Published online before print November 29, 2006

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(Journal of Leukocyte Biology. 2007;81:775-785.)
© 2007 by Society for Leukocyte Biology

MCP-1 deficiency causes altered inflammation with impaired skeletal muscle regeneration

Paula K. Shireman^*,,,,1, Verónica Contreras-Shannon^||, Oscar Ochoa, Bijal P. Karia, Joel E. Michalek^¶ and Linda M. McManus^,#,**

^* South Texas Veterans Health Care System, San Antonio, Texas, USA; and Departments of
Surgery,
Medicine,
^|| Cellular and Structural Biology,
^¶ Epidemiology and Biostatistics,
^# Periodontics, and
^** Pathology and
Sam and Ann Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center, San Antonio, Texas, USA

¹ Correspondence: Departments of Surgery and Medicine and Sam and Ann Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center, MC 7741, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900, USA. E-mail: shireman{at}uthscsa.edu

We examined the role of MCP-1, a potent chemotactic and activating factor for macrophages, in perfusion, inflammation, and skeletal muscle regeneration post-ischemic injury. MCP-1–/– or C57Bl/6J control mice [wild-type (WT)] underwent femoral artery excision (FAE). Muscles were collected for histology, assessment of tissue chemokines, and activity measurements of lactate dehydrogenase (LDH) and myeloperoxidase. In MCP-1–/– mice, restoration of perfusion was delayed, and LDH and fiber size, indicators of muscle regeneration, were decreased. Altered inflammation was observed with increased neutrophil accumulation in MCP-1–/– versus WT mice at Days 1 and 3 (P0.003), whereas fewer macrophages were present in MCP-1–/– mice at Day 3. As necrotic tissue was removed in WT mice, macrophages decreased (Day 7). In contrast, macrophage accumulation in MCP-1–/– was increased in association with residual necrotic tissue and impaired muscle regeneration. Consistent with altered inflammation, neutrophil chemotactic factors (keratinocyte-derived chemokine and macrophage inflammatory protein-2) were increased at Day 1 post-FAE. The macrophage chemotactic factor MCP-5 was increased significantly in WT mice at Day 3 compared with MCP-1–/– mice. However, at post-FAE Day 7, MCP-5 was significantly elevated in MCP-1–/– mice versus WT mice. Addition of exogenous MCP-1 did not induce proliferation in murine myoblasts (C2C12 cells) in vitro. MCP-1 is essential for reperfusion and the successful completion of normal skeletal muscle regeneration after ischemic tissue injury. Impaired muscle regeneration in MCP-1–/– mice suggests an important role for macrophages and MCP-1 in tissue reparative processes.

Key Words: CCL2 • macrophage • neutrophils • chemokines • ischemia

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