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The TLR and IL-1 signalling network at a glance.

ABSTRACT: Toll-like receptors (TLRs) and the receptors for interleukin (IL)-1, IL-18 and IL-33 are required for defence against microbial pathogens but, if hyper-activated or not switched off efficiently, can cause tissue damage and inflammatory and autoimmune diseases. Understanding how the checks and balances in the system are integrated to fight infection without the network operating out of control will be crucial for the development of improved drugs to treat these diseases in the future. In this Cell Science at a Glance article and the accompanying poster, I provide a brief overview of how one of these intricate networks is controlled by the interplay of protein phosphorylation and protein ubiquitylation events, and the mechanisms in myeloid cells that restrict and terminate its activation to prevent inflammatory and autoimmune diseases. Finally, I suggest a few protein kinases that have been neglected as drug targets, but whose therapeutic potential should be explored in the light of recent advances in our understanding of their roles in the innate immune system.

SUBMITTER: Cohen P

PROVIDER: S-EPMC4038938 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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The TLR and IL-1 signalling network at a glance.

Cohen Philip P

Journal of cell science 20140514 Pt 11

Toll-like receptors (TLRs) and the receptors for interleukin (IL)-1, IL-18 and IL-33 are required for defence against microbial pathogens but, if hyper-activated or not switched off efficiently, can cause tissue damage and inflammatory and autoimmune diseases. Understanding how the checks and balances in the system are integrated to fight infection without the network operating out of control will be crucial for the development of improved drugs to treat these diseases in the future. In this Cel ...[more]

PMID: 24829146

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Project description: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.

Dataset Information

The TLR and IL-1 signalling network at a glance.

Publications

The TLR and IL-1 signalling network at a glance.

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