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M2 macrophages, but not M1 macrophages, support megakaryopoiesis by upregulating PI3K-AKT pathway activity.

Abstract

Dysfunctional megakaryopoiesis hampers platelet production, which is closely associated with thrombocytopenia (PT). Macrophages (MFs) are crucial cellular components in the bone marrow (BM) microenvironment. However, the specific effects of M1 MFs or M2 MFs on regulating megakaryocytes (MKs) are largely unknown. In the current study, aberrant BM-M1/M2 MF polarization, characterized by increased M1 MFs and decreased M2 MFs and accompanied by impaired megakaryopoiesis-supporting abilities, was found in patients with PT post-allotransplant. RNA-seq and western blot analysis showed that the PI3K-AKT pathway was downregulated in the BM MFs of PT patients. Moreover, in vitro treatment with PI3K-AKT activators restored the impaired megakaryopoiesis-supporting ability of MFs from PT patients. Furthermore, we found M1 MFs suppress, whereas M2 MFs support MK maturation and platelet formation in humans. Chemical inhibition of PI3K-AKT pathway reduced megakaryopoiesis-supporting ability of M2 MFs, as indicated by decreased MK count, colony-forming unit number, high-ploidy distribution, and platelet count. Importantly, genetic knockdown of the PI3K-AKT pathway impaired the megakaryopoiesis-supporting ability of MFs both in vitro and in a MF-specific PI3K-knockdown murine model, indicating a critical role of PI3K-AKT pathway in regulating the megakaryopoiesis-supporting ability of M2 MFs. Furthermore, our preliminary data indicated that TGF-beta released by M2 MFs may facilitate megakaryopoiesis through upregulation of the JAK2/STAT5 and MAPK/ERK pathways in MKs. Taken together, our data reveal that M1 and M2 MFs have opposing effects on MKs in a PI3K-AKT pathway-dependent manner, which may lead to new insights into the pathogenesis of thrombocytopenia and provide a potential therapeutic strategy to promote megakaryopoiesis.

Authors: Zhao HY, Zhang YY, Xing T, Tang SQ, Wen Q, Lyu ZS, Lv M, Wang Y, Xu LP, Zhang XH, Kong Y, Huang XJ,
Journal: Signal Transduct Target Ther; 2021 Jun 18 ; 6 (1) 234. doi:10.1038/s41392-021-00627-y
Year: 2021
PubMed: PMID: 34140465 (Go to PubMed)