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Published online before print November 29, 2006

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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0506356

Received for publication May 23, 2006.
Revised October 31, 2006.
Accepted for publication November 2, 2006.

Article

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

Paula K. Shireman ^*@, 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 & 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

^@ To whom correspondence should be addressed. E-mail: shireman{at}uthscsa.edu.

	Abstract

We examined the role of MCP-1, a potent chemotactic and activating factor for macrophages, in perfusion, inflammation, and skeletal muscle regeneration postischemic 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 MIP-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 elevated significantly 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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