title: Mac-1 Regulates IL-13 Activity in Macrophages by Directly Interacting with IL-13Rα1.
abstract: Mac-1 exhibits a unique inhibitory activity toward IL-13-induced JAK/STAT activation and thereby regulates macrophage to foam cell transformation. However, the underlying molecular mechanism is unknown. In this study, we report the identification of IL-13Rα1, a component of the IL-13 receptor (IL-13R), as a novel ligand of integrin Mac-1, using a co-evolution-based algorithm. Biochemical analyses demonstrated that recombinant IL-13Rα1 binds Mac-1 in a purified system and supports Mac-1-mediated cell adhesion. Co-immunoprecipitation experiments revealed that endogenous Mac-1 forms a complex with IL-13Rα1 in solution, and confocal fluorescence microscopy demonstrated that these two receptors co-localize with each other on the surface of macrophages. Moreover, we found that genetic inactivation of Mac-1 promotes IL-13-induced JAK/STAT activation in macrophages, resulting in enhanced polarization along the alternative activation pathway. Importantly, we observed that Mac-1(-/-) macrophages exhibit increased expression of foam cell differentiation markers including 15-lipoxygenase and lectin-type oxidized LDL receptor-1 both in vitro and in vivo. Indeed, we found that Mac-1(-/-)LDLR(-/-) mice develop significantly more foam cells than control LDLR(-/-) mice, using an in vivo model of foam cell formation. Together, our data establish for the first time a molecular mechanism by which Mac-1 regulates the signaling activity of IL-13 in macrophages. This newly identified IL-13Rα1/Mac-1-dependent pathway may offer novel targets for therapeutic intervention in the future.
authors.affiliation: From the Departments of Physiology and.
authors.forename: Chunzhang
authors.initials: C
authors.lastname: Cao
authors.affiliation: From the Departments of Physiology and.
authors.forename: Juanjuan
authors.initials: J
authors.lastname: Zhao
authors.affiliation: the Department of Biological Sciences, University of Maryland, Baltimore County, Baltimore, Maryland 21250.
authors.forename: Emily K
authors.initials: EK
authors.lastname: Doughty
authors.affiliation: Surgery, Center for Vascular and Inflammatory Diseases, the University of Maryland, School of Medicine, Baltimore, Maryland 21201 and.
authors.forename: Mary
authors.initials: M
authors.lastname: Migliorini
authors.affiliation: Surgery, Center for Vascular and Inflammatory Diseases, the University of Maryland, School of Medicine, Baltimore, Maryland 21201 and.
authors.forename: Dudley K
authors.initials: DK
authors.lastname: Strickland
authors.affiliation: the Department of Biological Sciences, University of Maryland, Baltimore County, Baltimore, Maryland 21250.
authors.forename: Maricel G
authors.initials: MG
authors.lastname: Kann
authors.affiliation: From the Departments of Physiology and lizhang@som.umaryland.edu.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation; D002462:Cell Membrane / Q000378:metabolism; D016764:Cell Polarity; D019143:Evolution, Molecular; D005487:Foam Cells / Q000166:cytology / Q000378:metabolism; D020868:Gene Silencing; D018793:Interleukin-13 / Q000378:metabolism*; D053661:Interleukin-13 Receptor alpha1 Subunit / Q000378:metabolism*; D053612:Janus Kinases / Q000378:metabolism; D016177:Macrophage-1 Antigen / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D011485:Protein Binding; D011994:Recombinant Proteins / Q000378:metabolism; D050791:STAT Transcription Factors / Q000378:metabolism; D012996:Solutions
chemical_list: D015415:Biomarkers; D018793:Interleukin-13; D053661:Interleukin-13 Receptor alpha1 Subunit; D016177:Macrophage-1 Antigen; D011994:Recombinant Proteins; D050791:STAT Transcription Factors; D012996:Solutions; D053612:Janus Kinases
keywords: bioinformatics; cell signaling; cytokine; integrin; macrophage