Integrin CD11b negatively regulates TLR-triggered inflammatory responses by activating Syk and promoting degradation of MyD88 and TRIF via Cbl-b
Integrin CD11b negatively regulates TLR-triggered inflammatory responses by activating Syk and promoting degradation of MyD88 and TRIF via Cbl-b
Han, C. et al. Nat. Immunol. 11, 734-742 (2010).
Speaker: Shu-Sheng Chen (陳沭勝) Time: 14:00~15:00, Oct. 6, 2010
Commentator: Dr. Chi-Chang Shieh (謝奇璋博士) Place: Room 601
Abstract:
Integrins mediates cell-adhesion and regulate the migration of cells into inflammatory sites. in addition, integrins transmit ‘outside-in’ or ‘inside-out’ signalings. Toll-like receptors (TLRs) initiate innate immune responses via activating the adaptor MyD88 signaling or the adaptor TRIF and sequentially inducing the production of proinflammatory cytokines and type I interferon. Some ITAM-containing transmembrane adaptors, such as DAP12, can regulate TLR signalings via activating the tyrosine kinase Syk. Previous studies demonstrated that deficiency in the integrin αM(CD11b; encoded by Itgam) led to dextran sodium sulfate-induced colitis and unregulated T cell tolerance. However, the regulatory mechanism of these molecules is still unclear. In the present study, the authors revealed that Itgam deficiency enhanced TLR-induced responses and rendered mice more susceptible to endotoxin shock and Gram-negative bacteria infection. In vitro study in macrophages showed that TLR-activated CD11b through PI3K-RapL pathways could negatively regulate TLR signaling and proinflammatory cytokine production. Furthermore, they demonstrated that phosphorylation of MyD88 (Tyr227) and TRIF (Try375) by activated Syk caused degradation of these adaptor proteins by E3 ubiquitin ligase Cbl-b and subsequentially impaired MyD88- and TRIF-dependent inflammatory responses. Taken together, CD11b plays a regulatory role in TLR-triggered inflammatory responses negatively by inhibiting the MyD88 and TRIF pathways.
References:
1. Terry K Means & Andrew D Luster. Integrins limit the Toll. Nat. Immunol. 11, 691-693 (2010).
2. Lionel B Ivashkiv. Cross-regulation of signaling by ITAM-associated receptors. Nat. Immunol. 10, 340-347 (2009).