| First Author | Swanson L | Year | 2020 |
| Journal | Proc Natl Acad Sci U S A | Volume | 117 |
| Issue | 43 | Pages | 26895-26906 |
| PubMed ID | 33055214 | Mgi Jnum | J:303336 |
| Mgi Id | MGI:6471276 | Doi | 10.1073/pnas.2011667117 |
| Citation | Swanson L, et al. (2020) TLR4 signaling and macrophage inflammatory responses are dampened by GIV/Girdin. Proc Natl Acad Sci U S A 117(43):26895-26906 |
| abstractText | 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. |
