Muscle resident macrophages control the immune cell reaction in a mouse model of notexin‐induced myoinjury

• Published in: Arthritis and rheumatism Vol. 62; no. 1; pp. 268 - 279
• Main Authors: Brigitte, Madly, Schilte, Clementine, Plonquet, Anne, Baba‐Amer, Yasmine, Henri, Adeline, Charlier, Caroline, Tajbakhsh, Shahragim, Albert, Matthew, Gherardi, Romain K., Chrétien, Fabrice
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01-01-2010; Wiley
• Subjects: Animals; Biological and medical sciences; Bone Marrow Transplantation; CD11c Antigen - metabolism; Chemokine CCL2 - metabolism; Chemokine CXCL1 - metabolism; Connective Tissue - drug effects; Connective Tissue - immunology; Connective Tissue - pathology; CX3C Chemokine Receptor 1; Disease Models, Animal; Diseases of the osteoarticular system; Elapid Venoms - toxicity; Flow Cytometry; Fluorescent Antibody Technique, Indirect; Immunoenzyme Techniques; Immunology; Life Sciences; Macrophages - drug effects; Macrophages - immunology; Macrophages - pathology; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Nude; Mice, Transgenic; Muscle, Skeletal - drug effects; Muscle, Skeletal - immunology; Muscle, Skeletal - pathology; Neurotoxins - toxicity; Neutrophil Infiltration - immunology; Receptors, Chemokine - metabolism; Vertebrata; Mammalia; Mouse; Animal; Rodentia; Rheumatology; Resident; Models; Macrophage
• ISSN: 0004-3591; 1529-0131
• DOI: 10.1002/art.27183

Objective
Skeletal muscle may be the site of a variety of poorly understood immune reactions, particularly after myofiber injury, which is typically observed in inflammatory myopathies. This study was undertaken to explore both the cell dynamics and functions of resident macrophages and dendritic cells (DCs) in damaged muscle, using a mouse model of notexin‐induced myoinjury to study innate immune cell reactions.
Methods
The myeloid cell reaction to notexin‐induced myoinjury was analyzed by microscopy and flow cytometry. Bone marrow (BM) transplantation studies were used to discriminate resident from exudate monocyte/macrophages. Functional tests included cytokine screening and an alloantigenic mixed leukocyte reaction to assess the antigen‐presenting cell (APC) function. Selective resident macrophage depletion was obtained by injection of diphtheria toxin (DT) into CD11b–DT receptor–transgenic mice transplanted with DT‐insensitive BM.
Results
The connective tissue surrounding mouse muscle/fascicle tissue (the epimysium/perimysium) after deep muscle injury displayed a resident macrophage population of CD11b+F4/80+CD11c−Ly‐6C−CX3CR1− cells, which concentrated first in the epimysium. These resident macrophages were being used by leukocytes as a centripetal migration pathway, and were found to selectively release 2 chemokines, cytokine‐induced neutrophil chemoattractant and monocyte chemoattractant protein 1, and to crucially contribute to massive recruitment of neutrophils and monocytes from the blood. Early epimysial inflammation consisted of a predominance of Ly‐6ChighCX3CR1lowCD11c− cells that were progressively substituted by Ly‐6ClowCX3CR1high cells displaying an intermediate, rather than high, level of CD11c expression. These CD11cintermediate cells were derived from circulating CCR2+ monocytes, functionally behaved as immature APCs in the absence of alloantigenic challenge, and migrated to draining lymph nodes while acquiring the phenotype of mature DCs (CD11c+Ia+CD80+ cells, corresponding to an inflammatory DC phenotype).
Conclusion
The results in this mouse model show that resident macrophages in the muscle epimysium/perimysium orchestrate the innate immune response to myoinjury, which is linked to adaptive immunity through the formation of inflammatory DCs.