Bone marrow brews central nervous system inflammation and autoimmunity

医学 炎症 骨髓 髓样 祖细胞 造血 干细胞 获得性免疫系统 免疫学 病理 生物 免疫系统 细胞生物学
作者
Mingming Liu,Qiang Liu
出处
期刊:Clinical and translational medicine [Springer Science+Business Media]
卷期号:12 (11) 被引量:2
标识
DOI:10.1002/ctm2.1125
摘要

Multiple sclerosis (MS) is a T-cell-mediated chronic inflammatory disease of the central nervous system (CNS) that manifests in young adults as a predominant cause of severe neurological disability, which imposes a heavy economic and psychological burden on the patient's family.1 Currently, there are many shortcomings in the efficacy of drugs to control the progression of the disease. These unmet clinical needs stem from incompletely understood immune mechanisms of MS. Past research on autoreactive T cells in MS patients has been limited to blood and cerebrospinal fluid.2 Of note, the location and factors that determine the initiation and evolution of autoreactive T cells, and the impact of these factors on the progression of MS disease, are still poorly understood. Bone marrow harbours haematopoietic stem and progenitor cells (HSPCs) that give rise to all immune cell types.3 Recent evidence has demonstrated the skull and vertebral bone marrow as a key reservoir of myeloid cells and lymphocytes for the meninges and CNS parenchyma.4, 5 These findings are partially supported by a previous study showing skull bone marrow and the brain surface are connected by direct vascular channels that enable myeloid cell migration into brain.6 Emerging evidence indicates that infectious or inflammatory stimuli induces adaptation of bone marrow HSPCs, leading to an increase in the output of myeloid cells by activation of lineage-specific transcription factors.7 These observations suggest a potential link between the activation of bone marrow HSPCs and the co-operation between the innate and adaptive immunity, raising several interesting questions particularly including whether this occurs in patients with chronic inflammatory diseases and its impact on disease outcome.8 The aetiology of MS is focused on myelin-reactive T cells that infiltrate the CNS to cause demyelinating lesions.9 One recently study coupled single cell sequencing and flow cytometry analysis of bone marrow HSPCs and their downstream cellular lineages in MS patients.8 The authors found that bone marrow HSPCs were predominantly skewed towards myeloid lineage concomitant with an increase of transcription factors in myeloid lineage but not lymphoid lineage. This finding is unexpected because MS is thought to be a T-cell-mediated autoimmune CNS inflammatory disease and the alterations in bone marrow myeloid cells have not been comprehensively depicted. Notably, the augmented myelopoiesis in bone marrow of MS patients was accompanied by enhanced clonal expansion of T cells. These and other observations led the authors to conclude that bone marrow HSPCs can sense and adapt to systemic immune activation in MS patients, a process that drives CNS inflammation and autoimmunity. To determine the fate of HSPCs and their downstream cellular lineages, the authors mirrored these observations in experimental autoimmune encephalomyelitis, a mouse model of MS. Lineage tracing revealed that increased bone marrow myelopoiesis led to augmented output of monocytes and neutrophils that subsequently invaded the CNS. Of interest, they showed that myelin-reactive T cells migrated into the bone marrow compartment in a CXCL12-CXCR4 dependent manner. Subsequently, the myelin-reactive T cells highly expressed CCL5, which resulted in bone marrow myelopoiesis in a CCL5-CCR5 axis dependent manner (Figure 1). The aberrant bone marrow myelopoiesis was ablated in bone marrow chimeric mice reconstituted with CCR5−/- HSCs or wild type mice receiving a CCR5 inhibitor, suggesting a detrimental role of CCL5-CCR5 axis in myelopoiesis that drives CNS inflammation and demyelination.8 These findings extend the previous understanding of autoreactive T cells within lymph organs and CNS into bone marrow in MS, implicating bone marrow as a treatment target to reset and correct the aberrant immune response leading to CNS autoimmunity in MS. This notion is supported by results from clinical trials, in which autologous haematopoietic stem cell transplantation, i.e. bone marrow transplantation, can arrest neurological deterioration and prolong medication-free interval in patients with aggressive MS.10 Given that immune suppressant drugs to treat MS often have side effects of suppressing myelopoiesis, it seems plausible to speculate that the reduced myelopoiesis may actually contribute to the benefit of these medications. Future investigations are required to identify possible therapies targeting bone marrow to restore immune homeostasis, and thus to control CNS autoimmune neuroinflammation. This work was supported in part by National Science Foundation of China (82171284, 82200279), National Key Research and Development Project of China (2021ZD0202400), Science and Technology Development Fund of Tianjin Education Commission for higher Education grant (2021ZD035) and Tianjin Key Medical Discipline (Specialty) Construction Project. The authors declare no competing interests exist.
最长约 10秒,即可获得该文献文件

科研通智能强力驱动
Strongly Powered by AbleSci AI
更新
PDF的下载单位、IP信息已删除 (2025-6-4)

科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
顾矜应助赵三岁采纳,获得10
1秒前
yyy2025完成签到,获得积分10
5秒前
木雨亦潇潇完成签到,获得积分10
12秒前
香蕉觅云应助nine2652采纳,获得10
14秒前
量子星尘发布了新的文献求助10
18秒前
芳华如梦完成签到 ,获得积分10
20秒前
20秒前
21秒前
21秒前
土豆丝完成签到 ,获得积分10
21秒前
琦琦完成签到,获得积分10
30秒前
zzzz完成签到,获得积分20
35秒前
GEZIKU完成签到 ,获得积分10
36秒前
43秒前
50秒前
赵三岁发布了新的文献求助10
57秒前
wwb完成签到,获得积分10
1分钟前
1分钟前
1分钟前
肯德基没有黄焖鸡完成签到 ,获得积分10
1分钟前
能干冰露完成签到,获得积分10
1分钟前
牛奶拌可乐完成签到 ,获得积分10
1分钟前
量子星尘发布了新的文献求助30
1分钟前
周小鱼完成签到 ,获得积分10
1分钟前
1分钟前
1分钟前
老张完成签到,获得积分10
1分钟前
1分钟前
zhugao完成签到,获得积分10
1分钟前
1分钟前
南风知我意完成签到,获得积分10
1分钟前
朴实寻琴完成签到 ,获得积分10
1分钟前
可可可爱完成签到 ,获得积分10
1分钟前
lsy完成签到,获得积分10
1分钟前
量子星尘发布了新的文献求助10
1分钟前
1分钟前
1分钟前
hwen1998完成签到 ,获得积分10
1分钟前
1分钟前
1分钟前
高分求助中
【提示信息,请勿应助】关于scihub 10000
Les Mantodea de Guyane: Insecta, Polyneoptera [The Mantids of French Guiana] 3000
徐淮辽南地区新元古代叠层石及生物地层 3000
The Mother of All Tableaux: Order, Equivalence, and Geometry in the Large-scale Structure of Optimality Theory 3000
Handbook of Industrial Diamonds.Vol2 1100
Global Eyelash Assessment scale (GEA) 1000
Picture Books with Same-sex Parented Families: Unintentional Censorship 550
热门求助领域 (近24小时)
化学 材料科学 医学 生物 工程类 有机化学 生物化学 物理 内科学 纳米技术 计算机科学 化学工程 复合材料 遗传学 基因 物理化学 催化作用 冶金 细胞生物学 免疫学
热门帖子
关注 科研通微信公众号,转发送积分 4038029
求助须知:如何正确求助?哪些是违规求助? 3575740
关于积分的说明 11373751
捐赠科研通 3305559
什么是DOI,文献DOI怎么找? 1819224
邀请新用户注册赠送积分活动 892652
科研通“疑难数据库(出版商)”最低求助积分说明 815022