Age-dependent Microglial Disease Phenotype Results in Functional Decline in Gut Macrophages.
Age-dependent Microglial Disease Phenotype Results in Functional Decline in Gut Macrophages.
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DOI：
10.1016/j.gastha.2022.09.006
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Becker, Laren
中科院分区：
文献类型：
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作者：
Bishop, Estelle Spear;Namkoong, Hong;Aurelian, Laure;McCarthy, Madison;Nallagatla, Pratima;Zhou, Wenyu;Neshatian, Leila;Gurland, Brooke;Habtezion, Aida;Becker, Laren
肌层巨噬细胞（MMs）是肠道肌层外的组织驻留巨噬细胞，对肠神经系统起支持作用。我们先前已表明，年龄相关的MM改变会引发低度肠神经系统炎症，导致神经元缺失和肠道蠕动紊乱。当前的研究旨在确定与这些变化相关的MM基因特征，尤其着重于与小胶质细胞（参与年龄相关认知衰退的中枢神经系统巨噬细胞群）中的基因进行比较。
对年轻（3个月）和年老（16 - 24个月）的C57BL/6小鼠以及人体组织进行了研究。将小鼠小肠、结肠和脊髓以及人结肠的免疫细胞分离，通过流式细胞术进行免疫表型分析，并通过单细胞RNA测序和实时定量PCR检测基因表达。通过体内注射pHrodo beads（Invitrogen）评估吞噬作用。通过对肌层整体标本进行免疫染色来计算巨噬细胞数量。
年轻和年老小鼠的MMs表达稳态小胶质细胞基因，包括Gpr34、C1qc、Trem2和P2ry12。随着年龄增长而数量增多的一个MM亚群呈现出一种老年状态（GS）表型，其特征是疾病相关小胶质细胞基因表达增加，包括Cd9、Clec7a、Itgax（CD11c）、Bhlhe40、Lgals3、IL - 1β和Trem2，且吞噬活性降低。GS表型的获得与α - 突触核蛋白聚集体的清除有关。人类MMs表现出类似的与年龄相关的GS表型获得，且伴有细胞内α - 突触核蛋白的积累。
MMs呈现出与年龄相关的基因变化，这些变化反映了小胶质细胞疾病相关的小胶质细胞表型，并导致功能下降。
Muscularis macrophages (MMs) are tissue-resident macrophages in the gut muscularis externa which play a supportive role to the enteric nervous system. We have previously shown that age-dependent MM alterations drive low-grade enteric nervous system inflammation, resulting in neuronal loss and disruption of gut motility. The current studies were designed to identify the MM genetic signature involved in these changes, with particular emphasis on comparison to genes in microglia, the central nervous system macrophage population involved in age-dependent cognitive decline. Young (3 months) and old (16–24 months) C57BL/6 mice and human tissue were studied. Immune cells from mouse small intestine, colon, and spinal cord and human colon were dissociated, immunophenotyped by flow cytometry, and examined for gene expression by single-cell RNA sequencing and quantitative real-time PCR. Phagocytosis was assessed by in vivo injections of pHrodo beads (Invitrogen). Macrophage counts were performed by immunostaining of muscularis whole mounts. MMs from young and old mice express homeostatic microglial genes, including Gpr34, C1qc, Trem2, and P2ry12. An MM subpopulation that becomes more abundant with age assumes a geriatric state (GS) phenotype characterized by increased expression of disease-associated microglia genes including Cd9, Clec7a, Itgax (CD11c), Bhlhe40, Lgals3, IL-1β, and Trem2 and diminished phagocytic activity. Acquisition of the GS phenotype is associated with clearance of α-synuclein aggregates. Human MMs demonstrate a similar age-dependent acquisition of the GS phenotype associated with intracellular α-synuclein accumulation. MMs demonstrate age-dependent genetic changes that mirror the microglial disease-associated microglia phenotype and result in functional decline.