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ASK1-dependent recruitment and activation of macrophages induce hair growth in skin wounds

¹ Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, The University of Tokyo, ² Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, and ³ Strategic Approach to Drug Discovery and Development in Pharmaceutical Sciences, Center of Excellence Program, Bunkyo-ku, Tokyo 113-0033, Japan
⁴ Department of Orthodontics and Dentofacial Orthopedics, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima 770-8504, Japan
⁵ Genome Science Division, Research Center for Advanced Science and Technology and Department, The University of Tokyo, Meguro-ku, Tokyo 153-8904, Japan

Correspondence to Hidenori Ichijo: ichijo{at}mol.f.u-tokyo.ac.jp

Apoptosis signal-regulating kinase 1 (ASK1) is a member of the mitogen-activated protein 3-kinase family that activates both c-Jun NH₂-terminal kinase and p38 pathways in response to inflammatory cytokines and physicochemical stress. We report that ASK1 deficiency in mice results in dramatic retardation of wounding-induced hair regrowth in skin. Oligonucleotide microarray analysis revealed that expression of several chemotactic and activating factors for macrophages, as well as several macrophage-specific marker genes, was reduced in the skin wound area of ASK1-deficient mice. Intracutaneous transplantation of cytokine-activated bone marrow-derived macrophages strongly induced hair growth in both wild-type and ASK1-deficient mice. These findings indicate that ASK1 is required for wounding-induced infiltration and activation of macrophages, which play central roles in inflammation-dependent hair regrowth in skin.

Abbreviations used in this paper: ASK1, apoptosis signal-regulating kinase 1; BMDM, bone marrow–derived macrophage; DC, dendritic cell; ERK, extracellular signal-regulated kinase; IL, interleukin; MCP-1, monocyte chemoattractant protein-1; MEF, mouse embryonic fibroblast; MHC, major histocompatability complex; MIP-1, macrophage inflammatory protein-1; MSP, macrophage-stimulating factor; WT, wild-type.

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