Dynamics of M1 macrophages in oral mucosal lesions during the development of acute graft-versus-host disease in rats

Abstract

The role of macrophage infiltrates in oral mucosal acute graft-versus-host disease (AGVHD) remains unclear, although clinical studies suggest that macrophage infiltration correlates directly with the severity of AGVHD. In this study, we investigated the role of M1 macrophage infiltration in the oral mucosa of rats with AGVHD. Lewis rat spleen cells were injected into (Lewis × Brown Norway) F rats to induce systemic GVHD. Tongue samples were evaluated using histology, immunohistochemistry, dual immunofluorescence, real-time reverse transcription-polymerase chain reaction, Transwell migration assays and Stamper-Woodruff binding assays. At the onset of oral mucosal AGVHD, dual immunofluorescence and migration assays revealed that M1 macrophages had accumulated in the basement membrane (BM) region via the laminin/CD29 β1 integrin pathway. Macrophage-secreted matrix metalloproteinase-2 was related to BM degradation. The adhesion of macrophages to the oral epithelium could be inhibited by pretreating macrophages with a CC chemokine receptor 2 (CCR2) antibody and/or pretreating lesion sections with monocyte chemoattractant protein-1 (MCP-1) antibody. Our data show that the migration and adhesion of M1 macrophages are associated with oral mucosal AGVHD, which is mediated in part by both laminin/CD29 β 1 intern and MCP-1/CCR2 pathways. Therefore, our study provides additional support for the contribution of macrophage infiltrate to the development of oral mucosal AGVHD.

hUC-EVs-ATO reduce the severity of acute GVHD by resetting inflammatory macrophages toward the M2 phenotype

“…M2 macrophages are considered anti-inflammatory cells, resulting in the induction of Tregs [52]. Previous studies have shown that M1 macrophages are predominant in aGVHD and that the M1/ M2 ratio is positively correlated with the occurrence of grade 2-4 aGVHD [12][13][14]. The realignment of the M1/ M2 ratio may be beneficial in reducing the severity of aGVHD.…”

“…A study by Hogenes et al [11] revealed that macrophage depletion decreased survival and aggravated the histomorphology of the xenogeneic reaction in aGVHD. A recent study implied that the infiltration of activated M1 macrophages was associated with aGVHD severity in the oral mucosa [12]. A higher M1/M2 ratio in grafts was observed to be correlated with the occurrence of grade 2-4 aGVHD [13].…”

Gene expression profile of chronic oral graft-versus-host disease

“…It is important to note that oGVHD is primarily driven by T lymphocytes, with the participation of macrophages [22]. The association between macrophage migration and adhesion and oGVHD is mediated, in part, by CCL2/ CCR2 [23]. CCR2+ macrophages are generally M2 or activated type [24] and can be associated with the pro-fibrotic characteristics of oGVHD.…”

Immunometabolic Therapeutic Targets of Graft-versus-Host Disease (GvHD)

“…Thus, M1 and M2 macrophages may be pathogenic in aGvHD and cGvHD, respectively [142]. The secretion of nitric oxide (NO) through NO synthase (iNOS) by M1 cells in inflamed tissue is a plausible mechanism for promoting aGvHD [143]. Furthermore, macrophages facilitate alloreactive T cell responses to host antigens [144].…”