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. 2012 Oct 29;3:322. doi: 10.3389/fimmu.2012.00322

Figure 3.

Figure 3

Regulatory function of TIR8/SIGIRR in pathology. TIR8/SIGIRR inhibits ILR (IL-1RI, IL-18R, T1/ST2) and TLR (TLR4, TLR7, TLR9, and possibly others) signaling and NF-κB activation. Gene-targeted mice demonstrate that Tir8/Sigirr acts as a non-redundant negative regulator in vivo in different inflammatory conditions dependent on ILR and TLR activation. For some of these, the pathway prominently regulated by TIR8/SIGIRR and playing a relevant role in the pathogenesis of the disease has been defined. For instance, in autoimmunity (EAE) TIR8/SIGIRR regulates IL-1-dependent Th17 cell differentiation, survival, and proliferation; in asthma TIR8/SIGIRR regulates the IL-33/ST2 pathway and Th2 responses; in models of infections (Candida albicans, Aspergillus fumigatus, Mycobacterium tuberculosis, and Pseudomonas aeruginosa) TIR8/SIGIRR regulates IL-1RI signaling controlling Th17 and Treg responses (fungal infections) and pro-inflammatory cytokine production (bacterial infections). In colitis-associated colon cancer, TIR8/SIGIRR plays a major role in controlling microbial flora-dependent activation of TLRs, but the control on ILRs-dependent inflammation can not be excluded. In other contexts (chronic lymphocytic leukemia, arthritis, kidney transplantation, and brain inflammation), the molecular pathway regulated by TIR8/SIGIRR remains to be addressed.