiation with a surprising role in maintenance of bacterial homeostasis (13). Given the proximity of mucosal surfaces to bacterial Ags and the vital role of antimicrobial peptides in host defense, we will discuss the potential role for antimicrobial peptides in the process of resolution.

Epithelial cells are uniquely positioned to serve as a direct line of communication between the immune system and the external environment. In their normal state, mucosal surfaces are exposed on the lumenal surface to high concentrations of foreign Ags, whereas at the same time, they are intimately associated with the immune system via subepithelial lymphoid tissue (36). Polarized epithelia form a physical selective barrier to allow absorption/secretion whereas preventing entry of pathogens into the body. The mucosal epithelium comprises a heterogeneous population of differentiated epithelia with distinct functions: absorptive enterocytes, mucus-secreting goblet cells, antimicrobial peptide-secreting Paneth cells, and enteroendocrine cells (37).

Antimicrobial peptides are secreted prophylactically by the epithelium into the viscous mucus layer, thus minimizing the instance of epithelium-adhering bacteria. Similarly, Paneth cells secrete antimicrobial peptides (defensins/lectins) maintaining intestinal crypt sterility. Consequently, the epithelium forms an important barrier, preventing the free mixing of lumenal antigenic material with the lamina propria, which houses the mucosal immune system (38), and defects in these defensive functions contribute to disease pathogenesis (e.g., loss of function in mucin-2/Paneth cells can contribute to inflammatory bowel disease) (39). Concordantly, antimicrobial peptide generation provides protection for other mucosal epithelial surfaces: lung epithelia produce defensins and LL-37 (40), corneal and conjunctival epithelia express LL-37 (41), and oral epithelia are protected by antimicrobial peptides secreted in saliva (42, 43).

Like many aspects of immunology, the view that the epithelium is merely a physical selective barrier has changed. The epithelium is now viewed as an active player in normal homeostatic mechanisms of mucosal immunity, and in some instances, the epithelium may centrally orchestrate mucosal innate immunity and inflammation (44).

The classically viewed antimicrobial peptides represent a diverse array of small peptides (12–50 aa), containing a positive charge and an amphipathic structure. The most studied antimicrobial peptides to date are cathelicidins and defensins. Cathelicidin (LL-37) is expressed by epithelial cells, neutrophils, monocytes, and macrophages, and can stimulate chemotaxis via the ALX/FPR2 receptor on these cells (45). Posttranslational processing is essential for its antimicrobial activity in vivo (46) and is accomplished by serine proteases such as kallikreins (47) or PMN proteases such as proteinase-3 (48). LL-37 antimicrobial activity was originally thought to neutralize endotoxin because of its cationic/amphipathic capacities to interact with anionic LPS or prevent LPS binding to CD14 (49). Aside from preventing sepsis by interfering with the ability of LPS to stimulate TLR4 signaling, LL-37 have subsequently been demonstrated to directly dampen proinflammatory signaling initiated by LPS (50). Mice deficient in the only known murine cathelicidin (encoded by the gene Cnlp) show significant increases in susceptibility to a number of mucosal infections (51).

Defensins are cationic antimicrobial peptides broadly classed as α- and β-defensins, the former predominantly expressed by PMN and Paneth cells, and the latter by epithelia (52). Similar to LL-37s, α-defensins are activated by proteolytic processing of an inactive precursor (53) and are stored in granules of PMN. In contrast with α-defensins, β-defensins typically have short N-terminal extensions, and all possess some measure of antimicrobial activity in their full-length forms. Defensins have broad antimicrobial actions on Gram-positive and -negative bacteria, and defects in defensin expression have been shown to contribute to a number of mucosal inflammatory diseases, including inflammatory bowel disease and necrotizing enterocolitis (54). β-Defensins are secreted in saliva and are thought to be protective against periodontitis and caries (43). Mutations of the 3′-untranslated region of β-defensin lead to chronic and aggressive periodontitis (55).

Given their name, antimicrobial peptides were originally thought to function merely as “natural antibiotics,” specialized in the killing of bacteria. This bias has hampered discovery of their diverse array of function in immunity and their regulation in host defense. Increasing evidence indicates that aside from their antimicrobial activity, antimicrobial peptides can modulate immune responses by inducing cytokine/chemokine production, inhibiting LPS-induced proinflammatory cytokine production, promoting wound healing, and modulating the responses of dendritic cells or T cells. As such, antimicrobial peptides may be viewed as bridging the gap between innate and adaptive immunity.

Cathelicidin has immunomodulatory functions; for instance, it is chemotactic to mast cells and PMN via interaction with the ALX/FPR2 receptor (45, 56), which is blocked by the anti-inflammatory LXA4 stable analog. Cathelicidin stimulates release of the anti-inflammatory PGD2 from mast cells (57), which as mentioned earlier can prime tissues for resolution by expressing enzymes necessary for resolution. Human β-defensin 2 also possesses immunomodulatory functions and, like LL-37, is known to be chemotactic for mast cells and activated PMN (58). β-Defensin 3 upregulates COX-2 and PGE2 biosynthesis in gingival fibroblasts (59). β-Defensins antagonize T cell tissue infiltration and promote exfiltration (60, 61). Considering their rapid release in response to “danger signals” and their consequent immunomodulatory activities has led to the concept that antimicrobial peptides can act as early warning signals for infection and the creation of term alarmins (62).

As part of their proresolving activity, both LL-37 (63, 64) and β-defensin 2 (65) are known to promote epithelial cell migration, necessary for mucosal restitution after physical injury or damage from immune activity. Human β-defensin 2 stimulates migration and proliferation and tube formation of endothelial cells in wounds, resulting in neovascularization and accelerated wound healing (66). LL-37 has been proposed to initiate tissue remodeling via matrix metalloproteinase activity and promote wound closure via induction of the Snail/Slug transcription factors, necessary for E-cadherin transcription and epithelial adherens junction formation (64).

A number of additional mechanisms exist to maintain homeostasis at mucosal surfaces. Among the innate antimicrobial defense molecules of humans is bactericidal permeability-increasing protein (BPI), a 55- to 60-kDa protein originally found in neutrophil azurophilic granules, on the neutrophil cell surface and, to a lesser extent, in specific granules of eosinophils (67). Subsequently, BPI was found to be expressed in epithelial cells (14). Based on an original transcriptional profiling approach to identify novel ATL-regulated genes in intestinal epithelial cells, BPI was found to be expressed in both human and murine epithelial cells of wide origin (oral, pulmonary, and gastrointestinal mucosa), and each was similarly regulated by ATL. Functional studies using a BPI-neutralizing antiserum revealed that surface-localized BPI blocks endotoxin-mediated signaling in epithelia and kills Salmonella typhimurium. More recently, molecular studies revealed that epithelial BPI is selectively induced by ATL and prominently regulated by the transcription factors Sp1/3 and C/EBPβ (68). Additional studies in human and murine tissue ex vivo revealed that BPI is diffusely expressed along the crypt-villous axis (14, 68), and that epithelial BPI protein levels decrease along the length of the intestine (69). More recent studies with SPM have revealed the expression of BPI in various mucosal epithelia (67).

As its name infers, BPI selectively exerts multiple antimicrobial actions against Gram-negative bacteria, including cytotoxicity through damage to bacterial inner/outer membranes, neutralization of bacterial LPS (endotoxin), as well as serving as an opsonin for phagocytosis of Gram-negative bacteria by neutrophils (70, 71). The high affinity of BPI for the lipid A region of LPS (72) targets its cytotoxic activity to Gram-negative bacteria. Binding of BPI to the Gram-negative bacterial outer membrane is followed by a time-dependent penetration of the molecule to the bacterial inner membrane where damage results in loss of membrane integrity, dissipation of electrochemical gradients, and bacterial death (73). BPI binds the lipid A region of LPS with high affinity (74, 75), and thereby prevents its interaction with other (proinflammatory) LPS-binding molecules, including LBP and CD14 (76). Because BPI binds the lipid A region common to all LPSs, it is able to neutralize endotoxin from a broad array of Gram-negative pathogens (71). The selective and potent action of BPI against Gram-negative bacteria and their LPS is fully manifest in biologic fluids, including plasma, serum, and whole blood (71, 77). In multiple animal models of Gram-negative sepsis and/or endotoxemia, administration of BPI congeners is associated with improved outcome (78, 79). These studies in epithelia have identified a previously unappreciated “molecular shield” for protection of mucosal surfaces against Gram-negative bacteria and their endotoxin.

There is much recent interest in ALPI, a 70-kDa, GPI-anchored protein expressed on the apical (luminal) aspect of intestinal epithelial cell (80). In the past, this molecule had been viewed as one of the better epithelial differentiation markers, with little understanding of the true function of this molecule within the mucosa. More recent studies have identified this molecule as a central player in microbial homeostasis (8183).

A recent microarray screen to identify RvE1-regulated genes in intestinal epithelial cells revealed two important findings. First, these studies revealed the previously unappreciated native expression of the RvE1 receptor ChemR23 on epithelial cells. A screen of various epithelial cell lines revealed prominent expression of ChemR23 on human intestinal epithelial cell lines (T84 and Caco-2). Unique was the pattern of expression on polarized epithelia. This analysis revealed that ChemR23 localizes predominantly to the apical membrane surface, which was somewhat unexpected given that most other G protein-coupled receptors exhibit basolateral expression in polarized epithelia (84). Such membrane distribution of ChemR23 suggested that the localized generation of RvE1 during PMN–epithelial interactions could occur at the apical (lumenal) aspect of the tissue. This is an intriguing possibility given that the other known function for RvE1 on mucosal epithelia is to promote the termination and clearance of PMN after transmigration (22), through well-characterized, CD55-dependent mechanisms (85, 86). Thus, the PMN–epithelial interactions that occur within the lumen of the intestine may initiate a proresolving signature to the epithelium during PMN transit through the mucosa.

Second, these microarray studies identified a prominent RvE1-dependent antimicrobial signature within the epithelium, including the induction of BPI and the BPI-like molecule PLUNC (palate, lung, nasal epithelium clone) (13). Also notable was the induction of epithelial ALPI by RvE1. Surface-expressed ALPI was shown to retard Gram-negative bacterial growth and to potently neutralize LPS through a mechanism involving dephosphorylation of 1,4′-bisphosphorylated glucosamine disaccharide of LPS lipid A (82, 83). This observation was translated to the murine model dextran sodium sulfate colitis and revealed that induction of ALPI by RvE1 in vivo strongly correlated with the resolution phase of inflammation (Fig. 2). Moreover, inhibition of ALPI activity was shown to increase the severity of colitic disease and abrogate the protective influences of RvE1 (13). Like those defining epithelial expression of BPI (14), these studies provide an example of the critical interface between inflammatory resolution and the importance of antimicrobial mechanisms.

FIGURE 2.

RvE1 biosynthesis and model for induction of epithelial ALPI. A, De novo synthesis of RvE1 at the mucosal surface. During epithelial cell–PMN interactions, RvE1 production is amplified by transcellular biosynthesis via the interactions of two or more cell types, each contributing an enzymatic product. In the example shown here, epithelial cell COX-2 generates 18-HEPE from dietary EPA and PMN-expressed 5-lipoxygenase (5-LO), and lta4H then generates RvE1 (see Refs. 34 and 88 for further details). Such locally generated RvE1 is then made available to activate apically expressed ChemR23, which, in turn, induces the expression of ALPI. Original magnification ×200. B, Induction of ALPI activity after in vivo administration of RvE1 during the resolution of inflammation of a mouse model of dextran sodium sulfate (DSS) colitis [see Campbell et al. (13)]. Original magnification ×400.

FIGURE 2.

RvE1 biosynthesis and model for induction of epithelial ALPI. A, De novo synthesis of RvE1 at the mucosal surface. During epithelial cell–PMN interactions, RvE1 production is amplified by transcellular biosynthesis via the interactions of two or more cell types, each contributing an enzymatic product. In the example shown here, epithelial cell COX-2 generates 18-HEPE from dietary EPA and PMN-expressed 5-lipoxygenase (5-LO), and lta4H then generates RvE1 (see Refs. 34 and 88 for further details). Such locally generated RvE1 is then made available to activate apically expressed ChemR23, which, in turn, induces the expression of ALPI. Original magnification ×200. B, Induction of ALPI activity after in vivo administration of RvE1 during the resolution of inflammation of a mouse model of dextran sodium sulfate (DSS) colitis [see Campbell et al. (13)]. Original magnification ×400.

Close modal

Given the close proximity of bacteria to mucosal surfaces, maintenance of tissue homeostasis presents a significant challenge. After successful handling of infiltrating bacteria, the generation of proresolving mediators accelerates the return to homeostasis. This review highlights not only the multifunctional role of antimicrobial peptides in inflammation, but also the interdependent relationship between the induction of antimicrobial peptides and the initiation of resolution pathways and the role of resolvins in this process (see Fig. 3). After microbial detection, “alarmins” or “classical” antimicrobial peptides are released by infiltrating immune cells, aiding the killing of bacteria, stimulating neutrophils to generate reactive oxygen species (with inadvertent tissue damage), promoting further release of antimicrobial peptides, and releasing both proinflammatory and anti-inflammatory lipids via COX-2 induction. As such, “classical” antimicrobial peptides could be considered to have both proinflammatory and anti-inflammatory properties, suggesting that antimicrobial peptides prime the inflammatory microenvironment of the mucosal surface for resolution. After generation of SPM, “nonclassical” antimicrobial peptides may accelerate return to homeostasis via continued bacterial killing, inhibition of LPS signaling, and inhibition of “classical” antimicrobial peptide release from leukocytes. As such, it would appear that an interdependent relationship exists between the activity of antimicrobial peptides and the initiation of resolution programs. Along these lines, RvE1 blocks LTB4-stimulated release of LL-37 by human PMN, and LXA4 inhibits proinflammatory actions of LL-37 (45).

FIGURE 3.

Temporal regulation and multifunctional roles of SPM-regulated antimicrobial peptides in the resolution of inflammation. After microbial detection, classical antimicrobial peptides are released by epithelial cells and recruited immune cells. Antimicrobial peptides aid in the killing of bacteria, stimulating PMNs to generate reactive oxygen species (with inadvertent tissue damage), and promote further release of antimicrobial peptides and proinflammatory and anti-inflammatory lipid mediators via COX-2 induction and acetylation. In the resolution phase, generation of SPM elicits the induction of “nonclassical” antimicrobial peptides such as ALPI and BPI (13, 14), which accelerate return to homeostasis via continued bacterial killing, and inhibition of LPS signaling (35). Furthermore, SPMs can block and/or counteract the release of “classical” antimicrobial peptides from leukocytes, dampening the “Alarmin” signals (45).

FIGURE 3.

Temporal regulation and multifunctional roles of SPM-regulated antimicrobial peptides in the resolution of inflammation. After microbial detection, classical antimicrobial peptides are released by epithelial cells and recruited immune cells. Antimicrobial peptides aid in the killing of bacteria, stimulating PMNs to generate reactive oxygen species (with inadvertent tissue damage), and promote further release of antimicrobial peptides and proinflammatory and anti-inflammatory lipid mediators via COX-2 induction and acetylation. In the resolution phase, generation of SPM elicits the induction of “nonclassical” antimicrobial peptides such as ALPI and BPI (13, 14), which accelerate return to homeostasis via continued bacterial killing, and inhibition of LPS signaling (35). Furthermore, SPMs can block and/or counteract the release of “classical” antimicrobial peptides from leukocytes, dampening the “Alarmin” signals (45).

Close modal

Overall, the contribution of microbes to health and disease has provided an elegant lesson in biology. Results from model disease systems and humans allowed the discovery of proresolving mechanisms that are fundamental to our understanding of disease pathogenesis. As summarized in this review, the interdependence of antimicrobial defense mechanisms with inflammatory disease resolution has provided an informative example of how these biochemical pathways yield insight toward a better understanding of tissue function. Ongoing studies of antimicrobial regulation in the mucosa, exemplified by SPM-regulated BPI and ALPI in intestinal epithelia, should provide templates for the design of new and effective therapies for inflammatory disease resolution.

E.L.C. is supported by a fellowship from the Crohn’s and Colitis Foundation of America. The S.P.C. laboratory is supported by National Institutes of Health Grants R37DK50189 and RO1HL60569. The C.N.S. laboratory is supported by National Institutes of Health Grants R01GM038765 and R01DE019938.

The content of this publication is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Diabetes and Digestive and Kidney Diseases; the National Institute of General Medical Sciences; the National Heart, Lung, and Blood Institute; the National Institute of Dental and Craniofacial Research; or the National Institutes of Health.

Abbreviations used in this article:

AA

arachidonic acid

ALPI

intestinal alkaline phosphatase

ASA

acetylsalicylic acid

ATL

aspirin-triggered lipoxin

BPI

bactericidal permeability-increasing protein

COX

cyclooxygenase

DHA

docosahexaenoic acid

EPA

eicosapentaenoic acid

LXA4

lipoxin A4 (5S,6R,15S-trihydroxytrihydroxy-7E,9E,11Z,13E-eicosatetraenoic acid)

PMN

polymorphonuclear leukocyte, neutrophil

PUFA

polyunsaturated fatty acid

RvD1

resolvin D1

RvE1

resolvin E1 (5S,6R,15S-trihydroxy-7E,9E,11Z,13E-eicosatetraenoic acid)

SPM

specialized proresolving mediator.

1
Majno
G.
,
Joris
I.
.
1996
.
Cells, Tissues and Disease: Principles of General Pathology.
Blackwell Science
,
Cambridge, MA
.
2
Serhan
C. N.
,
Chiang
N.
.
2008
.
Endogenous pro-resolving and anti-inflammatory lipid mediators: a new pharmacologic genus.
Br. J. Pharmacol.
153
(
Suppl. 1
):
S200
S215
.
3
Serhan
C. N.
,
Chiang
N.
,
Van Dyke
T. E.
.
2008
.
Resolving inflammation: dual anti-inflammatory and pro-resolution lipid mediators.
Nat. Rev. Immunol.
8
:
349
361
.
4
Serhan
C. N.
,
Clish
C. B.
,
Brannon
J.
,
Colgan
S. P.
,
Chiang
N.
,
Gronert
K.
.
2000
.
Novel functional sets of lipid-derived mediators with antiinflammatory actions generated from omega-3 fatty acids via cyclooxygenase 2-nonsteroidal antiinflammatory drugs and transcellular processing.
J. Exp. Med.
192
:
1197
1204
.
5
Bik
E. M.
2009
.
Composition and function of the human-associated microbiota.
Nutr. Rev.
67
(
Suppl. 2
):
S164
S171
.
6
Gilroy
D. W.
,
Colville-Nash
P. R.
,
Willis
D.
,
Chivers
J.
,
Paul-Clark
M. J.
,
Willoughby
D. A.
.
1999
.
Inducible cyclooxygenase may have anti-inflammatory properties.
Nat. Med.
5
:
698
701
.
7
Spite
M.
,
Serhan
C. N.
.
2010
.
Novel lipid mediators promote resolution of acute inflammation: impact of aspirin and statins.
Circ. Res.
107
:
1170
1184
.
8
Schwab
J. M.
,
Chiang
N.
,
Arita
M.
,
Serhan
C. N.
.
2007
.
Resolvin E1 and protectin D1 activate inflammation-resolution programmes.
Nature
447
:
869
874
.
9
Serhan
C. N.
,
Brain
S. D.
,
Buckley
C. D.
,
Gilroy
D. W.
,
Haslett
C.
,
O’Neill
L. A.
,
Perretti
M.
,
Rossi
A. G.
,
Wallace
J. L.
.
2007
.
Resolution of inflammation: state of the art, definitions and terms.
FASEB J.
21
:
325
332
.
10
Clària
J.
,
Serhan
C. N.
.
1995
.
Aspirin triggers previously undescribed bioactive eicosanoids by human endothelial cell-leukocyte interactions.
Proc. Natl. Acad. Sci. USA
92
:
9475
9479
.
11
Serhan
C. N.
,
Maddox
J. F.
,
Petasis
N. A.
,
Akritopoulou-Zanze
I.
,
Papayianni
A.
,
Brady
H. R.
,
Colgan
S. P.
,
Madara
J. L.
.
1995
.
Design of lipoxin A4 stable analogs that block transmigration and adhesion of human neutrophils.
Biochemistry
34
:
14609
14615
.
12
Bannenberg
G.
,
Serhan
C. N.
.
2010
.
Specialized pro-resolving lipid mediators in the inflammatory response: an update.
Biochim. Biophys. Acta
1801
:
1260
1273
.
13
Campbell
E. L.
,
MacManus
C. F.
,
Kominsky
D. J.
,
Keely
S.
,
Glover
L. E.
,
Bowers
B. E.
,
Scully
M.
,
Bruyninckx
W. J.
,
Colgan
S. P.
.
2010
.
Resolvin E1-induced intestinal alkaline phosphatase promotes resolution of inflammation through LPS detoxification.
Proc. Natl. Acad. Sci. USA
107
:
14298
14303
.
14
Canny
G.
,
Levy
O.
,
Furuta
G. T.
,
Narravula-Alipati
S.
,
Sisson
R. B.
,
Serhan
C. N.
,
Colgan
S. P.
.
2002
.
Lipid mediator-induced expression of bactericidal/permeability-increasing protein (BPI) in human mucosal epithelia.
Proc. Natl. Acad. Sci. USA
99
:
3902
3907
.
15
Rajasagi
N. K.
,
Reddy
P. B.
,
Suryawanshi
A.
,
Mulik
S.
,
Gjorstrup
P.
,
Rouse
B. T.
.
2011
.
Controlling herpes simplex virus-induced ocular inflammatory lesions with the lipid-derived mediator resolvin E1.
J. Immunol.
186
:
1735
1746
.
16
Gronert
K.
,
Maheshwari
N.
,
Khan
N.
,
Hassan
I. R.
,
Dunn
M.
,
Laniado Schwartzman
M.
.
2005
.
A role for the mouse 12/15-lipoxygenase pathway in promoting epithelial wound healing and host defense.
J. Biol. Chem.
280
:
15267
15278
.
17
Aoki
H.
,
Hisada
T.
,
Ishizuka
T.
,
Utsugi
M.
,
Kawata
T.
,
Shimizu
Y.
,
Okajima
F.
,
Dobashi
K.
,
Mori
M.
.
2008
.
Resolvin E1 dampens airway inflammation and hyperresponsiveness in a murine model of asthma.
Biochem. Biophys. Res. Commun.
367
:
509
515
.
18
Haworth
O.
,
Cernadas
M.
,
Yang
R.
,
Serhan
C. N.
,
Levy
B. D.
.
2008
.
Resolvin E1 regulates interleukin 23, interferon-gamma and lipoxin A4 to promote the resolution of allergic airway inflammation.
Nat. Immunol.
9
:
873
879
.
19
Levy
B. D.
,
Kohli
P.
,
Gotlinger
K.
,
Haworth
O.
,
Hong
S.
,
Kazani
S.
,
Israel
E.
,
Haley
K. J.
,
Serhan
C. N.
.
2007
.
Protectin D1 is generated in asthma and dampens airway inflammation and hyperresponsiveness.
J. Immunol.
178
:
496
502
.
20
Wang
B.
,
Gong
X.
,
Wan
J. Y.
,
Zhang
L.
,
Zhang
Z.
,
Li
H. Z.
,
Min
S.
.
2011
.
Resolvin D1 protects mice from LPS-induced acute lung injury.
Pulm. Pharmacol. Ther.
24
:
434
441
.
21
Hasturk
H.
,
Kantarci
A.
,
Goguet-Surmenian
E.
,
Blackwood
A.
,
Andry
C.
,
Serhan
C. N.
,
Van Dyke
T. E.
.
2007
.
Resolvin E1 regulates inflammation at the cellular and tissue level and restores tissue homeostasis in vivo.
J. Immunol.
179
:
7021
7029
.
22
Campbell
E. L.
,
Louis
N. A.
,
Tomassetti
S. E.
,
Canny
G. O.
,
Arita
M.
,
Serhan
C. N.
,
Colgan
S. P.
.
2007
.
Resolvin E1 promotes mucosal surface clearance of neutrophils: a new paradigm for inflammatory resolution.
FASEB J.
21
:
3162
3170
.
23
Hasturk
H.
,
Kantarci
A.
,
Ohira
T.
,
Arita
M.
,
Ebrahimi
N.
,
Chiang
N.
,
Petasis
N. A.
,
Levy
B. D.
,
Serhan
C. N.
,
Van Dyke
T. E.
.
2006
.
RvE1 protects from local inflammation and osteoclast- mediated bone destruction in periodontitis.
FASEB J.
20
:
401
403
.
24
Arita
M.
,
Yoshida
M.
,
Hong
S.
,
Tjonahen
E.
,
Glickman
J. N.
,
Petasis
N. A.
,
Blumberg
R. S.
,
Serhan
C. N.
.
2005
.
Resolvin E1, an endogenous lipid mediator derived from omega-3 eicosapentaenoic acid, protects against 2,4,6-trinitrobenzene sulfonic acid-induced colitis.
Proc. Natl. Acad. Sci. USA
102
:
7671
7676
.
25
Bento
A. F.
,
Claudino
R. F.
,
Dutra
R. C.
,
Marcon
R.
,
Calixto
J. B.
.
2011
.
Omega-3 fatty acid-derived mediators 17(R)-hydroxy docosahexaenoic acid, aspirin-triggered resolvin D1 and resolvin D2 prevent experimental colitis in mice.
J. Immunol
.
187
:
1957
1969
.
26
Lima-Garcia
J.
,
Dutra
R.
,
da Silva
K.
,
Motta
E.
,
Campos
M.
,
Calixto
J.
.
The precursor of resolvin D series and aspirin-triggered resolvin D1 display anti-hyperalgesic properties in adjuvant-induced arthritis in rats.
Br. J. Pharmacol
.
In press
.
27
Xu
Z. Z.
,
Zhang
L.
,
Liu
T.
,
Park
J. Y.
,
Berta
T.
,
Yang
R.
,
Serhan
C. N.
,
Ji
R. R.
.
2010
.
Resolvins RvE1 and RvD1 attenuate inflammatory pain via central and peripheral actions.
Nat. Med.
16
:
592
597
,
1p following 597
.
28
Takano
T.
,
Fiore
S.
,
Maddox
J. F.
,
Brady
H. R.
,
Petasis
N. A.
,
Serhan
C. N.
.
1997
.
Aspirin-triggered 15-epi-lipoxin A4 (LXA4) and LXA4 stable analogues are potent inhibitors of acute inflammation: evidence for anti-inflammatory receptors.
J. Exp. Med.
185
:
1693
1704
.
29
Ohira
T.
,
Arita
M.
,
Omori
K.
,
Recchiuti
A.
,
Van Dyke
T. E.
,
Serhan
C. N.
.
2010
.
Resolvin E1 receptor activation signals phosphorylation and phagocytosis.
J. Biol. Chem.
285
:
3451
3461
.
30
Arita
M.
,
Ohira
T.
,
Sun
Y. P.
,
Elangovan
S.
,
Chiang
N.
,
Serhan
C. N.
.
2007
.
Resolvin E1 selectively interacts with leukotriene B4 receptor BLT1 and ChemR23 to regulate inflammation.
J. Immunol.
178
:
3912
3917
.
31
Ariel
A.
,
Fredman
G.
,
Sun
Y. P.
,
Kantarci
A.
,
Van Dyke
T. E.
,
Luster
A. D.
,
Serhan
C. N.
.
2006
.
Apoptotic neutrophils and T cells sequester chemokines during immune response resolution through modulation of CCR5 expression.
Nat. Immunol.
7
:
1209
1216
.
32
Serhan
C. N.
,
Hong
S.
,
Gronert
K.
,
Colgan
S. P.
,
Devchand
P. R.
,
Mirick
G.
,
Moussignac
R. L.
.
2002
.
Resolvins: a family of bioactive products of omega-3 fatty acid transformation circuits initiated by aspirin treatment that counter proinflammation signals.
J. Exp. Med.
196
:
1025
1037
.
33
Sun
Y. P.
,
Oh
S. F.
,
Uddin
J.
,
Yang
R.
,
Gotlinger
K.
,
Campbell
E.
,
Colgan
S. P.
,
Petasis
N. A.
,
Serhan
C. N.
.
2007
.
Resolvin D1 and its aspirin-triggered 17R epimer. Stereochemical assignments, anti-inflammatory properties, and enzymatic inactivation.
J. Biol. Chem.
282
:
9323
9334
.
34
Spite
M.
,
Norling
L. V.
,
Summers
L.
,
Yang
R.
,
Cooper
D.
,
Petasis
N. A.
,
Flower
R. J.
,
Perretti
M.
,
Serhan
C. N.
.
2009
.
Resolvin D2 is a potent regulator of leukocytes and controls microbial sepsis.
Nature
461
:
1287
1291
.
35
Palmer
C. D.
,
Mancuso
C. J.
,
Weiss
J. P.
,
Serhan
C. N.
,
Guinan
E. C.
,
Levy
O.
.
17(R)-Resolvin D1 differentially regulates TLR4-mediated responses of primary human macrophages to purified LPS and live
E. coli. J. Leukoc. Biol
.
In press
.
36
Beagley
K. W.
,
Husband
A. J.
.
1998
.
Intraepithelial lymphocytes: origins, distribution, and function.
Crit. Rev. Immunol.
18
:
237
254
.
37
Laukoetter
M. G.
,
Nava
P.
,
Nusrat
A.
.
2008
.
Role of the intestinal barrier in inflammatory bowel disease.
World J. Gastroenterol.
14
:
401
407
.
38
McCole
D. F.
,
Barrett
K. E.
.
2007
.
Varied role of the gut epithelium in mucosal homeostasis.
Curr. Opin. Gastroenterol.
23
:
647
654
.
39
Kim
Y. S.
,
Ho
S. B.
.
2010
.
Intestinal goblet cells and mucins in health and disease: recent insights and progress.
Curr. Gastroenterol. Rep.
12
:
319
330
.
40
Singh
P. K.
,
Jia
H. P.
,
Wiles
K.
,
Hesselberth
J.
,
Liu
L.
,
Conway
B. A.
,
Greenberg
E. P.
,
Valore
E. V.
,
Welsh
M. J.
,
Ganz
T.
, et al
.
1998
.
Production of beta-defensins by human airway epithelia.
Proc. Natl. Acad. Sci. USA
95
:
14961
14966
.
41
Gordon
Y. J.
,
Huang
L. C.
,
Romanowski
E. G.
,
Yates
K. A.
,
Proske
R. J.
,
McDermott
A. M.
.
2005
.
Human cathelicidin (LL-37), a multifunctional peptide, is expressed by ocular surface epithelia and has potent antibacterial and antiviral activity.
Curr. Eye Res.
30
:
385
394
.
42
Sahasrabudhe
K. S.
,
Kimball
J. R.
,
Morton
T. H.
,
Weinberg
A.
,
Dale
B. A.
.
2000
.
Expression of the antimicrobial peptide, human beta-defensin 1, in duct cells of minor salivary glands and detection in saliva.
J. Dent. Res.
79
:
1669
1674
.
43
Abiko
Y.
,
Nishimura
M.
,
Kaku
T.
.
2003
.
Defensins in saliva and the salivary glands.
Med. Electron Microsc.
36
:
247
252
.
44
Shale
M.
,
Ghosh
S.
.
2009
.
How intestinal epithelial cells tolerise dendritic cells and its relevance to inflammatory bowel disease.
Gut
58
:
1291
1299
.
45
Wan
M.
,
Godson
C.
,
Guiry
P. J.
,
Agerberth
B.
,
Haeggström
J. Z.
.
2011
.
Leukotriene B4/antimicrobial peptide LL-37 proinflammatory circuits are mediated by BLT1 and FPR2/ALX and are counterregulated by lipoxin A4 and resolvin E1.
FASEB J.
25
:
1697
1705
.
46
Cole
A. M.
,
Shi
J.
,
Ceccarelli
A.
,
Kim
Y. H.
,
Park
A.
,
Ganz
T.
.
2001
.
Inhibition of neutrophil elastase prevents cathelicidin activation and impairs clearance of bacteria from wounds.
Blood
97
:
297
304
.
47
Yamasaki
K.
,
Schauber
J.
,
Coda
A.
,
Lin
H.
,
Dorschner
R. A.
,
Schechter
N. M.
,
Bonnart
C.
,
Descargues
P.
,
Hovnanian
A.
,
Gallo
R. L.
.
2006
.
Kallikrein-mediated proteolysis regulates the antimicrobial effects of cathelicidins in skin.
FASEB J.
20
:
2068
2080
.
48
Sørensen
O.
,
Arnljots
K.
,
Cowland
J. B.
,
Bainton
D. F.
,
Borregaard
N.
.
1997
.
The human antibacterial cathelicidin, hCAP-18, is synthesized in myelocytes and metamyelocytes and localized to specific granules in neutrophils.
Blood
90
:
2796
2803
.
49
Rosenfeld
Y.
,
Papo
N.
,
Shai
Y.
.
2006
.
Endotoxin (lipopolysaccharide) neutralization by innate immunity host-defense peptides. Peptide properties and plausible modes of action.
J. Biol. Chem.
281
:
1636
1643
.
50
Mookherjee
N.
,
Brown
K. L.
,
Bowdish
D. M.
,
Doria
S.
,
Falsafi
R.
,
Hokamp
K.
,
Roche
F. M.
,
Mu
R.
,
Doho
G. H.
,
Pistolic
J.
, et al
.
2006
.
Modulation of the TLR-mediated inflammatory response by the endogenous human host defense peptide LL-37.
J. Immunol.
176
:
2455
2464
.
51
Iimura
M.
,
Gallo
R. L.
,
Hase
K.
,
Miyamoto
Y.
,
Eckmann
L.
,
Kagnoff
M. F.
.
2005
.
Cathelicidin mediates innate intestinal defense against colonization with epithelial adherent bacterial pathogens.
J. Immunol.
174
:
4901
4907
.
52
van Wetering
S.
,
Sterk
P. J.
,
Rabe
K. F.
,
Hiemstra
P. S.
.
1999
.
Defensins: key players or bystanders in infection, injury, and repair in the lung?
J. Allergy Clin. Immunol.
104
:
1131
1138
.
53
Wilson
C. L.
,
Ouellette
A. J.
,
Satchell
D. P.
,
Ayabe
T.
,
López-Boado
Y. S.
,
Stratman
J. L.
,
Hultgren
S. J.
,
Matrisian
L. M.
,
Parks
W. C.
.
1999
.
Regulation of intestinal alpha-defensin activation by the metalloproteinase matrilysin in innate host defense.
Science
286
:
113
117
.
54
Salzman
N. H.
,
Underwood
M. A.
,
Bevins
C. L.
.
2007
.
Paneth cells, defensins, and the commensal microbiota: a hypothesis on intimate interplay at the intestinal mucosa
.
Semin. Immunol.
19
:
70
83
.
Epub 20May 07, 2007
.
55
Schaefer
A. S.
,
Richter
G. M.
,
Nothnagel
M.
,
Laine
M. L.
,
Rühling
A.
,
Schäfer
C.
,
Cordes
N.
,
Noack
B.
,
Folwaczny
M.
,
Glas
J.
, et al
.
2010
.
A 3′ UTR transition within DEFB1 is associated with chronic and aggressive periodontitis.
Genes Immun.
11
:
45
54
.
56
Yang
De
,
Chen
Q.
,
Schmidt
A. P.
,
Anderson
G. M.
,
Wang
J. M.
,
Wooters
J.
,
Oppenheim
J. J.
,
Chertov
O.
.
2000
.
LL-37, the neutrophil granule- and epithelial cell-derived cathelicidin, utilizes formyl peptide receptor-like 1 (FPRL1) as a receptor to chemoattract human peripheral blood neutrophils, monocytes, and T cells.
J. Exp. Med.
192
:
1069
1074
.
57
Niyonsaba
F.
,
Hirata
M.
,
Ogawa
H.
,
Nagaoka
I.
.
2003
.
Epithelial cell-derived antibacterial peptides human beta-defensins and cathelicidin: multifunctional activities on mast cells.
Curr. Drug Targets Inflamm. Allergy
2
:
224
231
.
58
Niyonsaba
F.
,
Iwabuchi
K.
,
Matsuda
H.
,
Ogawa
H.
,
Nagaoka
I.
.
2002
.
Epithelial cell-derived human beta-defensin-2 acts as a chemotaxin for mast cells through a pertussis toxin-sensitive and phospholipase C-dependent pathway.
Int. Immunol.
14
:
421
426
.
59
Chotjumlong
P.
,
Khongkhunthian
S.
,
Ongchai
S.
,
Reutrakul
V.
,
Krisanaprakornkit
S.
.
2010
.
Human beta-defensin-3 up-regulates cyclooxygenase-2 expression and prostaglandin E2 synthesis in human gingival fibroblasts.
J. Periodontal Res.
45
:
464
470
.
60
Feng
Z.
,
Dubyak
G. R.
,
Lederman
M. M.
,
Weinberg
A.
.
2006
.
Cutting edge: human beta defensin 3—a novel antagonist of the HIV-1 coreceptor CXCR4.
J. Immunol.
177
:
782
786
.
61
Ghannam
S.
,
Dejou
C.
,
Pedretti
N.
,
Giot
J. P.
,
Dorgham
K.
,
Boukhaddaoui
H.
,
Deleuze
V.
,
Bernard
F. X.
,
Jorgensen
C.
,
Yssel
H.
,
Pène
J.
.
2011
.
CCL20 and β-defensin-2 induce arrest of human Th17 cells on inflamed endothelium in vitro under flow conditions.
J. Immunol.
186
:
1411
1420
.
62
Oppenheim
J. J.
,
Yang
D.
.
2005
.
Alarmins: chemotactic activators of immune responses.
Curr. Opin. Immunol.
17
:
359
365
.
63
Otte
J. M.
,
Zdebik
A. E.
,
Brand
S.
,
Chromik
A. M.
,
Strauss
S.
,
Schmitz
F.
,
Steinstraesser
L.
,
Schmidt
W. E.
.
2009
.
Effects of the cathelicidin LL-37 on intestinal epithelial barrier integrity.
Regul. Pept.
156
:
104
117
.
64
Carretero
M.
,
Escámez
M. J.
,
García
M.
,
Duarte
B.
,
Holguín
A.
,
Retamosa
L.
,
Jorcano
J. L.
,
Río
M. D.
,
Larcher
F.
.
2008
.
In vitro and in vivo wound healing-promoting activities of human cathelicidin LL-37.
J. Invest. Dermatol.
128
:
223
236
.
65
Otte
J. M.
,
Werner
I.
,
Brand
S.
,
Chromik
A. M.
,
Schmitz
F.
,
Kleine
M.
,
Schmidt
W. E.
.
2008
.
Human beta defensin 2 promotes intestinal wound healing in vitro.
J. Cell. Biochem.
104
:
2286
2297
.
66
Baroni
A.
,
Donnarumma
G.
,
Paoletti
I.
,
Longanesi-Cattani
I.
,
Bifulco
K.
,
Tufano
M. A.
,
Carriero
M. V.
.
2009
.
Antimicrobial human beta-defensin-2 stimulates migration, proliferation and tube formation of human umbilical vein endothelial cells.
Peptides
30
:
267
272
.
67
Canny
G.
,
Levy
O.
.
2008
.
Bactericidal/permeability-increasing protein (BPI) and BPI homologs at mucosal sites
.
Trends Immunol
.
29
:
541
547
.
68
Canny
G.
,
Cario
E.
,
Lennartsson
A.
,
Gullberg
U.
,
Brennan
C.
,
Levy
O.
,
Colgan
S. P.
.
2006
.
Functional and biochemical characterization of epithelial bactericidal/permeability-increasing protein.
Am. J. Physiol. Gastrointest. Liver Physiol.
290
:
G557
G567
.
69
Canny
G. O.
,
Trifonova
R. T.
,
Kindelberger
D. W.
,
Colgan
S. P.
,
Fichorova
R. N.
.
2006
.
Expression and function of bactericidal/permeability-increasing protein in human genital tract epithelial cells.
J. Infect. Dis.
194
:
498
502
.
70
Elsbach
P.
,
Weiss
J.
.
1998
.
Role of the bactericidal/permeability-increasing protein in host defence.
Curr. Opin. Immunol.
10
:
45
49
.
71
Levy
O.
2000
.
A neutrophil-derived anti-infective molecule: bactericidal/permeability-increasing protein.
Antimicrob. Agents Chemother.
44
:
2925
2931
.
72
Gazzano-Santoro
H.
,
Parent
J. B.
,
Grinna
L.
,
Horwitz
A.
,
Parsons
T.
,
Theofan
G.
,
Elsbach
P.
,
Weiss
J.
,
Conlon
P. J.
.
1992
.
High-affinity binding of the bactericidal/permeability-increasing protein and a recombinant amino-terminal fragment to the lipid A region of lipopolysaccharide.
Infect. Immun.
60
:
4754
4761
.
73
Mannion
B. A.
,
Weiss
J.
,
Elsbach
P.
.
1990
.
Separation of sublethal and lethal effects of the bactericidal/permeability increasing protein on Escherichia coli.
J. Clin. Invest.
85
:
853
860
.
74
Levy
O.
,
Ooi
C. E.
,
Elsbach
P.
,
Doerfler
M. E.
,
Lehrer
R. I.
,
Weiss
J.
.
1995
.
Antibacterial proteins of granulocytes differ in interaction with endotoxin. Comparison of bactericidal/permeability-increasing protein, p15s, and defensins.
J. Immunol.
154
:
5403
5410
.
75
Ulevitch
R. J.
,
Tobias
P. S.
.
1999
.
Recognition of gram-negative bacteria and endotoxin by the innate immune system.
Curr. Opin. Immunol.
11
:
19
22
.
76
Gazzano-Santoro
H.
,
Mészáros
K.
,
Birr
C.
,
Carroll
S. F.
,
Theofan
G.
,
Horwitz
A. H.
,
Lim
E.
,
Aberle
S.
,
Kasler
H.
,
Parent
J. B.
.
1994
.
Competition between rBPI23, a recombinant fragment of bactericidal/permeability-increasing protein, and lipopolysaccharide (LPS)-binding protein for binding to LPS and gram-negative bacteria.
Infect. Immun.
62
:
1185
1191
.
77
Weiss
J.
,
Elsbach
P.
,
Olsson
I.
,
Odeberg
H.
.
1978
.
Purification and characterization of a potent bactericidal and membrane active protein from the granules of human polymorphonuclear leukocytes.
J. Biol. Chem.
253
:
2664
2672
.
78
Evans
T. J.
,
Carpenter
A.
,
Moyes
D.
,
Martin
R.
,
Cohen
J.
.
1995
.
Protective effects of a recombinant amino-terminal fragment of human bactericidal/permeability-increasing protein in an animal model of gram-negative sepsis.
J. Infect. Dis.
171
:
153
160
.
79
Lin
Y.
,
Leach
W. J.
,
Ammons
W. S.
.
1996
.
Synergistic effect of a recombinant N-terminal fragment of bactericidal/permeability-increasing protein and cefamandole in treatment of rabbit gram-negative sepsis.
Antimicrob. Agents Chemother.
40
:
65
69
.
80
Vaishnava
S.
,
Hooper
L. V.
.
2007
.
Alkaline phosphatase: keeping the peace at the gut epithelial surface.
Cell Host Microbe
2
:
365
367
.
81
Goldberg
R. F.
,
Austen
W. G.
 Jr.
,
Zhang
X.
,
Munene
G.
,
Mostafa
G.
,
Biswas
S.
,
McCormack
M.
,
Eberlin
K. R.
,
Nguyen
J. T.
,
Tatlidede
H. S.
, et al
.
2008
.
Intestinal alkaline phosphatase is a gut mucosal defense factor maintained by enteral nutrition.
Proc. Natl. Acad. Sci. USA
105
:
3551
3556
.
82
Mata-Haro
V.
,
Cekic
C.
,
Martin
M.
,
Chilton
P. M.
,
Casella
C. R.
,
Mitchell
T. C.
.
2007
.
The vaccine adjuvant monophosphoryl lipid A as a TRIF-biased agonist of TLR4.
Science
316
:
1628
1632
.
83
Moyle
P. M.
,
Toth
I.
.
2008
.
Self-adjuvanting lipopeptide vaccines.
Curr. Med. Chem.
15
:
506
516
.
84
Wozniak
M.
,
Keefer
J. R.
,
Saunders
C.
,
Limbird
L. E.
.
1997
.
Differential targeting and retention of G protein-coupled receptors in polarized epithelial cells.
J. Recept. Signal Transduct. Res.
17
:
373
383
.
85
Lawrence
D. W.
,
Bruyninckx
W. J.
,
Louis
N. A.
,
Lublin
D. M.
,
Stahl
G. L.
,
Parkos
C. A.
,
Colgan
S. P.
.
2003
.
Antiadhesive role of apical decay-accelerating factor (CD55) in human neutrophil transmigration across mucosal epithelia.
J. Exp. Med.
198
:
999
1010
.
86
Louis
N. A.
,
Hamilton
K. E.
,
Kong
T.
,
Colgan
S. P.
.
2005
.
HIF-dependent induction of apical CD55 coordinates epithelial clearance of neutrophils.
FASEB J.
19
:
950
959
.
87
Serhan
C. N.
2007
.
Resolution phase of inflammation: novel endogenous anti-inflammatory and proresolving lipid mediators and pathways.
Annu. Rev. Immunol.
25
:
101
137
.
88
Oh
S. F.
,
Pillai
P. S.
,
Recchiuti
A.
,
Yang
R.
,
Serhan
C. N.
.
2011
.
Pro-resolving actions and stereoselective biosynthesis of 18S E-series resolvins in human leukocytes and murine inflammation.
J. Clin. Invest.
121
:
569
581
.

S.P.C. and C.N.S. are inventors on patents assigned to Brigham and Women’s Hospital-Partners HealthCare on the composition, uses, and clinical development of anti-inflammatory and proresolving mediators and related compounds. The following are licensed for clinical development: lipoxins to Bayer HealthCare and resolvins and related materials to Resolvyx Pharmaceuticals. C.N.S. retains founder stock in Resolvyx. E.L.C. has no financial conflicts of interest.