| 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. | |
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MedLine Citation:
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PMID: 22948158 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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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:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2012-09-04 |
Journal Detail:
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Title: The Journal of biological chemistry Volume: 287 ISSN: 1083-351X ISO Abbreviation: J. Biol. Chem. Publication Date: 2012 Oct |
Date Detail:
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Created Date: 2012-10-29 Completed Date: 2013-01-07 Revised Date: 2013-04-16 |
Medline Journal Info:
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Nlm Unique ID: 2985121R Medline TA: J Biol Chem Country: United States |
Other Details:
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Languages: eng Pagination: 37406-19 Citation Subset: IM |
Affiliation:
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Division of Pharmacology and Toxicology, Department of Pharmaceutical Sciences, University of the Sciences in Philadelphia, Philadelphia, Pennsylvania 19104, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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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:
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HL068072/HL/NHLBI NIH HHS; HL073896/HL/NHLBI NIH HHS; HL62472/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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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 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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