SIGIRR, a Negative Regulator of TLR/IL-1R Signalling Promotes Microbiota Dependent Resistance to Colonization by Enteric Bacterial Pathogens

Abstract

Enteric bacterial pathogens such as enterohemorrhagic E. coli (EHEC) and Salmonella Typhimurium target the intestinal epithelial cells (IEC) lining the mammalian gastrointestinal tract. Despite expressing innate Toll-like receptors (TLRs), IEC are innately hypo-responsive to most bacterial products. This is thought to prevent maladaptive inflammatory responses against commensal bacteria, but it also limits antimicrobial responses by IEC to invading bacterial pathogens, potentially increasing host susceptibility to infection. One reason for the innate hypo-responsiveness of IEC is their expression of Single Ig IL-1 Related Receptor (SIGIRR), a negative regulator of interleukin (IL)-1 and TLR signaling. To address whether SIGIRR expression and the innate hypo-responsiveness of IEC impacts on enteric host defense, Sigirr deficient (−/−) mice were infected with the EHEC related pathogen Citrobacter rodentium. Sigirr −/− mice responded with accelerated IEC proliferation and strong pro-inflammatory and antimicrobial responses but surprisingly, Sigirr −/− mice proved dramatically more susceptible to infection than wildtype mice. Through haematopoietic transplantation studies, it was determined that SIGIRR expression by non-haematopoietic cells (putative IEC) regulated these responses. Moreover, the exaggerated responses were found to be primarily dependent on IL-1R signaling. Whilst exploring the basis for their susceptibility, Sigirr −/− mice were found to be unusually susceptible to intestinal Salmonella Typhimurium colonization, developing enterocolitis without the typical requirement for antibiotic based removal of competing commensal microbes. Strikingly, the exaggerated antimicrobial responses seen in Sigirr −/− mice were found to cause a rapid and dramatic loss of commensal microbes from the infected intestine. This depletion appears to reduce the ability of the microbiota to compete for space and nutrients (colonization resistance) with the invading pathogens, leaving the intestine highly susceptible to pathogen colonization. Thus, SIGIRR expression by IEC reflects a strategy that sacrifices maximal innate responsiveness by IEC in order to promote commensal microbe based colonization resistance against bacterial pathogens.

Interleukin-1 (IL-1) Signaling in Intestinal Stromal Cells Controls KC/CXCL1 Secretion, Which Correlates with Recruitment of IL-22-Secreting Neutrophils at Early Stages of Citrobacter rodentium Infection

“…In this study, we found evidence that IL-1R-dependent signaling plays a critical protective role during C. rodentium infection, in agreement with earlier studies (17,30). The most unusual finding in the present study was that infiltration of CD11b ϩ Ly6G ϩ Ly6C ϩ neutrophils, the main source of IL-22 secretion, was significantly delayed in the colon at an early time point during C. rodentium infection.…”

The structures of the colonic mucosa-associated and luminal microbial communities are distinct and differentially affected by a prolonged murine stressor

“…Many colonic pathogens, like enteropathogenic or enterohemorrhagic Escherichia coli (EPEC or EHEC, respectively), which are often modeled by murine challenge with Citrobacter rodentium, colonize the intestinal epithelium and can cause severe colitis along the epithelial barrier. 55,56 The colonic microbiota are known to influence susceptibility and resistance to these attaching and effacing pathogens, 57,58 since disrupting the mucosa-associated populations with antibiotics increased disease severity upon pathogen challenge. 59,60 Stressor induced shifts to luminal populations might also have downstream effects upon host metabolism.…”

The Human Milk Oligosaccharide 2′-Fucosyllactose Quenches Campylobacter jejuni–Induced Inflammation in Human Epithelial Cells HEp-2 and HT-29 and in Mouse Intestinal Mucosa

“…Bowel tissues fixed in 10% formalin, paraffin embedded, cut for histologic analysis, and stained with hematoxylin and eosin were subjected to pathologic scoring by 3 blinded observers (13,28).…”