IL-36R signaling integrates innate and adaptive immune-mediated protection against enteropathogenic bacteria

Abstract

Enteropathogenic bacterial infections are a global health issue associated with high mortality, particularly in developing countries. Efficient host protection against enteropathogenic bacterial infection is characterized by coordinated responses between immune and nonimmune cells. In response to infection in mice, innate immune cells are activated to produce interleukin (IL)-23 and IL-22, which promote antimicrobial peptide (AMP) production and bacterial clearance. IL-36 cytokines are proinflammatory IL-1 superfamily members, yet their role in enteropathogenic bacterial infection remains poorly defined. Using the enteric mouse pathogen, C.rodentium, we demonstrate that signaling via IL-36 receptor (IL-36R) orchestrates a crucial innate-adaptive immune link to control bacterial infection. IL-36R-deficient mice (Il1rl2−/−) exhibited significant impairment in expression of IL-22 and AMPs, increased intestinal damage, and failed to contain C. rodentium compared to controls. These defects were associated with failure to induce IL-23 and IL-6, two key IL-22 inducers in the early and late phases of infection, respectively. Treatment of Il1rl2−/− mice with IL-23 during the early phase of C. rodentium infection rescued IL-22 production from group 3 innate lymphoid cells (ILCs), whereas IL-6 administration during the late phase rescued IL-22-mediated production from CD4+ T cell, and both treatments protected Il1rl2−/− mice from uncontained infection. Furthermore, IL-36R-mediated IL-22 production by CD4+ T cells was dependent upon NFκB-p65 and IL-6 expression in dendritic cells (DCs), as well as aryl hydrocarbon receptor (AhR) expression by CD4+ T cells. Collectively, these data demonstrate that the IL-36 signaling pathway integrates innate and adaptive immunity leading to host defense against enteropathogenic bacterial infection.

IL‐36 cytokines and gut immunity

“…3,4,6,7,18,26 During inflammation, IL-36 receptor agonists are mainly expressed by keratinocytes, epithelial cells and inflammatory monocytes/macrophages. 3,13,16,17,27,28 . In vitro studies demonstrate that macrophages/monocytes, as well as bone marrow-derived macrophages (BMDMs), respond to Toll-like receptor ligands, including LPS, flagellin, CpG and poly I:C or inflammatory cytokines including IL-1a, IL-1b, IFN-c or IL-18 to induce the expression of IL-36 receptor antagonists 3,8,[29][30][31][32][33] (Figure 1).…”

“…The upregulation of IL-36a and IL-36c has been detected in numerous mouse models of intestinal inflammation, and multiple groups have confirmed the colonic elevation of IL-36a in patients with active IBD. [12][13][14][15][16][17] In the gut, IL-36 receptor agonists are expressed by inflammatory monocytes, and intestinal epithelial cells. 12,[14][15][16][17] Using a murine model of intestinal inflammation for both acute and chronic settings, the dichotomous roles of IL-36 cytokines in IBD have been addressed by multiples studies.…”

“…12,[14][15][16][17] Using a murine model of intestinal inflammation for both acute and chronic settings, the dichotomous roles of IL-36 cytokines in IBD have been addressed by multiples studies. [12][13][14][15][16][17]…”

“…3,4,[6][7][8][9] Remarkably, depending on the location of expression, the phases and the context of the disease, IL-36 cytokines can either favour inflammation or promote the resolution of gut inflammation. [10][11][12][13][14][15][16][17] IL-36 has been comprehensively studied in the context of skin inflammation; however, over the last decade, IL-36 cytokines have been found to have functions in viral/ bacterial/fungal infections, systemic lupus erythematosus, psoriasis, obesity and inflammatory bowel diseases. 7,10,12,15,16,[18][19][20][21][22][23][24][25] In this review, we briefly summarize the regulation of IL-36 and then discuss the current knowledge of IL-36 biology related to gut inflammation and resolution of intestinal damage.…”

Act Locally, Act Globally—Microbiota, Barriers, and Cytokines in Atherosclerosis

“…IL-23 is also essential for host defense against infections and potential invasion of the commensal microbiota and metabolites translocation [213], with many of these functions enabled by the downstream action of IL-23-driven cytokines IL-22 and IL-17 or IL-36 [71,234,235]. Administration of recombinant IL-23 was able to promote bacterial clearance via induction of IL-22 secretion by ILC3 [236]. Interestingly, IL-23 could also act via intestinal epithelial cells, inducing the c-type lectin RegIIIβ-mediated recruitment of IL-22-producing cells, and in the absence of this signaling (Il23r flox/flox Villin-Cre), mice were susceptible to DSS colitis and were characterized by dysbiosis [237].…”