Muscle resident macrophages control the immune cell reaction in a mouse model of notexin-induced myoinjury
Madly Brigitte
INSERM U955, Groupe Hospitalier Henri Mondor-Albert Chenevier, Assistance Publique Hôpitaux de Paris, and Université Paris 12 Val-de-Marne, Créteil, France
Search for more papers by this authorClementine Schilte
INSERM U818 and Institut Pasteur, Paris, France
Search for more papers by this authorAnne Plonquet
Groupe Hospitalier Henri Mondor-Albert Chenevier and Assistance Publique Hôpitaux de Paris, Créteil, France
Search for more papers by this authorYasmine Baba-Amer
INSERM U955, Groupe Hospitalier Henri Mondor-Albert Chenevier, Assistance Publique Hôpitaux de Paris, and Université Paris 12 Val-de-Marne, Créteil, France
Search for more papers by this authorAdeline Henri
INSERM U955 and Université Paris 12 Val-de-Marne, Créteil, France
Search for more papers by this authorCorresponding Author
Romain K. Gherardi
INSERM U955, Groupe Hospitalier Henri Mondor-Albert Chenevier, Assistance Publique Hôpitaux de Paris, and Université Paris 12 Val-de-Marne, Créteil, France
Drs. Gherardi and Chrétien contributed equally to this work.
INSERM U955-E10, Faculty of Medicine of Créteil, 8 rue du Général Sarrail, 94010 Créteil Cedex, FranceSearch for more papers by this authorFabrice Chrétien
INSERM U955, Groupe Hospitalier Henri Mondor-Albert Chenevier, Assistance Publique Hôpitaux de Paris, Université Paris 12 Val-de-Marne, Créteil, and Institut Pasteur, Paris, France
Drs. Gherardi and Chrétien contributed equally to this work.
Search for more papers by this authorMadly Brigitte
INSERM U955, Groupe Hospitalier Henri Mondor-Albert Chenevier, Assistance Publique Hôpitaux de Paris, and Université Paris 12 Val-de-Marne, Créteil, France
Search for more papers by this authorClementine Schilte
INSERM U818 and Institut Pasteur, Paris, France
Search for more papers by this authorAnne Plonquet
Groupe Hospitalier Henri Mondor-Albert Chenevier and Assistance Publique Hôpitaux de Paris, Créteil, France
Search for more papers by this authorYasmine Baba-Amer
INSERM U955, Groupe Hospitalier Henri Mondor-Albert Chenevier, Assistance Publique Hôpitaux de Paris, and Université Paris 12 Val-de-Marne, Créteil, France
Search for more papers by this authorAdeline Henri
INSERM U955 and Université Paris 12 Val-de-Marne, Créteil, France
Search for more papers by this authorCorresponding Author
Romain K. Gherardi
INSERM U955, Groupe Hospitalier Henri Mondor-Albert Chenevier, Assistance Publique Hôpitaux de Paris, and Université Paris 12 Val-de-Marne, Créteil, France
Drs. Gherardi and Chrétien contributed equally to this work.
INSERM U955-E10, Faculty of Medicine of Créteil, 8 rue du Général Sarrail, 94010 Créteil Cedex, FranceSearch for more papers by this authorFabrice Chrétien
INSERM U955, Groupe Hospitalier Henri Mondor-Albert Chenevier, Assistance Publique Hôpitaux de Paris, Université Paris 12 Val-de-Marne, Créteil, and Institut Pasteur, Paris, France
Drs. Gherardi and Chrétien contributed equally to this work.
Search for more papers by this authorAbstract
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.
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