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.

Abstract

Toll IL-1R 8/single Ig IL-1-related receptor (TIR8/SIGIRR) is a member of the IL-1R family, expressed by epithelial tissues and immature dendritic cells, and is regarded as a negative regulator of TLR/IL-1R 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–/–-infected mice showed an increased number of neutrophils and macrophages in the lungs; however, mycobacteria-specific CD4 and CD8 T cells were similar in Tir8–/– and Tir8+/+ mice. Exaggerated mortality of Tir8–/– mice was due to massive liver necrosis and was accompanied by increased levels of IL-1β and TNF-α in lung mononuclear cells and serum, as well as by increased production of IL-1β and TNF-α by M. tuberculosis-infected dendritic cells in vitro. Accordingly, blocking IL-1β and TNF-α 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 in M. tuberculosis infection.