Editors' ChoiceTLR SIGNALING

Inhibition by Integrin

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Science Signaling  27 Jul 2010:
Vol. 3, Issue 132, pp. ec230
DOI: 10.1126/scisignal.3132ec230

The activation of Toll-like receptors (TLRs) by microbial components is critical to the mounting of an effective innate immune response. Stimulation of TLRs results in the production of type I interferons and proinflammatory cytokines, which help to clear the host of pathogens. However, excessive cytokine production damages, and may even kill, the host; thus, a number of mechanisms exist to inhibit TLR signaling. Immunoreceptor tyrosine-based activation motif (ITAM)–containing proteins are thought to regulate TLR signaling through the activation of the kinase Syk; however, the mechanism involved is unclear (see commentary by Means and Luster). Noting that integrins can signal through ITAM-mediated activation of the Src-Syk axis, Han et al. studied mice lacking Itgam, the gene that encodes CD11b, one subunit of the integrin Mac-1. They found that Itgam–/– mice produced more proinflammatory cytokines after exposure to the TLR4 ligand lipopolysaccharide (LPS) than did Itgam+/– mice and were more susceptible to LPS-induced death. Stimulation of various TLRs in human and mouse macrophages resulted in the activation of CD11b, which depended on phosphatidylinositol 3-kinase and RapL, an effector of the integrin-associated GTPase, Rap. In vitro, TLR-dependent activation of the kinase Src and its target Syk in Itgam–/– macrophages was reduced compared with that in Itgam+/– cells. In response to TLR4 stimulation of macrophages, Syk interacted with, and phosphorylated, the TLR adaptor proteins MyD88 and TRIF, which was inhibited in Itgam–/– cells. Phosphorylation of MyD88 and TRIF led to their degradation, which depended on Cbl-b, an E3 ubiquitin ligase. Together, these data suggest that the integrin subunit CD11b is activated by TLR signaling and initiates a Syk-dependent, negative feedback mechanism that targets components of TLR signaling pathways for degradation.

C. Han, J. Jin, S. Xu, H. Liu, N. Li, X. Cao, Integrin CD11b negatively regulates TLR-triggered inflammatory responses by activating Syk and promoting degradation of MyD88 and TRIF via Cbl-b. Nat. Immunol. 11, 734–742 (2010). [PubMed]

T. K. Means, A. D. Luster, Integrins limit the Toll. Nat. Immunol. 11, 691–693 (2010). [PubMed]

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