Innate lymphoid cell composition shift upon Campylobacter jejuni induced colitis, a process inhibited by targeting mTOR signaling in Il10−/− mice

Abstract

Abstract Innate lymphoid cells (ILCs) are important innate effector cells involved in host mucosal immunity. The role of ILCs in regulating homeostasis following commensal bacterial colonization and enteropathogenic bacterial infection is unclear. Herein, we profiled ILC repertoire following Campylobacter jejuni (C. jejuni)-induced colitis as well as responses following anti-inflammatory treatment. Germ-free (GF) Il10−/− mice were colonized with SPF biota or human clinical isolate C. jejuni 81-176. Rapamycin (1.5mg/kg, daily), an inhibitor of mTOR signaling, was used to inhibit C. jejuni-induced colitis. ILC profile was assayed by Flow Cytometry analysis using specific markers (Lineage marker, CD90.2, CD127, CD117, ST2, and NKp46). Inflammatory cytokine production was detected using RNAscope. Compared to WT-C57Bl6 mice, ILC distribution was similar in absence of intestinal microbiome (GF mice), whereas presence of microbiota leaded to elevated NCR−ILC3 (30% vs 5%, P< 0.01) and lower ILC2 (1% vs 21%, P< 0.05) in the colon of Il10−/− mice. C. jejuni-induced colitis caused an increase of ILC1 (50% vs 18%, P< 0.0001) with decrease of NCR−ILC3 (13% vs 43%, P< 0.0001) in the colonic lamina propria, compared to uninfected mice. RNAscope revealed an augmented inflammatory cytokines, such as IFN-γ, IL-17A, TNF-α, and IL-22, in mucosal immune cells, and elevated IL-33 expression in epithelial cells. Rapamycin treatment inhibited C. jejuni-induced colitis (histology score 0.07 vs 4.0, P< 0.0001), which associated with re-establishment of ILC profile and decreased cytokine production. In conclusion, ILC trans differentiation correlates with the development of C. jejuni-induced colitis, a process inhibited by blocking mTOR signaling.