Continuous infiltration of small peritoneal macrophages in the mouse peritoneum through CCR2-dependent and -independent routes during fibrosis and mesothelioma development induced by a multiwalled carbon nanotube, MWNT-7
The Journal of toxicological sciences(2023)
摘要
Although toxicities of multiwalled carbon nanotube (MWCNT) have been found to be related with activities of macrophages phagocytosing the fibers, the exact relationship between mac-rophage population and pathogenesis of fibrosis and mesotheliomas induced by MWCNTs is largely unknown. CCL2-CCR2 axis, a major monocyte/macrophage infiltration route, is thought to be involved in not only acute inflammation but also the formation of tumor microenvironment. We therefore described a time-course of alteration of macrophage population in an attempt to clarify the contribution of the Ccr2 gene to mesotheliomagenesis. Wild-type (WT) C57BL/6 mice and Ccr2-knockout (KO) mice were intra-peritoneally administered with MWNT-7 and were sequentially necropsied at 1, 7, 28, 90, and 245 day(s) after the injection. Peritoneal fibrosis was prominent in all MWCNT-treated mice, with a lower sever-ity in the KO mice. No differences were observed in the incidences of neoplastic lesions of mesothelia between WT and KO mice. A flow cytometric analysis revealed that after gross disappearance of mac-rophages after MWCNT exposure, small peritoneal macrophages (SPMs) were exclusively refurbished by the CCR2-dependent route at day 1 (as Ly-6C+MHC class II- cells), followed by additional CCR2-independent routes (as Ly-6C-IVITIC class II- cells); i.e., the only route in KO mice; with a delay of 1-7 days. The SPMs derived from both routes appeared to differentiate into maturated cells as Ly-6C-MHC class II+, whose ratio increased in a time-dependent manner among the total SPM population. Additional-ly, most macrophages expressed Ml-like features, but a small fraction of macrophages exhibited an M1/ M2 mixed status in MWCNT-treated animals. Our findings demonstrate a long-persistent activation of the CCL2-CCR2 axis after MWCNT exposure and enable a better understanding of the participation and potential roles of SPMs in fibrous material-induced chronic toxicities.
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关键词
Ccr2-knockout mice,Chronic inflammation,Fibrosis,Macrophages,Mesothelioma,MWCNT
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