Flagelin 22

Group 3 innate lymphoid cells (ILC3s) produce interleukin (IL)-22 and coordinate with other cells in the gut to mount productive host immunity against bacterial infection. However, the role of ILC3s in Salmonella enterica serovar Typhimurium (S. Typhimurium) infection, which causes foodborne enteritis in humans, remains elusive. Here we show that S. Typhimurium exploits ILC3-produced IL-22 to promote its infection in mice. Specifically, S. Typhimurium secretes flagellin through activation of the TLR5-MyD88-IL-23 signalling pathway in antigen presenting cells (APCs) to selectively enhance IL-22 production by ILC3s, but not T cells. Deletion of ILC3s but not T cells in mice leads to better control of S. Typhimurium infection. We also show that S. Typhimurium can directly invade ILC3s and cause caspase-1-mediated ILC3 pyroptosis independently of flagellin. Genetic ablation of Casp1 in mice leads to increased ILC3 survival and IL-22 production, and enhanced S. Typhimurium infection. Collectively, our data suggest a key host defence mechanism against S. Typhimurium infection via induction of ILC3 death to limit intracellular bacteria and reduce IL-22 production.

Ulcerative colitis (UC) is a type of inflammatory bowel disease (IBD), which is a chronic, relapsing condition associated with the disorder of gut microbial communities. A previous study reported that levels of Roseburia intestinalis (R.I), a butyrate‑producing bacterium, are significantly decreased in patients with IBD and exert an anti‑inflammatory function in dextran sulfate sodium (DSS)‑induced colitis. However, the role of R.I flagellin in UC and its underlying molecular mechanism are not yet fully understood. Therefore, a DSS‑induced colitis model in C57Bl/6 mice and the LPS/ATP‑induced THP‑1 macrophages were treated with R.I flagellin, which were used to investigate the anti‑inflammatory effects of R.I flagellin. The results demonstrated that R.I flagellin decreased colitis‑associated disease activity index, colonic shortening and the pathological damage of the colon tissues in murine colitis models. Furthermore, R.I flagellin decreased the serum levels of proinflammatory cytokines and inhibited activation of the nucleotide‑binding oligomerization segment‑like receptor family 3 (NLRP3) inflammasome in murine colitis. R.I flagellin was also demonstrated to decrease the Gasdermin D to yield the N‑terminal fragment membrane pore and inhibit inflammasome‑triggered pyroptosis. In vitro analysis indicated that microRNA (miR)‑223‑3p was involved in the regulation of R.I flagellin on NLRP3 inflammasome activation. Taken together, the results of the present study demonstrated that R.I flagellin inhibited activation of the NLRP3 inflammasome and pyroptosis via miR‑223‑3p/NLRP3 signaling in macrophages, suggesting that R.I flagellin may be used as a novel probiotic product for the treatment of UC.

The progression of chronic obstructive pulmonary disease (COPD), a lung inflammatory disease being the fourth cause of death worldwide, is marked by acute exacerbations. These episodes are mainly caused by bacterial infections, frequently due to Streptococcus pneumoniae. This susceptibility to infection involves a defect in interleukin (IL)-22, which plays a pivotal role in mucosal defense mechanism. Administration of flagellin, a Toll-like receptor 5 (TLR-5) agonist, can protect mice and primates against respiratory infections in a non-pathological background. We hypothesized that TLR-5-mediated stimulation of innate immunity might improve the development of bacteria-induced exacerbations in a COPD context. Mice chronically exposed to cigarette smoke (CS), mimicking COPD symptoms, are infected with S. pneumoniae, and treated in a preventive and a delayed manner with flagellin. Both treatments induced a lower bacterial load in the lungs and blood, and strongly reduced the inflammation and lung lesions associated with the infection. This protection implicated an enhanced production of IL-22 and involved the recirculation of soluble factors secreted by spleen cells. This is also associated with higher levels of the S100A8 anti-microbial peptide in the lung. Furthermore, human mononuclear cells from non-smokers were able to respond to recombinant flagellin by increasing IL-22 production while active smoker cells do not, a defect associated with an altered IL-23 production. This study shows that stimulation of innate immunity by a TLR-5 ligand reduces CS-induced susceptibility to bacterial infection in mice, and should be considered in therapeutic strategies against COPD exacerbations.