Border-associated macrophages mediate the neuroinflammatory response in an alpha-synuclein model of Parkinson disease.
Border-associated macrophages mediate the neuroinflammatory response in an alpha-synuclein model of Parkinson disease.
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DOI：
10.1038/s41467-023-39060-w
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发表时间：
2023-06-26
影响因子：
16.6
通讯作者：
Harms, A. S.
中科院分区：
文献类型：
--
作者：
Schonhoff, A. M.;Figge, D. A.;Williams, G. P.;Jurkuvenaite, A.;Gallups, N. J.;Childers, G. M.;Webster, J. M.;Standaert, D. G.;Goldman, J. E.;Harms, A. S.
由于α-syn的积累导致的多巴胺能细胞损失是帕金森病发病机制的核心特征。由α-突触核蛋白特异性诱导的神经炎症已被证明会加剧神经变性，但中枢神经系统（CNS）驻留巨噬细胞在此过程中的作用仍不清楚。我们发现，CNS驻留巨噬细胞的特定亚群，边界相关巨噬细胞（BAM），在介导α-突触核蛋白相关神经炎症中发挥重要作用，这是由于它们作为启动CD 4 T细胞应答所必需的抗原呈递细胞的独特作用，而小胶质细胞上MHCII抗原呈递的丧失对神经炎症没有影响。此外，α-突触核蛋白表达导致边界相关巨噬细胞数量的增加和独特的损伤相关激活状态。通过单细胞RNA测序和耗竭实验的组合方法，我们发现边界相关巨噬细胞在免疫细胞募集、浸润和抗原呈递中发挥重要作用。此外，在死后PD脑中，在T细胞附近鉴定出边界相关巨噬细胞。这些结果表明，边界相关巨噬细胞通过其在协调α-突触核蛋白介导的神经炎症反应中的作用，在介导帕金森病发病机制中发挥作用。神经炎症机制与帕金森病有关。在这里，我们确定了边界相关巨噬细胞（BAM），作为通过II类抗原呈递和T细胞浸润的α-突触核蛋白介导的神经炎症反应的必要条件。
Dopaminergic cell loss due to the accumulation of α-syn is a core feature of the pathogenesis of Parkinson disease. Neuroinflammation specifically induced by α-synuclein has been shown to exacerbate neurodegeneration, yet the role of central nervous system (CNS) resident macrophages in this process remains unclear. We found that a specific subset of CNS resident macrophages, border-associated macrophages (BAMs), play an essential role in mediating α-synuclein related neuroinflammation due to their unique role as the antigen presenting cells necessary to initiate a CD4 T cell response whereas the loss of MHCII antigen presentation on microglia had no effect on neuroinflammation. Furthermore, α-synuclein expression led to an expansion in border-associated macrophage numbers and a unique damage-associated activation state. Through a combinatorial approach of single-cell RNA sequencing and depletion experiments, we found that border-associated macrophages played an essential role in immune cell recruitment, infiltration, and antigen presentation. Furthermore, border-associated macrophages were identified in post-mortem PD brain in close proximity to T cells. These results point to a role for border-associated macrophages in mediating the pathogenesis of Parkinson disease through their role in the orchestration of the α-synuclein-mediated neuroinflammatory response. Neuroinflammatory mechanisms are implicated in Parkinson disease. Here we identify border-associated macrophages (BAMs), as essential for the α-synuclein-mediated neuroinflammatory response via class II antigen presentation, and T cell infiltration.
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影响因子：
30.5
作者：
Goldmann T;Wieghofer P;Jordão MJ;Prutek F;Hagemeyer N;Frenzel K;Amann L;Staszewski O;Kierdorf K;Krueger M;Locatelli G;Hochgerner H;Zeiser R;Epelman S;Geissmann F;Priller J;Rossi FM;Bechmann I;Kerschensteiner M;Linnarsson S;Jung S;Prinz M
通讯作者：
Prinz M
影响因子：
32.4
作者：
Hammond, Timothy R.;Dufort, Connor;Stevens, Beth
通讯作者：
Stevens, Beth
影响因子：
15.9
作者：
Brochard, Vanessa;Combadiere, Behazine;Hunot, Stephane
通讯作者：
Hunot, Stephane
影响因子：
5.3
作者：
Harms AS;Thome AD;Yan Z;Schonhoff AM;Williams GP;Li X;Liu Y;Qin H;Benveniste EN;Standaert DG
通讯作者：
Standaert DG
影响因子：
32.4
作者：
Mrdjen, Dunja;Pavlovic, Anto;Becher, Burkhard
通讯作者：
Becher, Burkhard