Beta2 Integrins Inhibit TLR Responses by Reducing NF-kappaB Pathway Activation
Yee, Nathan Ken
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Although originally considered to be the archetypal cell activation pathway, signals through immunoreceptor tyrosine-based activation motifs (ITAM) are known to be inhibitory and have recently been appreciated to cross-regulate TLR responses. ITAM signaling in myeloid cells is mediated by the ITAM-containing adapters DAP12 and FcRgamma, which can associate with many cell surface receptors including the beta2 integrins. However, the ability of these ITAM-containing adapters to dampen TLR responses, the relationship between the beta2 integrins themselves and TLR activity is unclear. We demonstrate here that beta2 integrins are required for negatively regulating TLR activation in macrophages and DCs. beta2 integrin-deficient myeloid cells (Itgb2-/-) are hypersensitive to TLR stimulation and produce more inflammatory cytokines in response to a panel of TLR agonists. Itgb2-/- mice also hyperrespond to LPS injection, demonstrating that beta2 integrins control TLR activity in vivo. This hypersensitivity is not due to previously associated functions of beta2 integrins, including changes to IL-10, A20, ABIN-3, Hes-1 or Cbl-b. Instead, beta2 integrin-mediated TLR inhibition directly dampens NF-kappaB activation by controlling p65 activation and binding to target promoters. Furthermore, beta2 integrins also control type I IFN synthesis and signaling, perhaps by modulating expression of SOCS-1 via miR-155. Thus, control of TLR responses by beta2 integrins involves multiple, potentially overlapping mechanisms.
- Immunology