Document Detail

SR-A/MARCO-mediated ligand delivery enhances intracellular TLR and NLR function, but ligand scavenging from cell surface limits TLR4 response to pathogens.
MedLine Citation:
PMID:  21098741     Owner:  NLM     Status:  MEDLINE    
Phagocytic and pathogen sensing receptors are responsible for particle uptake and inflammation. It is unclear how these receptors' systems influence each other's function to shape an innate response. The class-A scavenger receptors SR-A (scavenger receptor A) and MARCO (macrophage receptor with collagenous structure) are 2 well-characterized phagocytic receptors that are unable to initiate inflammatory responses by themselves, yet are implicated in the pathogenesis of various inflammatory disorders. However, the mechanism for such an apparent discrepancy is still unclear. We utilized SR-A(-/-), MARCO(-/-), and SR-A(-/-)-MARCO(-/-) mice, along with microbe-derived, environmental, and synthetic polyanions to assess the inflammatory responses following combinatorial ligation of SR-A/MARCO and selected Toll-like receptors (TLRs) and nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) by their shared ligands. In addition to ligating SR-A and MARCO, these agonists also selectively activated the cell-surface sensor TLR4, endosomal TLR3, and the cytosolic NOD2 and NALP3 (NACHT domain-, leucine-rich repeat-, and pyrin domain-containing protein 3). We show that, following recognition of common ligands, SR-A and MARCO attenuate TLR4-mediated responses while enhancing responses by the intracellular TLR3, NOD2, and NALP3. We conclude that SR-A/MARCO-mediated rapid ligand internalization prevented sensing by surface TLRs while increasing ligand availability in intracellular compartments, thus allowing sensing and robust responses by intracellular sensors.
Subhankar Mukhopadhyay; Audrey Varin; Yunying Chen; Baoying Liu; Karl Tryggvason; Siamon Gordon
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-11-23
Journal Detail:
Title:  Blood     Volume:  117     ISSN:  1528-0020     ISO Abbreviation:  Blood     Publication Date:  2011 Jan 
Date Detail:
Created Date:  2011-01-28     Completed Date:  2011-03-21     Revised Date:  2014-02-20    
Medline Journal Info:
Nlm Unique ID:  7603509     Medline TA:  Blood     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1319-28     Citation Subset:  AIM; IM    
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MeSH Terms
Antigen Presentation / physiology
Cell Membrane / immunology,  metabolism*,  physiology
Cells, Cultured
Cytokines / metabolism
Mice, Inbred C57BL
Mice, Knockout
Nod Signaling Adaptor Proteins / metabolism,  physiology*
Peritonitis / immunology,  metabolism
Protein Transport / immunology
Receptors, Immunologic / genetics,  metabolism,  physiology*
Scavenger Receptors, Class A / genetics,  metabolism,  physiology*
Toll-Like Receptor 4 / metabolism*,  physiology
Toll-Like Receptors / metabolism,  physiology*
Grant Support
G0500623//Medical Research Council; //Medical Research Council
Reg. No./Substance:
0/Cytokines; 0/Ligands; 0/Marco protein, mouse; 0/Nod Signaling Adaptor Proteins; 0/Receptors, Immunologic; 0/Scavenger Receptors, Class A; 0/Toll-Like Receptor 4; 0/Toll-Like Receptors

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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