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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 117; no. 43; pp. 26895 - 26906
• Main Authors: Swanson, Lee, Katkar, Gajanan D., Tam, Julian, Pranadinata, Rama F., Chareddy, Yogitha, Coates, Jane, Anandachar, Mahitha Shree, Castillo, Vanessa, Olson, Joshua, Nizet, Victor, Kufareva, Irina, Das, Soumita, Ghosh, Pradipta
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 27.10.2020
• Subjects: 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; 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; macrophages; Girdin; ccdc88a; inflammation; TIR domain
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2011667117

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.