Document Detail


Toll-like receptor 2 (TLR2), transforming growth factor-β, hyaluronan (HA), and receptor for HA-mediated motility (RHAMM) are required for surfactant protein A-stimulated macrophage chemotaxis.
MedLine Citation:
PMID:  22948158     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The innate immune system protects the host from bacterial and viral invasion. Surfactant protein A (SPA), a lung-specific collectin, stimulates macrophage chemotaxis. However, the mechanisms regulating this function are unknown. Hyaluronan (HA) and its receptors RHAMM (receptor for HA-mediated motility, CD168) and CD44 also regulate cell migration and inflammation. We therefore examined the role of HA, RHAMM, and CD44 in SPA-stimulated macrophage chemotaxis. Using antibody blockade and murine macrophages, SPA-stimulated macrophage chemotaxis was dependent on TLR2 but not the other SPA receptors examined. Anti-TLR2 blocked SPA-induced production of TGFβ. In turn, TGFβ1-stimulated chemotaxis was inhibited by HA-binding peptide and anti-RHAMM antibody but not anti-TLR2 antibody. Macrophages from TLR2(-/-) mice failed to migrate in response to SPA but responded normally to TGFβ1 and HA, effects that were blocked by anti-RHAMM antibody. Macrophages from WT and CD44(-/-) mice had similar responses to SPA, whereas those from RHAMM(-/-) mice had decreased chemotaxis to SPA, TGFβ1, and HA. In primary macrophages, SPA-stimulated TGFβ production was dependent on TLR2, JNK, and ERK but not p38. Pam3Cys, a specific TLR2 agonist, stimulated phosphorylation of JNK, ERK, and p38, but only JNK and ERK inhibition blocked Pam3Cys-stimulated chemotaxis. We have uncovered a novel pathway for SPA-stimulated macrophage chemotaxis where SPA stimulation via TLR2 drives JNK- and ERK-dependent TGFβ production. TGFβ1, in turn, stimulates macrophage chemotaxis in a RHAMM and HA-dependent manner. These findings are highly relevant to the regulation of innate immune responses by SPA with key roles for specific components of the extracellular matrix.
Authors:
Joseph P Foley; David Lam; Hongmei Jiang; Jie Liao; Naeun Cheong; Theresa M McDevitt; Aisha Zaman; Jo Rae Wright; Rashmin C Savani
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-09-04
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  287     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2012 Oct 
Date Detail:
Created Date:  2012-10-29     Completed Date:  2013-01-07     Revised Date:  2013-11-05    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  37406-19     Citation Subset:  IM    
Affiliation:
Division of Pharmacology and Toxicology, Department of Pharmaceutical Sciences, University of the Sciences in Philadelphia, Philadelphia, Pennsylvania 19104, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Antigens, CD44 / genetics,  metabolism*
Cell Line
Chemotaxis*
Cytoskeleton / metabolism
Extracellular Matrix Proteins / genetics,  metabolism*
Gene Knockout Techniques
Hyaluronic Acid / metabolism,  physiology*
Lipoproteins / pharmacology
MAP Kinase Signaling System
Macrophages / metabolism,  physiology*
Mice
Mink
Mitogen-Activated Protein Kinases / metabolism
Pseudopodia / metabolism,  physiology
Pulmonary Surfactant-Associated Protein A / physiology*
Toll-Like Receptor 2 / agonists,  genetics,  metabolism*
Transforming Growth Factor beta1 / metabolism,  physiology*
Grant Support
ID/Acronym/Agency:
HL068072/HL/NHLBI NIH HHS; HL073896/HL/NHLBI NIH HHS; HL62472/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Antigens, CD44; 0/Cd44 protein, mouse; 0/Extracellular Matrix Proteins; 0/Lipoproteins; 0/Pulmonary Surfactant-Associated Protein A; 0/Tlr2 protein, mouse; 0/Toll-Like Receptor 2; 0/Transforming Growth Factor beta1; 0/hyaluronan-mediated motility receptor; 112208-00-1/N-palmitoyl-S-(2,3-bis(palmitoyloxy)propyl)cysteinyl-seryl-lysyl-lysyl-lysyl-lysine; 9004-61-9/Hyaluronic Acid; EC 2.7.11.24/Mitogen-Activated Protein Kinases
Comments/Corrections

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