TLR Signaling Keeping the Balance

John F. Foley

Science Signaling, AAAS, Washington, DC 20005, USA

Stimulation of Toll-like receptors (TLRs) by microbial molecules is important in innate immune responses. Most TLRs signal through the adaptor molecule myeloid differentiation marker 88 (MyD88) to sequentially activate interleukin-1 receptor (IL-1R)-associated kinase 4 (IRAK4), IRAK1, extracellular signal-regulated kinase (ERK) 1 and 2, and the transcription factor nuclear factor B (NF-B), which leads to the production of proinflammatory cytokines. TLR3 uses the adaptor molecule TRIF. TLR-mediated stimulation of interferon regulatory factors (IRFs) leads to the production of type I interferons (IFNs), which can be anti-inflammatory. TLR signaling must be carefully modulated to prevent excessive inflammation or autoimmune responses. An et al. found that stimulation of individual TLRs in splenocytes from mice deficient in the tyrosine phosphatase SHP-1 resulted in increased production of proinflammatory cytokines but decreased production of type I IFNs compared to that in splenocytes from wild-type mice. TLR-stimulated activation of NF-B and ERK1/2 was higher in SHP-1–deficient splenocytes than in wild-type splenocytes, whereas that of IRF3 and IRF7 was lower. TLR-meditated activation of IRAK1 in splenocytes was inhibited by overexpression of SHP-1, although this did not require its phosphatase activity. The authors found a physical association between IRAK1 and SHP-1 in macrophages that was enhanced upon TLR stimulation. Finally, overexpression of IRAK1 inhibited both MyD88- and TRIF-dependent activation of IRFs, whereas inactivation of IRAK1 had the opposite effect. Although some aspects of the mechanism involved remain unclear, these data suggest that SHP-1 serves to balance the outcome of TLR signaling by binding to and inhibiting IRAK1. As O’Neill points out in commentary, a more complete understanding of both the positive and negative regulators of TLR signaling will help in the design of more effective therapeutics.

H. An, J. Hou, J. Zhou, W. Zhao, H. Xu, Y. Zheng, Y. Yu, S. Liu, X. Cao, Phosphatase SHP-1 promotes TLR- and RIG-I-activated production of type I interferon by inhibiting the kinase IRAK1. Nat. Immunol. 9, 542-550 (2008). [PubMed]

L. A. J. O’Neill, ‘Fine tuning’ TLR signaling. Nat. Immunol. 9, 459-461 (2008). [PubMed]