Distinguishing the effects of systemic CSF1R inhibition by PLX3397 on microglia and peripheral immune cells.
Distinguishing the effects of systemic CSF1R inhibition by PLX3397 on microglia and peripheral immune cells.
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DOI：
10.1186/s12974-023-02924-5
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发表时间：
2023-10-21
影响因子：
9.3
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中科院分区：
文献类型：
--
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小胶质细胞是中枢神经系统 (CNS) 的主要免疫细胞，源自卵黄囊并在发育过程中填充在大脑中。一旦小胶质细胞迁移到中枢神经系统，它们就会自我更新，并需要 CSF1R 信号来维持。 Pexidartinib (PLX3397, PLX) 是一种 CSF1R 的小分子抑制剂，已被证明可以有效地消耗小胶质细胞，因为小胶质细胞的维持依赖于 CSF1R。然而，有一些相互矛盾的报告表明 PLX 对外周免疫细胞（尤其是淋巴来源的免疫细胞）具有潜在的脱靶效应。鉴于 PLX 系列药物使用中存在的争议，确定 PLX 在多大程度上影响淋巴（脾和骨髓）和非淋巴（肾、肺和心脏）器官的外周免疫特征变得非常重要。 PLX3397 660 mg/kg 饲料治疗 7 天显着降低了大脑中 CD45+ 巨噬细胞、CX3CR1-GFP 细胞、CD11b+CD45 中间细胞和 P2RY12 的表达。然而，除了心脏外，淋巴和非淋巴器官的外周免疫细胞受到的影响很小，心脏中的 CD3+ 细胞、炎症和巡逻单核细胞以及 CD11b+Ly6G+ 中性粒细胞显着减少。然后，我们用 1 毫克/公斤的 LPS 刺激免疫系统，导致先天免疫细胞数量显着减少。在这种情况下，PLX 并没有改变初始小鼠血清和大脑中的细胞因子谱，但在 LPS 刺激组中却改变了，导致 TNFα、IL-1α、IFN-γ 和 IL-1β 显着减少。此外，PLX 在旷场测试中没有改变运动活性，这表明小胶质细胞不会导致 LPS 诱导的疾病行为。我们的结果提供了对未接受 LPS 治疗和 LPS 治疗期间接受 PLX3397 治疗的大脑、淋巴和非淋巴器官的免疫细胞群的评估，这可以作为了解此类方法后果的资源。在线版本包含可在 10.1186/s12974-023-02924-5 获取的补充材料。
Microglia, the primary immune cells of the central nervous system (CNS), are derived from the yolk sac and populate the brain during development. Once microglia migrate to the CNS, they are self-renewing and require CSF1R signaling for their maintenance. Pexidartinib (PLX3397, PLX), a small molecule inhibitor of the CSF1R, has been shown to effectively deplete microglia since microglial maintenance is CSF1R-dependent. There have, however, been several conflicting reports that have shown the potential off-target effects of PLX on peripheral immune cells particularly those of lymphoid origin. Given this controversy in the use of the PLX family of drugs, it has become important to ascertain to what extent PLX affects the peripheral immune profile in lymphoid (spleen, and bone marrow) and non-lymphoid (kidney, lungs, and heart) organs. PLX3397 chow treatment at 660 mg/kg for 7 days significantly reduced CD45+ macrophages, CX3CR1-GFP cells, CD11b+CD45intermediate cells, and P2RY12 expression in the brain. However, there were minimal effects on peripheral immune cells from both lymphoid and non-lymphoid organs except in the heart where there was a significant decrease in CD3+ cells, inflammatory and patrolling monocytes, and CD11b+Ly6G+ neutrophils. We then stimulated the immune system with 1 mg/kg of LPS which resulted in a significant reduction in the number of innate immune cells. In this context, PLX did not alter the cytokine profile in the serum and the brain of naïve mice but did so in the LPS-stimulated group resulting in a significant reduction in TNFα, IL-1α, IFN-γ and IL-1β. Furthermore, PLX did not alter locomotor activity in the open field test suggesting that microglia do not contribute to LPS-induced sickness behavior. Our results provide an assessment of immune cell populations with PLX3397 treatment on brain, lymphoid and non-lymphoid organs without and during LPS treatment that can serve as a resource for understanding consequences of such approaches. The online version contains supplementary material available at 10.1186/s12974-023-02924-5.
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影响因子：
4.6
作者：
Biesmans S;Meert TF;Bouwknecht JA;Acton PD;Davoodi N;De Haes P;Kuijlaars J;Langlois X;Matthews LJ;Ver Donck L;Hellings N;Nuydens R
通讯作者：
Nuydens R
影响因子：
20.3
作者：
Fantin, Alessandro;Vieira, Joaquim M.;Ruhrberg, Christiana
通讯作者：
Ruhrberg, Christiana
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：
25
作者：
Davalos, D;Grutzendler, J;Gan, WB
通讯作者：
Gan, WB
影响因子：
7.1
作者：
Han J;Sarlus H;Wszolek ZK;Karrenbauer VD;Harris RA
通讯作者：
Harris RA