title: The chemotaxis of M1 and M2 macrophages is regulated by different chemokines.
abstract: The homing of proinflammatory (M1) and the "alternatively activated" anti-inflammatory (M2) macrophages plays a different role in the process of inflammation. Chemokines are the major mediators of macrophage chemotaxis, but how they differentially regulate M1 and M2 macrophages remains largely unclear. In the present study, we attempted to screen chemokines that differentially induce chemotaxis of M1 and M2 macrophages and to explore the underlying mechanism. Among the 41 chemokines that specifically bind to 20 chemokine receptors, CCL19, CCL21, CCL24, CCL25, CXCL8, CXCL10, and XCL2 specifically induced M1 macrophage chemotaxis, whereas CCL7 induced chemotaxis of both M1 and M2 macrophages. Whereas the differential effects of these chemokines on M1/M2 macrophage chemotaxis could be attributable to the predominant expression of their cognate receptors on the macrophage subsets, CCR7, the receptor for CCL19/CCL21, appeared to be an exception. Immunoblot analysis indicated an equivalent level of CCR7 in the whole cell lysate of M1 and M2 macrophages, but CCL19 and CCL21 only induced M1 macrophage chemotaxis. Both immunoblot and confocal microscopy analyses demonstrated that CCR7 was predominantly expressed on the cell surface of M1 but in the cytosol of M2 macrophages before ligand stimulation. As a result, CCL19 or CCL21 induced activation of both MEK1-ERK1/2 and PI3K-AKT cascades in M1 but not in M2 macrophages. Intriguingly, CCL19/CCL21-mediated M1 macrophage chemotaxis was blocked by specific inhibition of PI3K rather than MEK1. Together, these findings suggest that recruitment of M1 and M2 macrophages is fine tuned by different chemokines with the involvement of specific signaling pathways.
authors.affiliation: *Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China; School of Life Sciences and Technology, Tongji University, Shanghai, China; and Neuroinflammation Discovery Performance Unit, GlaxoSmithKline R&D China, Shanghai, 201203, China.
authors.forename: Wenjuan
authors.initials: W
authors.lastname: Xuan
authors.affiliation: *Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China; School of Life Sciences and Technology, Tongji University, Shanghai, China; and Neuroinflammation Discovery Performance Unit, GlaxoSmithKline R&D China, Shanghai, 201203, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Qu
authors.affiliation: *Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China; School of Life Sciences and Technology, Tongji University, Shanghai, China; and Neuroinflammation Discovery Performance Unit, GlaxoSmithKline R&D China, Shanghai, 201203, China.
authors.forename: Biao
authors.initials: B
authors.lastname: Zheng
authors.affiliation: *Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China; School of Life Sciences and Technology, Tongji University, Shanghai, China; and Neuroinflammation Discovery Performance Unit, GlaxoSmithKline R&D China, Shanghai, 201203, China.
authors.forename: Sidong
authors.initials: S
authors.lastname: Xiong
authors.affiliation: *Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China; School of Life Sciences and Technology, Tongji University, Shanghai, China; and Neuroinflammation Discovery Performance Unit, GlaxoSmithKline R&D China, Shanghai, 201203, China guohuang.g.fan@gmail.com.
authors.forename: Guo-Huang
authors.initials: GH
authors.lastname: Fan
mesh_terms: D015153:Blotting, Western; D002478:Cells, Cultured; D018925:Chemokines / Q000276:immunology*; D002634:Chemotaxis, Leukocyte / Q000276:immunology*; D005455:Fluorescent Antibody Technique; D006801:Humans; D007249:Inflammation / Q000276:immunology; D008264:Macrophages / Q000276:immunology*; D018613:Microscopy, Confocal; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology
chemical_list: D018925:Chemokines
keywords: macrophage polarization; migration; screening