Top Reads Free

B cell–activating factor of the TNF family is a key B cell survival factor that is not only essential for B cell function but also T cell costimulation. Given that dendritic cells (DCs) are a major source of BAFF, in this Top Read, Zhao et al. (p. 518) sought to determine if BAFF gene silencing in mature DCs (mDCs) could induce a tolerogenic phenotype (tolerogenic DCs [tolDCs]). CRISPR/Cas9-mediated silencing of BAFF endowed mDCs with an immature phenotype that was associated with increased tolerogenicity. In vivo, treatment of mice with BAFF-silenced DCs significantly alleviated disease signs of collagen-induced arthritis (CIA). These phenotypic changes correlated with a reduction in Th17 populations and an increase in regulatory T cell (Treg) populations. Furthermore, administration of BAFF-silenced DCs to mice with CIA decreased serum concentrations of IL-1β, IL-17, IL-6, and IL-12p70, as well as suppressed production of autoantibody isotypes IgG1 and IgG2a. In vitro experiments revealed that BAFF-silenced DCs promoted expression of IL-10 and Foxp3 mRNA in CD4⁺ T cells and inhibited expression of ROR-γt mRNA and IL-17. Collectively, this study demonstrates that BAFF-silenced DCs can ameliorate CIA via induction of Treg populations and suppression of Th17 populations. As such, BAFF may be a promising target for generation of tolDCs for the treatment of autoimmune arthritis.

Although airway allergic inflammation (AAI) is associated with expression of tropomyosin receptor kinase A (TrkA) by eosinophils, the functional role of TrkA in regulating eosinophil recruitment and function during AAI remains poorly understood. In this Top Read, Dileepan et al. (p. 682) demonstrated that eotaxin-1, a major chemoattractant for eosinophils during AAI, activated TrkA in eosinophils. To specifically inhibit TrkA kinase activity, the authors used a chemical-genetic approach in which a mutation within the ATP-binding pocket in subdomain V of TrkA allowed selective and reversible inhibition by the ATP analog 1-NM-PP1. In vitro, inhibition of TrkA enhanced eosinophil spreading on VCAM-1, but inhibited eotaxin-1–mediated eosinophil migration, calcium flux, cell polarization, and ERK1/2 activation, suggesting TrkA is important for the signaling pathways activated by eotaxin-1 during migration. Consistent with these observations, blockade of matrix metalloprotease inhibited eotaxin-induced TrkA activation. Importantly, inhibition of TrkA in Alternaria alternata extract–treated mice significantly suppressed eosinophilia and Th2 cytokine production, eosinophil-specific chemokines, structural changes in the airways, and airway hyperresponsiveness. In summary, these results demonstrate that TrkA activation by eotaxin-1 promotes eosinophil migration and airway inflammation and suggests that manipulation of the TrkA signaling pathway may serve as a therapeutic for allergic airway disease.

This Top Read by Wong et al. (p. 644) demonstrates that neutralization of IL-10 during the early stages of Mycobacterium tuberculosis infection in nonhuman primates (NHP) may improve outcomes at later stages. Neutralization of IL-10 had no effect on overall lung inflammation or on the number of granulomas. At 4 wk postinfection, however, a significant number of granulomas in the IL-10–neutralized lung showed reduced local inflammation. This effect was not evident at 8 wk, indicating that IL-10 may influence inflammation at early time points. Interestingly, granulomas with reduced inflammation at 4 wk showed attenuated bacterial burden at 8 wk. IL-10 neutralization did not affect the composition of T cell populations within the granulomas, although there was a higher frequency of IL-17–producing T cells and a temporal enhancement of innate cytokine responses after 8 wk. Increased collagenization and fibrosis was also evident in the lungs of the NHP treated with the IL-10–neutralizing Ab. Computational modeling determined that the early local immunological and structural changes caused by IL-10 depletion would lead to reduced bacterial burden and increased lesion sterilization. Together, these data demonstrate that early expression of IL-10 may impair local responses to M. tuberculosis.

This Top Read further elucidates the role type 2 cytokines play in eosinophilia and asthma. Beckert et al. (p. 550) administered equimolar doses of IL-4, IL-5, or IL-13 intranasally either singularly or in combination to evaluate their impact on eosinophil biomarkers and asthmatic phenotypes. Mice receiving IL-5 alone had a greater percentage of eosinophils in the bone marrow (BM) and lung. Singular administration of IL-13 increased the percentage of eosinophils in the bronchoalveolar lavage (BAL). When IL-5 and IL-13 were given in combination, eosinophil percentages in the BAL, lung, blood, and BM all were increased when compared with administration of either cytokine alone. Absolute numbers of eosinophils in the lung increased in response to IL-5 administered in combination with IL-4 and/or IL-13. Based on biomarker analysis, IL-13 administration increased activation of airway granulocytes, and this effect was synergistic with IL-5 and IL-13. Administration of IL-13 alone, however, had the greatest impact on airway hyperresponsiveness. As numerous mAbs targeting type 2 cytokines are being used to treat asthma, these data provide further clarification of the mechanisms underlying this disease and should improve therapeutic approaches.