TLR4 signaling and macrophage inflammatory responses are dampened by GIV/Girdin

Author:

Swanson LeeORCID,Katkar Gajanan D.,Tam Julian,Pranadinata Rama F.,Chareddy Yogitha,Coates Jane,Anandachar Mahitha ShreeORCID,Castillo VanessaORCID,Olson Joshua,Nizet VictorORCID,Kufareva IrinaORCID,Das SoumitaORCID,Ghosh PradiptaORCID

Abstract

Sensing of pathogens by Toll-like receptor 4 (TLR4) induces an inflammatory response; controlled responses confer immunity but uncontrolled responses cause harm. Here we define how a multimodular scaffold, GIV (a.k.a. Girdin), titrates such inflammatory response in macrophages. Upon challenge with either live microbes or microbe-derived lipopolysaccharides (a ligand for TLR4), macrophages with GIV mount a more tolerant (hypo-reactive) transcriptional response and suppress proinflammatory cytokines and signaling pathways (i.e., NFkB and CREB) downstream of TLR4 compared to their GIV-depleted counterparts. Myeloid-specific gene-depletion studies confirmed that the presence of GIV ameliorates dextran sodium sulfate-induced colitis and sepsis-induced death. The antiinflammatory actions of GIV are mediated via its C-terminally located TIR-like BB-loop (TILL) motif which binds the cytoplasmic TIR modules of TLR4 in a manner that precludes receptor dimerization; such dimerization is a prerequisite for proinflammatory signaling. Binding of GIV’s TILL motif to TIR modules inhibits proinflammatory signaling via other TLRs, suggesting a convergent paradigm for fine-tuning macrophage inflammatory responses.

Funder

HHS | NIH | National Institute of Allergy and Infectious Diseases

HHS | NIH | National Cancer Institute

HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

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