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肌肉驻留巨噬细胞在蜂毒明肽诱导的小鼠肌损伤模型中控制免疫细胞反应。

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

作者信息

Brigitte Madly, Schilte Clementine, Plonquet Anne, Baba-Amer Yasmine, Henri Adeline, Charlier Caroline, Tajbakhsh Shahragim, Albert Matthew, Gherardi Romain K, Chrétien Fabrice

机构信息

INSERM U955, Groupe Hospitalier Henri Mondor-Albert Chenevier, Assistance Publique Hôpitaux de Paris, Université Paris 12 Val-de-Marne, Créteil, France.

出版信息

Arthritis Rheum. 2010 Jan;62(1):268-79. doi: 10.1002/art.27183.

Abstract

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-6C(high)CX3CR1(low)CD11c- cells that were progressively substituted by Ly-6C(low)CX3CR1(high) cells displaying an intermediate, rather than high, level of CD11c expression. These CD11c(intermediate) 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.

摘要

目的

骨骼肌可能是多种尚未完全了解的免疫反应发生的部位,尤其是在肌纤维损伤后,这种情况在炎性肌病中较为常见。本研究旨在利用蝰蛇毒诱导的小鼠肌损伤模型来研究天然免疫细胞反应,从而探究受损肌肉中驻留巨噬细胞和树突状细胞(DCs)的细胞动态及功能。

方法

通过显微镜检查和流式细胞术分析骨髓细胞对蝰蛇毒诱导的肌损伤的反应。采用骨髓(BM)移植研究来区分驻留单核细胞/巨噬细胞和渗出单核细胞/巨噬细胞。功能测试包括细胞因子筛选和同种异体抗原混合淋巴细胞反应,以评估抗原呈递细胞(APC)功能。通过向移植了对白喉毒素(DT)不敏感骨髓的CD11b-DT受体转基因小鼠注射DT来实现选择性驻留巨噬细胞清除。

结果

深度肌肉损伤后,小鼠肌肉/肌束组织(肌外膜/肌束膜)周围的结缔组织中存在一群CD11b+F4/80+CD11c-Ly-6C-CX3CR1-的驻留巨噬细胞,它们首先聚集在肌外膜。这些驻留巨噬细胞被白细胞用作向心迁移途径,并被发现选择性释放两种趋化因子,即细胞因子诱导的中性粒细胞趋化因子和单核细胞趋化蛋白1,并对从血液中大量募集中性粒细胞和单核细胞起关键作用。早期肌外膜炎症以Ly-6C(高)CX3CR1(低)CD11c-细胞为主,逐渐被Ly-6C(低)CX3CR1(高)细胞取代,这些细胞表达的CD11c水平处于中等而非高水平。这些CD11c(中等)细胞来源于循环中的CCR2+单核细胞,在没有同种异体抗原刺激的情况下,其功能表现为未成熟的APC,并迁移至引流淋巴结,同时获得成熟DCs的表型(CD11c+Ia+CD80+细胞,对应炎性DC表型)。

结论

该小鼠模型中的结果表明,肌肉肌外膜/肌束膜中的驻留巨噬细胞协调了对肌损伤的天然免疫反应,通过炎性DCs的形成与适应性免疫相关联。

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