TLR4 signaling and macrophage inflammatory responses are dampened by GIV/Girdin.
Girdin
TIR domain
ccdc88a
inflammation
macrophages
Journal
Proceedings of the National Academy of Sciences of the United States of America
ISSN: 1091-6490
Titre abrégé: Proc Natl Acad Sci U S A
Pays: United States
ID NLM: 7505876
Informations de publication
Date de publication:
27 10 2020
27 10 2020
Historique:
pubmed:
16
10
2020
medline:
18
12
2020
entrez:
15
10
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33055214
pii: 2011667117
doi: 10.1073/pnas.2011667117
pmc: PMC7604444
doi:
Substances chimiques
Ccdc88a protein, mouse
0
Microfilament Proteins
0
Tlr4 protein, mouse
0
Toll-Like Receptor 4
0
Vesicular Transport Proteins
0
girdin protein, mouse
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
26895-26906Subventions
Organisme : NCI NIH HHS
ID : R01 CA238042
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR001442
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA100768
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA160911
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI155696
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI118985
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK107585
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI141630
Pays : United States
Organisme : NIDDK NIH HHS
ID : T32 DK007202
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA023100
Pays : United States
Déclaration de conflit d'intérêts
The authors declare no competing interest.
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