Resistin-like Molecule α Promotes Pathogenic Th17 Cell Responses and Bacterial-Induced Intestinal Inflammation

Abstract

Resistin-like molecule (RELM) α belongs to a family of secreted mammalian proteins that have putative immunomodulatory functions. Recent studies have identified a pathogenic role for RELMα in chemically-induced colitis through effects on innate cell populations. However, whether RELMα regulates intestinal adaptive immunity to enteric pathogens is unknown. Here, we employed Citrobacter rodentium as a physiologic model of pathogenic Escherichia coli-induced diarrheal disease, colitis and Th17 cell responses. In response to Citrobacter, RELMα expression was induced in intestinal epithelial cells, infiltrating macrophages and eosinophils of the infected colons. Citrobacter-infected RELMα−/− mice exhibited reduced infection-induced intestinal inflammation, characterized by decreased leukocyte recruitment to the colons and reduced immune cell activation compared to wild-type mice. Interestingly, Citrobacter colonization and clearance were unaffected in RELMα−/− mice, suggesting that the immune stimulatory effects of RELMα following Citrobacter infection were pathologic rather than host-protective. Further, infected RELMα−/− mice exhibited decreased CD4+ T cell expression of the pro-inflammatory cytokine IL-17A. To directly test whether RELMα promoted Citrobacter-induced intestinal inflammation via IL-17A, infected WT and IL-17A−/− mice were treated with recombinant RELMα. RELMα treatment of Citrobacter-infected WT mice exacerbated intestinal inflammation and IL-17A expression whereas IL-17A−/− mice were protected from RELMα-induced intestinal inflammation. Finally, infected RELMα−/− mice exhibited reduced levels of serum IL-23p19 compared to WT mice, and RELMα−/− peritoneal macrophages showed deficient IL-23p19 induction. Together, these data identify a pro-inflammatory role for RELMα in bacterial-induced colitis and suggest that the IL-23/Th17 axis is a critical mediator of RELMα-induced inflammation.

Polarizing the T helper 17 response inCitrobacter rodentiuminfection via expression of resistin-like molecule α

“…3 Here, we relate these findings to our other previous work demonstrating that RELMα limits Th2 inflammation. 7 These studies suggested that the RELMα-mediated effects observed might be a consequence of the counter-regulation of Th2/Th17 cytokine responses.…”

“…22 Our recent data demonstrating that RELMα can promote expression of IL-12p40 and IL-23p19, cytokines that are critical for Th1/Th17 polarization, and the accumulation of Th17 CD4 + T cells further highlights the importance of macrophages in shaping the local cytokine milieu. 3 RELMα is most commonly associated with AAMacs and helminth infection, where it functions to negatively regulate expression of Th2 cytokines such as IL-13. 7,8 Given the existence of crossregulation between Th2 and Th17 cytokine production, 19 we hypothesized that an additional mechanism by which RELMα promotes Th17 cytokine responses may involve indirect effects on the local cytokine environment.…”

“…1 In Citrobacter rodentium infection, a mouse model for enteropathogenic and enterhemorrhagic infections of humans, 2 we recently showed that Resistin-Like Molecule (RELM) α promoted infectioninduced intestinal inflammation via effects on macrophages. 3 RELMα is a secreted protein that is most commonly associated with alternatively activated macrophages (AAMac), which are recruited in T helper type (Th) 2 cytokine-dominated environments, such as helminth infection and allergy. [4][5][6] In Th2 cytokine-biased immune responses, RELMα exhibited critical immunomodulatory functions.…”

Resistin-Like Molecule α in Allergen-Induced Pulmonary Vascular Remodeling

“…The proinflammatory role of RELMa was also shown in a model of Citrobacterinduced colitis, in which Citrobacter exposure induced RELMa expression in intestinal epithelial cells, infiltrating macrophages, and eosinophils of the infected colon (28). In that study, Citrobacter-infected RELMa 2/2 mice exhibited less infection-induced intestinal inflammation than did WT mice, as evidenced by decreased leukocyte recruitment to the colon and reduced immune cell activation.…”

“…IL-17F is also chemotactic for neutrophils, and increases the expression of genes for CXC and CCL chemokines and inflammatory cytokines in the lung (38). The Citrobacter-infected colitis model showed that the IL-23/Th17 axis is a critical mediator of RELMa-induced inflammation (28) In conclusion, RELMa is a proinflammatory mediator that contributes to allergen-induced pulmonary vascular remodeling by inducing an inflammatory response in the small, intra-alveolar vessels. n…”