Structural and functional distinctions of co-resident microglia and monocyte-derived macrophages after retinal degeneration.
Structural and functional distinctions of co-resident microglia and monocyte-derived macrophages after retinal degeneration.
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DOI：
10.1186/s12974-022-02652-2
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发表时间：
2022-12-12
影响因子：
9.3
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中科院分区：
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驻留的小胶质细胞和入侵的外周免疫细胞都可以对中枢神经系统的损伤和退化做出反应。然而，在死亡和垂死的神经元被清除并重新建立稳态后，尚不清楚常驻免疫细胞是否完全恢复正常功能以及外周免疫细胞驻留的程度。 使用流式细胞术、体内视网膜成像、免疫组织化学和单细胞 mRNA 测序，我们评估了诱导变性的 Arr1−/− 小鼠模型中光感受器丧失期间和之后视网膜中驻留的小胶质细胞和单核细胞衍生的巨噬细胞。 我们发现光感受器损失导致单核吞噬细胞小幅持续增加，并且在退化减弱后，这些细胞重新建立了让人想起健康视网膜的空间镶嵌。转录组分析显示，该群体仍然存在异常异质性，其中几个亚群表达的基因模式与轻度激活的表型一致。大约三分之一的“新常驻”细胞表达传统上与小胶质细胞和单核细胞谱系相关的标记物，这使得它们的病因学不明确。使用基于Cre的诱导型荧光谱系追踪范例来确认新常驻免疫细胞的起源，我们发现在退化消退后，小胶质细胞和单核细胞衍生的巨噬细胞数量大致相等。体内视网膜成像和免疫组织化学分析表明，这两个亚群仍然对局部损伤部位有功能反应，尽管平均而言，单核细胞衍生的细胞比本地常驻群体具有较低的形态复杂性，表达更高水平的 MHCII，并且具有较低的迁移活动。在变性过程中浸润视网膜的单核细胞分化为单核细胞衍生的巨噬细胞，可以长期保留在视网膜中。这些单核细胞衍生的巨噬细胞采用分支形态和小胶质细胞样基因表达。然而，它们在形态和基因表达方面仍然与常驻小胶质细胞不同，并且在功能上似乎有所不同，对随后的视网膜损伤表现出较低的反应性。这些发现支持这样的观点，即由于衰老和进行性视网膜疾病中的细胞损失而发生的局部免疫群体的持续变化可能包括骨髓来源细胞亚群的建立，这些细胞亚群对随后的损伤的反应能力随着时间的推移而减弱。在线版本包含可在 10.1186/s12974-022-02652-2 获取的补充材料。
Both resident microglia and invading peripheral immune cells can respond to injury and degeneration in the central nervous system. However, after dead and dying neurons have been cleared and homeostasis is re-established, it is unknown whether resident immune cells fully resume normal functions and to what degree the peripheral immune cells take up residence. Using flow cytometry, in vivo retinal imaging, immunohistochemistry, and single-cell mRNA sequencing, we assess resident microglia and monocyte-derived macrophages in the retina during and after the loss of photoreceptors in the Arr1−/− mouse model of inducible degeneration. We find that photoreceptor loss results in a small, sustained increase in mononuclear phagocytes and, after degeneration wanes, these cells re-establish a spatial mosaic reminiscent of healthy retinas. Transcriptomic analysis revealed the population remained unusually heterogeneous, with several subpopulations expressing gene patterns consistent with mildly activated phenotypes. Roughly a third of “new resident” cells expressed markers traditionally associated with both microglial and monocytic lineages, making their etiology ambiguous. Using an inducible Cre-based fluorescent lineage tracing paradigm to confirm the origins of new resident immune cells, we found approximately equal numbers of microglia and monocyte-derived macrophages after degeneration had subsided. In vivo retinal imaging and immunohistochemical analysis showed that both subpopulations remained functionally responsive to sites of local damage, though on average the monocyte-derived cells had less morphological complexity, expressed higher levels of MHCII, and had less migratory activity than the native resident population. Monocytic cells that infiltrate the retina during degeneration differentiate into monocyte-derived macrophages that can remain in the retina long-term. These monocyte-derived macrophages adopt ramified morphologies and microglia-like gene expression. However, they remain distinguishable in morphology and gene expression from resident microglia and appear to differ functionally, showing less responsiveness to subsequent retinal injuries. These findings support the idea that persistent changes in the local immune population that occur in response to cell loss in aging and progressive retinal diseases may include the establishment of subpopulations of bone marrow-derived cells whose ability to respond to subsequent insults wanes over time. The online version contains supplementary material available at 10.1186/s12974-022-02652-2.
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影响因子：
1.8
作者：
Levine, Emily S.;Zam, Azhar;Zhang, Pengfei;Pechko, Alina;Wang, Xinlei;FitzGerald, Paul;Pugh, Edward N., Jr.;Zawadzki, Robert J.;Burns, Marie E.
通讯作者：
Burns, Marie E.
影响因子：
5.3
作者：
Jung, S;Aliberti, J;Littman, DR
通讯作者：
Littman, DR
影响因子：
4.6
作者：
Ronning, Kaitryn E.;Kaden, Sarah J.;Burns, Marie E.
通讯作者：
Burns, Marie E.
影响因子：
25
作者：
Madisen L;Zwingman TA;Sunkin SM;Oh SW;Zariwala HA;Gu H;Ng LL;Palmiter RD;Hawrylycz MJ;Jones AR;Lein ES;Zeng H
通讯作者：
Zeng H
DOI：
10.1073/pnas.1807123115
发表时间：
2018-11-27
影响因子：
11.1
作者：
Paschalis EI;Lei F;Zhou C;Kapoulea V;Dana R;Chodosh J;Vavvas DG;Dohlman CH
通讯作者：
Dohlman CH