An unbalanced monocyte macrophage polarization in the bone marrow microenvironment of patients with poor graft function after allogeneic haematopoietic stem cell transplantation

Abstract

Poor graft function (PGF) is a severe complication of allogeneic haematopoietic stem cell transplantation (allo-HSCT). Murine studies have demonstrated that effective haematopoiesis depends on the specific bone marrow (BM) microenvironment. Increasing evidence shows that BM macrophages (MФs), which constitute an important component of BM immune microenvironment, are indispensable for the regulation of haematopoietic stem cells (HSCs) in the BM. However, little is known about the number and function of BM MФs or whether they directly interact with HSCs in PGF patients. In the current prospective case-control study, PGF patients showed a significant increase in classically activated inflammatory MФs (M1; 2·18 ± 0·11% vs. 0·82 ± 0·06%, P < 0·0001), a striking reduction in alternatively activated anti-inflammatory MФs (M2; 3·02 ± 0·31% vs. 21·89 ± 0·90%, P < 0·0001), resulting in a markedly increased M1/M2 ratio (0·82 ± 0·06 vs. 0·06 ± 0·002; P < 0·0001) in the BM compared with good graft function patients. Meanwhile, standard monocyte subsets were altered in PGF patients. Dysfunctional BM MФs, which were characterized by reduced proliferation, migration and phagocytosis, were evident in PGF patients. Furthermore, BM MФs from PGF patients with high tumour necrosis factor-α and interleukin 12 levels and low transforming growth factor-β levels, led to impaired BM CD34 cell function. In summary, our data indicate that an unbalanced BM M1/M2 ratio and dysfunctional MФs may contribute to the occurrence of PGF following allo-HSCT.

Advances in the understanding of poor graft function following allogeneic hematopoietic stem-cell transplantation

“… 57 – 59 A recent case-control study revealed a significant increase in M1 (classically activated inflammatory macrophages) and a striking reduction in M2 (alternatively activated anti-inflammatory macrophages) in PGF patients compared with those with GGF. 60 The functions of BM macrophages, such as proliferation, migration, and phagocytosis, were impaired in PGF patients. Moreover, when cocultured with BM macrophages from PGF patients, the function of CD34 + cells was impaired through the upregulation of the p38 MAPK pathway.…”

Developing role of B cells in the pathogenesis and treatment of chronic GVHD

“…As a selective Janus kinase (JAK) 1/2 inhibitor, ruxolitinib blocks T cell activation and survival, while also influencing the differentiation and mutation of dendritic cells (Bendstrup et al , ). Pirfernidone is used in idiopathic pulmonary fibrosis (Du et al , ), and is also effective in murine models of sclerodermatous cGVHD, as it inhibits macrophage infiltration and TGF‐ production (Zhao et al , ), while macrophage reconstitution is very important to haematopoietic microenvironment and development of GVHD after transplantation. Low‐dose subcutaneous IL2 is another strategy for corticoid‐refractory cGVHD due to its crucial role in augmenting Treg expansion, survival and activity (Koreth et al , ).…”

Different subsets of haematopoietic cells and immune cells in bone marrow between young and older donors

“…Macrophages can be referred to as either classical macrophages (M1) or alternative macrophages (M2) [35,36]. As previously reported [21,22] for analysis of M1 and M2, BMMNCs were stained with anti-CD14-PE, anti-CD68-FITC, anti-CCR2-BV421, anti-CX3CR1-PerCP/ Cy5.5 and anti-CD163-PE/Cy7 (BioLegend, San Diego, CA, USA). M1 and M2 were identified as CD14 + CCR2 + CD68 + and CD14 + CX3CR1 + CD163 + , respectively.…”

“…Moreover, aGVHD is generally considered to be associated with increased percentages of donor T helper-1 (Th1) and T cytotoxic-1 (Tc1) cells and decreased percentages of T helper-2 (Th2) and T cytotoxic-2 (Tc2) cells [16][17][18][19]. Macrophages were involved in aGVHD, poor graft function and some other complications post allo-HSCT [20][21][22][23]. However, little is known about the differences in the percentages of cytokine-producing T cell subsets and macrophage subsets in BM between young and older donors.…”