Journal Article

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

Kufareva, Irina, Das, Soumita, Chareddy, Yogitha, Pranadinata, Rama F., Tam, Julian, Coates, Jane, Ghosh, Pradipta, Anandachar, Mahitha Shree, Castillo, Vanessa, Swanson, Lee, Nizet, Victor, Katkar, Gajanan D., Olson, Joshua

2020

Overview

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.

• Publisher: National Academy of Sciences
• Subject: Animals / Biological Sciences / Colitis / Colitis - metabolism / Cyclic AMP response element-binding protein / Cytokines / Depletion / Dextran / Dextrans / Dimerization / Disease Models, Animal / Female / HEK293 Cells / Humans / Immune system / Immunology and Inflammation / Inflammation / Inflammatory response / Lipopolysaccharides / Macrophages / Macrophages - metabolism / Mice / Mice, Knockout / Microfilament Proteins - metabolism / Modules / NF-κB protein / Proteins / RAW 264.7 Cells / Receptors / Sepsis / Sepsis - metabolism / Signal Transduction / Signaling / Sodium sulfate / TLR4 protein / Toll-Like Receptor 4 - metabolism / Toll-like receptors / Transcription / Vesicular Transport Proteins - metabolism