IL-23 Contributes to Campylobacter jejuni-Induced Intestinal Pathology via Promoting IL-17 and IFNγ Responses by Innate Lymphoid Cells

Abstract

Human pathogen Campylobacter jejuni is a significant risk factor for the development of long-term intestinal dysfunction although the cellular and molecular mechanisms remain scantily defined. IL-23 is an emerging therapeutic target for the treatment of inflammatory intestinal diseases, however its role in C. jejuni-driven intestinal pathology is not fully understood. IL-10 deficient mice represent a robust model to study the pathogenesis of C. jejuni infection because C. jejuni infection of mice lacking IL-10 results in symptoms and pathology that resemble human campylobacteriosis. To determine the role of IL-23 in C. jejuni-driven intestinal inflammation, we studied the disease pathogenesis in IL-23-/- mice with inhibited IL-10Rα signaling. These mice exhibited reduced intestinal pathology independent from bacterial clearance. Further, levels of IFNγ, IL-17, IL-22, TNF, and IL-6 were reduced and associated with reduced accumulation of neutrophils, monocytes and macrophages in the colon. Flow cytometry analysis revealed reduced production of IL-17 and IFNγ by group 1 and 3 innate lymphoid cells. Thus, our data suggest that IL-23 contributes to intestinal inflammation in C. jejuni infected mice by promoting IL-17 and IFNγ production by innate lymphoid cells.

Innate Lymphoid Cells in Response to Intracellular Pathogens: Protection Versus Immunopathology

“…Consistently, IL-23-deficient mice displayed reduced intestinal pathology and low levels of IFNγ, IL-17 and IL-22 in the colon following C. jejuni infection ( Jing et al., 2020 ). However, in contrast to IFNγ and IL-17, abrogation of IL-22 signaling in mice with impaired IL-10 signaling did not have impact on C. jejuni -induced colitis and bacterial clearance ( Jing et al., 2020 ). Interestingly, in another study in IL-10-sufficient mice, IL-22 deficiency led to increased bacterial burden in the colon ( Heimesaat et al., 2016 ), suggesting that differences in intestinal microenvironment can affect C. jejuni colonization and disease development.…”

“…IL-23 is a wellknown inducer of IL-22 and IL-17. Consistently, IL-23-deficient mice displayed reduced intestinal pathology and low levels of IFNg, IL-17 and IL-22 in the colon following C. jejuni infection (Jing et al, 2020). However, in contrast to IFNg and IL-17, abrogation of IL-22 signaling in mice with impaired IL-10 signaling did not have impact on C. jejuni-induced colitis and bacterial clearance (Jing et al, 2020).…”

“…Monocyte-derived dendritic cells from human PBMCs showed upregulation of both IL-17 and IL-22 cytokines after C. jejuni infection ( Edwards et al., 2010 ). A recent study revealed IL-23 as a critical driver of inflammation during C. jejuni infection ( Jing et al., 2020 ). Additionally, previous studies showed the pathogenic role of IL-23 in other models of infectious colitis ( Kullberg et al., 2006 ; Buonomo et al., 2013 ).…”

“…Interestingly, in another study in IL-10-sufficient mice, IL-22 deficiency led to increased bacterial burden in the colon ( Heimesaat et al., 2016 ), suggesting that differences in intestinal microenvironment can affect C. jejuni colonization and disease development. Furthermore, IL-23 induced IL-17 and IFNγ by ILC1s and ILC3s, promoting colon inflammation during the early stage of C. jejuni infection ( Figure 7 ) ( Jing et al., 2020 ). IL-17 is also known as an important activator of innate immune responses that induce neutrophil recruitment ( Pappu et al., 2012 ).…”

M2 Macrophages Serve as Critical Executor of Innate Immunity in Chronic Allograft Rejection

“…IL-23, a heterodimeric cytokine essential for expression of IL-17, shares p40 subunit with IL-12 that induces the production of IFN-γ (12). It was reported that IL-23 involved in IL-17 and IFN-γ related tissue inflammatory response by innate lymphoid cells, including macrophages (13,14). Treated with recombinant IL-23, unpolarized mouse peritoneal macrophages represent significantly increased production of IL-17A and IFN-γ via STAT3-RORγ T pathways, but not M1/M2 related cytokines, and neither polarized M1 nor M2-like macrophages can convert to such an IL-17/IFN-γ high-producing subset: M(IL-23) (15).…”