Complement peptide C3a receptor 1 promotes optic nerve degeneration in DBA/2J mice.
Complement peptide C3a receptor 1 promotes optic nerve degeneration in DBA/2J mice.
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DOI：
10.1186/s12974-020-02011-z
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发表时间：
2020-11-11
影响因子：
9.3
通讯作者：
Howell GR
中科院分区：
文献类型：
--
作者：
Harder JM;Williams PA;Braine CE;Yang HS;Thomas JM;Foxworth NE;John SWM;Howell GR
青光眼的风险随着年龄的增长和眼内压的升高而显著增加，这两个因素与神经炎症有关。补体级联是一个复杂的免疫过程，具有许多生物活性的终产物，包括炎症介质。补体级联激活已在青光眼患者和青光眼模型中显示。然而，补体介导的炎症在青光眼中的功能在很大程度上未经测试。在这里，补体肽C3 a受体1在DBA/2 J小鼠（青光眼的高眼压模型）中被遗传破坏，以测试其对神经变性的贡献。将C3 ar 1的无效等位基因回交到DBA/2 J小鼠中。在多个年龄段比较C3 ar 1缺陷和足够DBA/2 J小鼠中虹膜疾病、高眼压、视神经变性、视网膜神经节细胞活性、RGCs丢失和髓样细胞浸润的发展。对来自原代培养物的小胶质细胞进行RNA测序以确定C3 ar 1对小胶质细胞基因表达的总体影响。C3 ar 1缺乏降低了高眼压小鼠变性的风险，而不影响10.5月龄时的眼内压升高。在受影响的小鼠百分比中发现了差异，但在疾病进展的个体特征中没有发现差异。C3 ar 1缺乏的保护作用，然后克服了额外的老化和高眼压损伤。小胶质细胞和其他髓源性细胞是鉴定的表达C3 ar 1的主要细胞。在C3 ar 1的情况下，与神经炎症和其他免疫功能相关的基因的小胶质细胞表达与WT相比差异表达。对这些数据的网络分析表明，IL 10信号通路是小胶质细胞中C3 AR 1信号传导的主要相互作用伙伴。C3 AR 1是一种损伤性神经炎性因子。这些数据有助于表明补体激活通过多种机制（包括炎症）导致神经退行性疾病。小胶质细胞和浸润性骨髓细胞表达高水平的C3 ar 1，是介导其作用的主要候选者。C3 AR 1似乎是小胶质细胞反应性和神经炎性功能的主要调节剂，这是由于其与IL 10信号传导和其他免疫相关途径的相互作用。靶向骨髓源性细胞和C3 AR 1信号传导的治疗有望增加或改善神经保护性治疗策略。在线版本包含补充材料，可通过10.1186/s12974-020-02011-z获得。
The risk of glaucoma increases significantly with age and exposure to elevated intraocular pressure, two factors linked with neuroinflammation. The complement cascade is a complex immune process with many bioactive end-products, including mediators of inflammation. Complement cascade activation has been shown in glaucoma patients and models of glaucoma. However, the function of complement-mediated inflammation in glaucoma is largely untested. Here, the complement peptide C3a receptor 1 was genetically disrupted in DBA/2J mice, an ocular hypertensive model of glaucoma, to test its contribution to neurodegeneration. A null allele of C3ar1 was backcrossed into DBA/2J mice. Development of iris disease, ocular hypertension, optic nerve degeneration, retinal ganglion cell activity, loss of RGCs, and myeloid cell infiltration in C3ar1-deficient and sufficient DBA/2J mice were compared across multiple ages. RNA sequencing was performed on microglia from primary culture to determine global effects of C3ar1 on microglia gene expression. Deficiency in C3ar1 lowered the risk of degeneration in ocular hypertensive mice without affecting intraocular pressure elevation at 10.5 months of age. Differences were found in the percentage of mice affected, but not in individual characteristics of disease progression. The protective effect of C3ar1 deficiency was then overcome by additional aging and ocular hypertensive injury. Microglia and other myeloid-derived cells were the primary cells identified that express C3ar1. In the absence of C3ar1, microglial expression of genes associated with neuroinflammation and other immune functions were differentially expressed compared to WT. A network analysis of these data suggested that the IL10 signaling pathway is a major interaction partner of C3AR1 signaling in microglia. C3AR1 was identified as a damaging neuroinflammatory factor. These data help suggest complement activation causes glaucomatous neurodegeneration through multiple mechanisms, including inflammation. Microglia and infiltrating myeloid cells expressed high levels of C3ar1 and are the primary candidates to mediate its effects. C3AR1 appeared to be a major regulator of microglia reactivity and neuroinflammatory function due to its interaction with IL10 signaling and other immune related pathways. Targeting myeloid-derived cells and C3AR1 signaling with therapies is expected to add to or improve neuroprotective therapeutic strategies. The online version contains supplementary material available at 10.1186/s12974-020-02011-z.
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DOI：
10.1084/jem.181.1.151
发表时间：
1995-01-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Kim YU;Kinoshita T;Molina H;Hourcade D;Seya T;Wagner LM;Holers VM
通讯作者：
Holers VM
DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
32.4
作者：
Hammond, Timothy R.;Dufort, Connor;Stevens, Beth
通讯作者：
Stevens, Beth
DOI：
10.1073/pnas.1608769114
发表时间：
2017-05-09
影响因子：
11.1
作者：
Harder, Jeffrey M.;Braine, Catherine E.;John, Simon W. M.
通讯作者：
John, Simon W. M.
影响因子：
4.4
作者：
Chou, Tsung-Han;Bohorquez, Jorge;Porciatti, Vittorio
通讯作者：
Porciatti, Vittorio