CSF-1 maintains pathogenic but not homeostatic myeloid cells in the central nervous system during autoimmune neuroinflammation.
CSF-1 maintains pathogenic but not homeostatic myeloid cells in the central nervous system during autoimmune neuroinflammation.
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DOI：
10.1073/pnas.2111804119
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发表时间：
2022-04-05
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
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作者：
多发性硬化（MS）及其动物模型实验性自身免疫性脑脊髓炎（EAE）是以中枢神经系统（CNS）中髓样细胞积聚为特征的自身免疫性疾病。有害和有益的骨髓细胞都存在于EAE/MS中，MS治疗的目标是优先去除有害的骨髓细胞。CSF-1受体（CSF-1 R）存在于骨髓细胞上，对它们的存活很重要。CSF-1 R可以结合两种配体CSF-1和IL-34，但尚不清楚它们在EAE/MS中的功能是否不同。我们发现，阻断CSF-1只消耗CNS中有害的髓系细胞并抑制EAE，而阻断IL-34则没有效果。因此，我们建议，阻断CSF-1可能是MS的治疗。集落刺激因子1（CSF-1 R）的受体是重要的，在实验性自身免疫性脑脊髓炎（EAE），多发性硬化症（MS）的动物模型，介导病理髓样细胞的生存和功能。CSF-1 R的配体CSF-1和IL-34具有相似的生物活性，但具有不同的组织和环境依赖性表达模式，表明它们具有不同的作用。这可能是EAE的情况，因为CSF-1表达在CNS中上调，而IL-34保持组成型表达。我们发现，用中和抗体靶向CSF-1阻止了正在进行的EAE，其功效上级于CSF-1 R抑制剂BLZ 945，而IL-34中和没有效果，表明致病性骨髓细胞由CSF-1维持。抗CSF-1和BLZ 945处理均大大减少了CNS中单核细胞衍生的细胞和小胶质细胞的数量。然而，抗CSF-1选择性地耗尽发炎CNS区域中的炎性小胶质细胞和单核细胞，而BLZ 945几乎耗尽整个CNS中的所有髓样细胞，包括静止的小胶质细胞。抗CSF-1治疗减少了灰质中脱髓鞘病变和小胶质细胞活化的大小。最后，我们发现骨髓源性免疫细胞是CSF-1 R依赖性病理学的主要介质，而小胶质细胞发挥较小的作用。我们的研究结果表明，靶向CSF-1可以有效改善MS病理，同时保持骨髓细胞的稳态功能，从而最大限度地减少与CSF-1 R依赖性细胞消融相关的风险。
Multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), are autoimmune diseases characterized by accumulation of myeloid cells in the central nervous system (CNS). Both harmful and beneficial myeloid cells are present in EAE/MS, and a goal of MS therapy is to preferentially remove harmful myeloid cells. The receptor for CSF-1 (CSF-1R) is found on myeloid cells and is important for their survival. CSF-1R can bind two ligands, CSF-1 and IL-34, but it is not known whether their functions in EAE/MS differ. We found that blocking CSF-1 depleted only harmful myeloid cells in the CNS and suppressed EAE, whereas blocking IL-34 had no effect. Thus, we propose that blocking CSF-1 could be a therapy for MS. The receptor for colony stimulating factor 1 (CSF-1R) is important for the survival and function of myeloid cells that mediate pathology during experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). CSF-1 and IL-34, the ligands of CSF-1R, have similar bioactivities but distinct tissue and context-dependent expression patterns, suggesting that they have different roles. This could be the case in EAE, given that CSF-1 expression is up-regulated in the CNS, while IL-34 remains constitutively expressed. We found that targeting CSF-1 with neutralizing antibody halted ongoing EAE, with efficacy superior to CSF-1R inhibitor BLZ945, whereas IL-34 neutralization had no effect, suggesting that pathogenic myeloid cells were maintained by CSF-1. Both anti–CSF-1 and BLZ945 treatment greatly reduced the number of monocyte-derived cells and microglia in the CNS. However, anti–CSF-1 selectively depleted inflammatory microglia and monocytes in inflamed CNS areas, whereas BLZ945 depleted virtually all myeloid cells, including quiescent microglia, throughout the CNS. Anti–CSF-1 treatment reduced the size of demyelinated lesions and microglial activation in the gray matter. Lastly, we found that bone marrow–derived immune cells were the major mediators of CSF-1R–dependent pathology, while microglia played a lesser role. Our findings suggest that targeting CSF-1 could be effective in ameliorating MS pathology, while preserving the homeostatic functions of myeloid cells, thereby minimizing risks associated with ablation of CSF-1R–dependent cells.
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DOI：
10.1073/pnas.1205858109
发表时间：
2012-09-11
影响因子：
11.1
作者：
Capotondo, Alessia;Milazzo, Rita;Biffi, Alessandra
通讯作者：
Biffi, Alessandra
影响因子：
32.4
作者：
Croxford, Andrew L.;Lanzinger, Margit;Becher, Burkhard
通讯作者：
Becher, Burkhard
影响因子：
10.9
作者：
Cannarile MA;Weisser M;Jacob W;Jegg AM;Ries CH;Rüttinger D
通讯作者：
Rüttinger D
影响因子：
15.9
作者：
Giles, David A.;Duncker, Patrick C.;Segal, Benjamin M.
通讯作者：
Segal, Benjamin M.
多发性硬化症：实验模型和现实。
影响因子：
12.7
作者：
Lassmann H;Bradl M
通讯作者：
Bradl M