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SAA小鼠模型中T细胞分化及巨噬细胞亚型的研究*
({{custom_author.role_cn}}), {{javascript:window.custom_author_cn_index++;}}T Cell Differentiation and Macrophage Polarization in the Aplastic Anemia Mouse Model
({{custom_author.role_en}}), {{javascript:window.custom_author_en_index++;}}目的:探讨重型再生障碍性贫血(severe aplastic anemia,SAA)小鼠模型中淋巴细胞功能亚群和巨噬细胞亚型的特点。方法:B6D2F1小鼠经过全身照射(total body irradation,TBI)后,接受C57BL/6小鼠的淋巴细胞输注,建立SAA小鼠模型;以仅接受TBI的B6D2F1小鼠为对照组。在造模成功后收集两组小鼠外周血、淋巴结、脾脏和骨髓,通过流式细胞术检测小鼠T淋巴细胞亚群及CD4+和CD8+细胞表型分化情况;流式细胞术和免疫组化观察小鼠骨髓中巨噬细胞比例及其极化状态。结果:与TBI对照组相比,SAA组小鼠在造模的第12~13天出现严重骨髓衰竭,表现为骨髓造血面积明显减少,外周血白细胞、血红蛋白和血小板均显著下降。SAA组小鼠淋巴结、脾脏和外周血中CD8+淋巴细胞比例升高,CD4+/CD8+淋巴细胞比值显著下降。SAA小鼠的CD4+和CD8+淋巴细胞中,CD44+CD62L-效应记忆T细胞增多,而CD44-CD62L+的初始 T细胞和CD44+CD62L+中央记忆T细胞比例显著下降。SAA小鼠骨髓中CD11b+F4/80+巨噬细胞增多,且巨噬细胞以CD86-cCD206+和iNOS-cCD206+的M2型巨噬细胞为主。结论:SAA小鼠模型中,CD4+/CD8+淋巴细胞比值显著下降,淋巴细胞主要为表达CD44+CD62L-的效应记忆T细胞;骨髓巨噬细胞增多,且以M2型巨噬细胞为主。
Objective: To explore the changes of T cell subsets and macrophage subtypes in severe aplastic anemia (SAA) mouse models. Methods: To induce the SAA mouse models, the B6D2F1 mice first received a 5 5 Gy total body irradiation (TBI) and then were infused with C57BL/6 lymph node cells at 4×106/mouse via a tail vein injection, while the B6D2F1 mice receiving TBI alone were used as the control group. The mice were euthanized on day 12-13, and their peripheral blood, lymph nodes, spleen, and bone marrow were collected for analysis. T cell subsets and phenotypic differentiation of CD4+ and CD8+ cells were detected by flow cytometry, and the proportion and polarization of macrophages in bone marrow were detected by flow cytometry and immunohistochemistry. Results: Relative to control mice that received 5 Gy TBI without lymph node cells infusion, SAA mouse models exhibited severe bone marrow failure characterized by a significant reduction in the hematopoietic area of the sternum and decreased levels of white blood cells, hemoglobin, and platelets in peripheral blood 12-13 days post-radiation. In the SAA group, the frequencies of CD8+ T cells increased and the ratio of CD4+/CD8+ lymphocytes decreased significantly in lymph nodes, spleen, and peripheral blood. In CD4+ and CD8+ T cells of SAA mouse models, the percentage of CD44+CD62L- effector memory T cells increased, while the proportion of Naïve T cells and CD44+CD62L+ central memory T cells decreased significantly. CD11b+F4/80+ macrophages increased in the bone marrow of SAA mouse models, and most macrophages were CD86- cCD206+ and iNOS- cCD206+ M2 macrophages. Conclusions: In the SAA mouse models, the ratio of CD4+/CD8+ lymphocytes is significantly decreased, and the lymphocytes are mainly CD44+CD62L- effector memory T cells. Bone marrow macrophages increased and were mainly polarized towards M2 macrophages.
再生障碍性贫血 / 小鼠模型 / 巨噬细胞极化 / T细胞 {{custom_keyword}} /
Aplastic anemia / Mouse model / Macrophage polarization / T cells {{custom_keyword}} /
图2 SAA小鼠模型中CD4+/CD8+淋巴细胞亚群的变化Fig.2 Changes of CD4+/CD8+ lymphocyte subsets in SAA mouse models A. Mice were induced to develop SAA, and then their lymph nodes, spleens, and peripheral blood were examined at 12-13 days post-radiation. Expression of CD4 and CD8 in CD3+ T cells of SAA mice models were analyzed by flow cytometry B. The ratio of CD4+ T cells to CD8+ T cells subsets in lymph nodes of SAA mouse models C. The ratio of CD4+ T cells to CD8+ T cells subsets in spleen of SAA mouse models D. The ratio of CD4+ T cells to CD8+ T cells subsets in peripheral blood of SAA mouse models |
图3 SAA小鼠模型CD4+和CD8+T细胞中CD44、CD62L的表达Fig.3 Expression of CD44 and CD62L on CD4+ and CD8+ T lymphocytes in SAA mouse models A. Flow cytometry plots representing CD44 and CD62L strategy for CD4+ T cells in lymph nodes, spleen, and peripheral blood B. Flow cytometry plots representing CD44 and CD62L strategy for CD8+ T cells. Numbers on plots represent the percent of cells within the gated region C. Bar graphs summarize the data of the CD4+ lymphocyte subset D. Bar graphs summarize the data of the CD8+ lymphocyte subset |
图4 SAA小鼠模型骨髓中巨噬细胞比例Fig.4 Percentage of macrophages in the bone marrow of SAA mouse models A. The gating strategy to identify macrophages in bone marrow via flow cytometry B. Bar graphs summarize the data C. The immunohistochemistry staining assay of CD68 and F4/80 in the bone marrow of SAA mouse models (200× magnification) |
图5 SAA小鼠模型骨髓中巨噬细胞极化状态Fig.5 The distribution of macrophage subtypes in the bone marrow of SAA mouse models A. Macrophage subtypes in CD11b+F4/80+ population were detected by flow cytometry. CD86 and iNOS were used as M1 macrophage markers, and cCD206 was used as M2 macrophage marker B. Bar graphs summarize the data C. The immunohistochemistry staining assay of CD86, CD206, and CD163 in the bone marrow of SAA mouse models (200× magnification) |
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Aplastic anemia (AA) is rare disorder of bone marrow failure which if severe and not appropriately treated is highly fatal. AA is characterized by morphologic marrow features, namely hypocellularity, and resultant peripheral cytopenias. The molecular pathogenesis of AA is not fully understood, and a uniform process may not be the culprit across all cases. An antigen-driven and likely autoimmune dysregulated T-cell homeostasis is implicated in the hematopoietic stem cell injury which ultimately founds the pathologic features of the disease. Defective telomerase function and repair may also play a role in some cases as evidenced by recurring mutations in related telomerase complex genes such as TERT and TERC. In addition, recurring mutations in BCOR/BCORL, PIGA, DNMT3A, and ASXL1 as well as cytogenetic abnormalities, namely monosomy 7, trisomy 8, and uniparental disomy of the 6p arm seem to be intimately related to AA pathogenesis. The increased incidence of late clonal disease has also provided clues to accurately describe plausible predispositions to the development of AA. The emergence of newer genomic sequencing and other techniques is incrementally improving the understanding of the pathogenic mechanisms of AA, the detection of the disease, and ultimately offers the potential to improve patient outcomes. In this comprehensive review, we discuss the current understanding of the immunobiology, molecular pathogenesis, and future directions of such for AA.© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
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Macrophages are extremely heterogeneous and plastic cells with an important role not only in physiological conditions, but also during inflammation (both for initiation and resolution). In the early 1990s, two different phenotypes of macrophages were described: one of them called classically activated (or inflammatory) macrophages (M1) and the other alternatively activated (or wound-healing) macrophages (M2). Currently, it is known that functional polarization of macrophages into only two groups is an over-simplified description of macrophage heterogeneity and plasticity; indeed, it is necessary to consider a continuum of functional states. Overall, the current available data indicate that macrophage polarization is a multifactorial process in which a huge number of factors can be involved producing different activation scenarios. Once a macrophage adopts a phenotype, it still retains the ability to continue changing in response to new environmental influences. The reversibility of polarization has a critical therapeutic value, especially in diseases in which an M1/M2 imbalance plays a pathogenic role. In this review, we assess the high plasticity of macrophages and their potential to be exploited to reduce chronic/detrimental inflammation. On the whole, the evidence detailed in this review underscores macrophage polarization as a target of interest for immunotherapy.© 2018 John Wiley & Sons Ltd.
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The microenvironment of solid tumors is characterized by a reactive stroma with an abundance of inflammatory mediators and leukocytes, dysregulated vessels and proteolytic enzymes. TAM, major players in the connection between inflammation and cancer, summarize a number of functions (e.g., promotion of tumor cell proliferation and angiogenesis, incessant matrix turnover, repression of adaptive immunity), which ultimately have an important impact on disease progression. Thus, together with other myeloid-related cells present at the tumor site (Tie2 macrophages and MDSCs), TAM represent an attractive target of novel biological therapies of tumors.
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Macrophages are important immune cells in innate immunity, and have remarkable heterogeneity and polarization. Under pathological conditions, in addition to the resident macrophages, other macrophages are also recruited to the diseased tissues, and polarize to various phenotypes (mainly M1 and M2) under the stimulation of various factors in the microenvironment, thus playing different roles and functions. Liver diseases are hepatic pathological changes caused by a variety of pathogenic factors (viruses, alcohol, drugs, etc.), including acute liver injury, viral hepatitis, alcoholic liver disease, metabolic-associated fatty liver disease, liver fibrosis, and hepatocellular carcinoma. Recent studies have shown that macrophage polarization plays an important role in the initiation and development of liver diseases. However, because both macrophage polarization and the pathogenesis of liver diseases are complex, the role and mechanism of macrophage polarization in liver diseases need to be further clarified. Therefore, the origin of hepatic macrophages, and the phenotypes and mechanisms of macrophage polarization are reviewed first in this paper. It is found that macrophage polarization involves several molecular mechanisms, mainly including TLR4/NF-κB, JAK/STATs, TGF-β/Smads, PPARγ, Notch, and miRNA signaling pathways. In addition, this paper also expounds the role and mechanism of macrophage polarization in various liver diseases, which aims to provide references for further research of macrophage polarization in liver diseases, contributing to the therapeutic strategy of ameliorating liver diseases by modulating macrophage polarization.
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Macrophages play an important role in a wide variety of physiologic and pathologic processes. Plasticity and functional polarization are hallmarks of macrophages. Macrophages commonly exist in two distinct subsets: classically activated macrophages (M1) and alternatively activated macrophages (M2). M2b, a subtype of M2 macrophages, has attracted increasing attention over the past decade due to its strong immune-regulated and anti-inflammatory effects. A wide variety of stimuli and multiple factors modulate M2b macrophage polarization in vitro and in vivo. M2b macrophages possess both protective and pathogenic roles in various diseases. Understanding the mechanisms of M2b macrophage activation and the modulation of their polarization might provide a great perspective for the design of novel therapeutic strategies. The purpose of this review is to discuss current knowledge of M2b macrophage polarization, the roles of M2b macrophages in a variety of diseases and the stimuli to modulate M2b macrophage polarization.©2018 The Authors. Society for Leukocyte Biology Published by Wiley Periodicals, Inc.
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Interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) have been implicated historically in the immune pathophysiology of aplastic anemia (AA) and other bone marrow (BM) failure syndromes. We recently defined the essential roles of IFN-γ produced by donor T cells and the IFN-γ receptor in the host in murine immune-mediated BM failure models. TNF-α has been assumed to function similarly to IFN-γ. We used our murine models and mice genetically deficient in TNF-α or TNF-α receptors (TNF-αRs) to establish an analogous mechanism. Unexpectedly, infusion of TNF-α donor lymph node (LN) cells into CByB6F1 recipients or injection of FVB LN cells into TNF-αR recipients both induced BM failure, with concurrent marked increases in plasma IFN-γ and TNF-α levels. Surprisingly, in TNF-α recipients, BM damage was attenuated, suggesting that TNF-α of host origin was essential for immune destruction of hematopoiesis. Depletion of host macrophages before LN injection reduced T-cell IFN-γ levels and reduced BM damage, whereas injection of recombinant TNF-α into FVB-LN cell-infused TNF-α recipients increased T-cell IFN-γ expression and accelerated BM damage. Furthermore, infusion of TNF-αR donor LN cells into CByB6F1 recipients reduced BM T-cell infiltration, suppressed T-cell IFN-γ production, and alleviated BM destruction. Thus, TNF-α from host macrophages and TNF-αR expressed on donor effector T cells were critical in the pathogenesis of murine immune-mediated BM failure, acting by modulation of IFN-γ secretion. In AA patients, TNF-α-producing macrophages in the BM were more frequent than in healthy controls, suggesting the involvement of this cytokine and these cells in human disease.
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The study of T cell biology has been accelerated by substantial progress at the technological level, particularly through the continuing advancement of flow cytometry. The conventional approach of observing T cells as either T helper or T cytotoxic is overly simplistic and does not allow investigators to clearly identify immune mechanisms or alterations in physiological processes that impact on clinical outcomes. The complexity of T cell sub-populations, as we understand them today, combined with the immunological and functional diversity of these subsets represent significant complications for the study of T cell biology. In this article, we review the use of classical markers in delineating T cell sub-populations, from "truly naïve" T cells (recent thymic emigrants with no proliferative history) to "exhausted senescent" T cells (poorly proliferative cells that display severe functional abnormalities) wherein the different phenotypes of these populations reflect their disparate functionalities. In addition, since persistent infections and chronological aging have been shown to be associated with significant alterations in human T cell distribution and function, we also discuss age-associated and cytomegalovirus-driven alterations in the expression of key subset markers.© 2013 International Society for Advancement of Cytometry.
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A multicolor flow cytometry panel was designed and optimized to define the following nine mouse T cell subsets: Treg (CD3 CD4 CD8 FoxP3 ), CD4 T naïve (CD3 CD4 CD8 FoxP3 CD44 CD62L ), CD4 T central memory (CD3 CD4 CD8 FoxP3 CD44 CD62L ), CD4 T effector memory (CD3 CD4 CD8 FoxP3 CD44 CD62L ), CD4 T EMRA (CD3 CD4 CD8 FoxP3 CD44 CD62L ), CD8 T naïve (CD3 CD8 CD4 CD44 CD62L ), CD8 T central memory (CD3 CD8 CD4 CD44 CD62L ), CD8 T effector memory (CD3 CD8 CD4 CD44 CD62L ), and CD8 T EMRA (CD3 CD8 CD4 CD44 CD62L ). In each T cell subset, a dual staining for Ki-67 expression and DNA content was employed to distinguish the following cell cycle phases: G (Ki67, with 2n DNA), G (Ki67, with 2n DNA), and S-G /M (Ki67, with 2n < DNA ≤ 4n). This panel was established for the analysis of mouse (C57BL/6J) spleen.© 2021 The Authors. Cytometry Part A published by Wiley Periodicals LLC. on behalf of International Society for Advancement of Cytometry.
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Macrophages are found in tissues, body cavities, and mucosal surfaces. Most tissue macrophages are seeded in the early embryo before definitive hematopoiesis is established. Others are derived from blood monocytes. The macrophage lineage diversification and plasticity are key aspects of their functionality. Macrophages can also be generated from monocytes and undergo classical (LPS+IFN-γ) or alternative (IL-4) activation., macrophages with different polarization and different activation markers coexist in tissues. Certain mouse strains preferentially promote T-helper-1 (Th1) responses and others Th2 responses. Their macrophages preferentially induce iNOS or arginase and have been called M1 and M2, respectively. In many publications, M1 and classically activated and M2 and alternatively activated are used interchangeably. We tested whether this is justified by comparing the gene lists positively [M1(=LPS+)] or negatively [M2(=LPS-)] correlated with the ratio of and in transcriptomes of LPS-treated peritoneal macrophages with classically (LPS, IFN-γ) vs. alternatively activated (IL-4) bone marrow derived macrophages, both from published datasets. Although there is some overlap between M1(=LPS+) and classically activated (LPS+IFN-γ) and M2(=LPS-) and alternatively activated macrophages, many more genes are regulated in opposite or unrelated ways. Thus, M1(=LPS+) macrophages are not equivalent to classically activated, and M2(=LPS-) macrophages are not equivalent to alternatively activated macrophages. This fundamental discrepancy explains why most surface markers identified on generated macrophages do not translate to the situation. Valid M1/M2 surface markers remain to be discovered.
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The immune-induced aplastic anemia (AA) mouse model has been used for the study of AA. However, there were no uniform conditions for establishing a model and no assessment of immunological homeostasis. Our study aimed to identify the conditions of establishing a model and assess the AA model in immunology and pathology.We induced an AA mouse model by the combination between sublethal irradiation and spleen-thymus lymphocyte infusion. The success of establishing the AA model was identified by blood routine tests and pathology of bone marrow. The frequency of Th17 and Treg cells was measured by flow cytometry. The frequency of CD34+ and CD41+ cells was detected by immunohistochemical technique.IL-6, IL-8, IL-17, TNF-α and IFN-γ were evaluated by ELISA.The Cs sublethal irradiation (5 Gy) and spleen-thymus lymphocyte infusion (5 106) induced the AA mouse model successfully. The AA mice had a long lifetime and manifested pancytopenia and bone marrow failure. The percentage of Th17 cells increased and the percentage of Treg cells decreased distinctly in AA mice. The area of hematopoietic tissues and count of CD34+ cells and CD41+ cells were significantly reduced in AA mice.The level of cytokines, IL-6, IL-8, IL-17, TNF-α and IFN-γ, was increased significantly in peripheral blood and bone marrow.Our data suggest that the improved AA mouse model conforms to the diagnosis standard of AA and simulates the immune internal environment of human AA. The AA mouse model has a longer lifetime and unbalances of Th17/Treg cells caused the destruction of CD34+ cells and CD41+ cells, which was immune-mediated pathogenesis to adapt to long-term research.
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The cell-surface glycoprotein CD44 is involved in a multitude of important physiological functions including cell proliferation, adhesion, migration, hematopoiesis, and lymphocyte activation. The diverse physiological activity of CD44 is manifested in the pathology of a number of diseases including cancer, arthritis, bacterial and viral infections, interstitial lung disease, vascular disease, and wound healing. This diversity in biological activity is conferred by both a variety of distinct CD44 isoforms generated through complex alternative splicing, posttranslational modifications (e.g., N- and O-glycosylation), interactions with a number of different ligands, and the abundance and spatial distribution of CD44 on the cell surface. The extracellular matrix glycosaminoglycan hyaluronic acid (HA) is the principle ligand of CD44. This review focuses both CD44-hyaluronan dependent and independent CD44 signaling and the role of CD44 HA interaction in various pathophysiologies. The review also discusses recent advances in novel treatment strategies that exploit the CD44 HA interaction either for direct targeting or for drug delivery.
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L-selectin (CD62L) is a type-I transmembrane glycoprotein and cell adhesion molecule that is expressed on most circulating leukocytes. Since its identification in 1983, L-selectin has been extensively characterized as a tethering/rolling receptor. There is now mounting evidence in the literature to suggest that L-selectin plays a role in regulating monocyte protrusion during transendothelial migration (TEM). The N-terminal calcium-dependent (C-type) lectin domain of L-selectin interacts with numerous glycans, including sialyl Lewis X (sLe) for tethering/rolling and proteoglycans for TEM. Although the signals downstream of L-selectin-dependent adhesion are poorly understood, they will invariably involve the short 17 amino acid cytoplasmic tail. In this review we will detail the expression of L-selectin in different immune cell subsets, and its influence on cell behavior. We will list some of the diverse glycans known to support L-selectin-dependent adhesion, within luminal and abluminal regions of the vessel wall. We will describe how each domain within L-selectin contributes to adhesion, migration and signal transduction. A significant focus on the L-selectin cytoplasmic tail and its proposed contribution to signaling via the ezrin-radixin-moesin (ERM) family of proteins will be outlined. Finally, we will discuss how ectodomain shedding of L-selectin during monocyte TEM is essential for the establishment of front-back cell polarity, bestowing emigrated cells the capacity to chemotax toward sites of damage.
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Severe aplastic anemia (SAA) is a bone marrow failure disease induced by hyperfunctional autoimmunic Th1 lymphocytes. Memory T cells (TM) are a component of the adaptive immune system. They ensure the host of more aggressive and faster immune response to efficiently eliminate the specific antigens after re-exposure and thus play a key role in T-cell functions. In this study we investigate the quantities and functions of memory T cells in SAA patients before and after immunosuppressive therapy (IST) to further clarify the mechanism of SAA apoptosis of bone marrow hematopoietic cells. Results showed that the percentage of CD4+ effector T cells in peripheral blood and bone marrow lymphocytes was decreased in SAA patients. The ratio of CD4+ memory T lymphocytes to CD8+ memory T subsets (CD4+/CD8+TM) in SAA patients was also lower. The percentage of CD8+ effector T cells in peripheral blood and CD8+ central memory T cells in the bone marrow lymphocytes was significantly higher in newly diagnosed patients. Furthermore, the median expressions of perforin and granzyme B on memory T cells were higher in SAA patients compared to those in normal controls. After IST, the quantities and functions of memory T cells return to normal level. Therefore, we concluded that the abnormal immunomodulatory ability on memory T cells may contribute to the imbalance of Th1/Th2 subsets and thus lead to over-function of T lymphocytes and hematopoiesis failure in SAA.
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Severe aplastic anemia (SAA) results from profound hematopoietic stem cell loss. T cells and interferon gamma (IFNγ) have long been associated with SAA, yet the underlying mechanisms driving hematopoietic stem cell loss remain unknown. Using a mouse model of SAA, we demonstrate that IFNγ-dependent hematopoietic stem cell loss required macrophages. IFNγ was necessary for bone marrow macrophage persistence, despite loss of other myeloid cells and hematopoietic stem cells. Depleting macrophages or abrogating IFNγ signaling specifically in macrophages did not impair T-cell activation or IFNγ production in the bone marrow but rescued hematopoietic stem cells and reduced mortality. Thus, macrophages are not required for induction of IFNγ in SAA and rather act as sensors of IFNγ. Macrophage depletion rescued thrombocytopenia, increased bone marrow megakaryocytes, preserved platelet-primed stem cells, and increased the platelet-repopulating capacity of transplanted hematopoietic stem cells. In addition to the hematopoietic effects, SAA induced loss of non-hematopoietic stromal populations, including podoplanin-positive stromal cells. However, a subset of podoplanin-positive macrophages was increased during disease, and blockade of podoplanin in mice was sufficient to rescue disease. Our data further our understanding of disease pathogenesis, demonstrating a novel role for macrophages as sensors of IFNγ, thus illustrating an important role for the microenvironment in the pathogenesis of SAA.Copyright© 2018 Ferrata Storti Foundation.
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Severe aplastic anemia (SAA) is an acquired, T cell-driven bone marrow (BM) failure disease characterized by elevated interferon gamma (IFNγ), loss of hematopoietic stem cells (HSCs), and altered BM microenvironment, including dysfunctional macrophages (MΦs). T lymphocytes are therapeutic targets for treating SAA, however, the underlying mechanisms driving SAA development and how innate immune cells contribute to disease remain poorly understood. In a murine model of SAA, increased beta-chemokines correlated with disease and were partially dependent on IFNγ. IFNγ was required for increased expression of the chemokine receptor CCR5 on MΦs. CCR5 antagonism in murine SAA improved survival, correlating with increased platelets and significantly increased platelet-biased CD41 HSCs. T cells are key drivers of disease, however, T cell-specific CCR5 expression and T cell-derived CCL5 were not necessary for disease. CCR5 antagonism reduced BM MΦs and diminished their expression of Tnf and Ccl5, correlating with reduced frequencies of IFNγ-secreting BM T cells. Mechanistically, CCR5 was intrinsically required for maintaining BM MΦs during SAA. Ccr5 expression was significantly increased in MΦs from aged mice and humans, relative to young counterparts. Our data identify CCR5 signaling as a key axis promoting the development of IFNγ-dependent BM failure, particularly relevant in aging where Ccr5 expression is elevated.
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PDF(2947 KB)
图1 SAA小鼠模型的体重与骨髓造血变化图2 SAA小鼠模型中CD4+/CD8+淋巴细胞亚群的变化图3 SAA小鼠模型CD4+和CD8+T细胞中CD44、CD62L的表达图4 SAA小鼠模型骨髓中巨噬细胞比例图5 SAA小鼠模型骨髓中巨噬细胞极化状态/
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