Damping excessive inflammation and tissue damage in Mycobacterium tuberculosis infection by toll IL-1 receptor 8/Single Ig IL-1-related receptor, a negative regulator of IL-1/TLR signaling

Toll IL-IR Mingle Ig IL-1-related receptor (TIR8,1SIGIRR) is a member of the IL-111 family, expressed by epithelial tissues and immature dendritic cells, and is regarded as a negative regulator of TLR/IL-lR signaling. Tir8-deficient mice were rapidly killed by intranasal administration of low doses of Mycobacterium tuberculosis, despite controlling efficiently the number of viable bacilli in different organs. Tir8(-1-) -infected mice showed an increased number of neutrophils and macrophages in the lungs; however, mycobacteria-specific CD4 and CD8 T cells were similar in Tir(-/-) and Tir8(+/+) mice. Exaggerated mortality of Tir8-1- mice was due to massive liver necrosis and was accompanied by increased levels of IL-1,6 and TNF-a in lung mononuclear cells and serum, as well as by increased production of IIL-113 and TNF-a by M. tuberculosis-infected dendritic cells in vitro. Accordingly, blocking JIL-1 beta and TNF-a with a mix of anti-cytokine Abs, significantly prolonged survival of Tir8(-/-) mice. Thus, TIR8/SIGIRR plays a key role in damping inflammation and tissue damage inM. tuberculosis infection.