Document Detail


Metalloproteinase-mediated Shedding of Integrin β2 promotes macrophage efflux from inflammatory sites.
MedLine Citation:
PMID:  22170060     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Macrophage exiting from inflammatory sites is critical to limit the local innate immune response. With tissue insult, resident tissue macrophages rapidly efflux to lymph nodes where they modulate the adaptive immune response, and inflammatory macrophages attracted to the site of injury then exit during the resolution phase. However, the mechanisms that regulate macrophage efflux are poorly understood. This study has investigated soluble forms of integrin β2 whose levels are elevated in experimental peritonitis at times when macrophages are exiting the peritoneum, suggesting that its proteolytic shedding may be involved in macrophage efflux. Both constitutive and inducible metalloproteinase-dependent shedding of integrin β2 from mouse macrophages are demonstrated. Soluble integrin β2 is primarily released as a heterodimeric complex with αM that retains its ability to bind its ligands intracellular adhesion molecule-1, fibrin, and collagen and thus may serve as a soluble antagonist. In a model of accelerated exiting, administration of a metalloproteinase inhibitor prevents macrophage efflux by 50% and impedes loss of macrophage integrin β2 from the cell surface. Exiting of peritoneal macrophages in mice lacking integrin β2 is accelerated, and antibody disruption of integrin β2-substrate interactions can reverse 50% of the metalloprotease inhibitor blockade of macrophage exiting. Thus, our study demonstrates the ability of metalloproteinase-mediated shedding of integrin β2 to promote macrophage efflux from inflammatory sites, and the release of soluble integrin heterodimers may also limit local inflammation.
Authors:
Ivan G Gomez; Jingjing Tang; Carole L Wilson; Wei Yan; Jay W Heinecke; John M Harlan; Elaine W Raines
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2011-12-14
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  287     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2012 Feb 
Date Detail:
Created Date:  2012-02-15     Completed Date:  2012-04-16     Revised Date:  2013-06-27    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  4581-9     Citation Subset:  IM    
Affiliation:
Dept. of Pathology, University of Washington, Harborview Medical Center, 325 9th Ave., Box 359675, Seattle, WA 98104, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Antigens, CD18 / genetics,  metabolism*
Cell Movement*
Cells, Cultured
Collagen / genetics,  metabolism
Fibrin / genetics,  metabolism
Humans
Inflammation / genetics,  metabolism,  pathology
Intercellular Adhesion Molecule-1 / genetics,  metabolism
Macrophages, Peritoneal / metabolism*,  pathology
Metalloproteases / genetics,  metabolism*
Mice
Mice, Mutant Strains
Peritonitis / genetics,  metabolism*,  pathology
Protein Multimerization*
alpha-Macroglobulins / genetics,  metabolism
Grant Support
ID/Acronym/Agency:
5P01 HL018645/HL/NHLBI NIH HHS; 5P01 HL030086/HL/NHLBI NIH HHS; HL081795/HL/NHLBI NIH HHS; P01 HL018645/HL/NHLBI NIH HHS; P30 DK017047/DK/NIDDK NIH HHS; R01 HL067267/HL/NHLBI NIH HHS; R01 HL067267/HL/NHLBI NIH HHS; R01 HL081795/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Antigens, CD18; 0/alpha-Macroglobulins; 126547-89-5/Intercellular Adhesion Molecule-1; 9001-31-4/Fibrin; 9007-34-5/Collagen; EC 3.4.-/Metalloproteases
Comments/Corrections

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