Microglia-derived ADAM9 promote GHRH neurons pyroptosis by Mad2L2-JNK-caspase-1 pathway in subarachnoid hemorrhage.

IF 9.3 1区医学 Q1 IMMUNOLOGY Journal of Neuroinflammation Pub Date : 2024-11-19 DOI:10.1186/s12974-024-03299-x

Jian Mao, Yun Bao, Fan Liu, Qiyun Ye, Junxiang Peng, Jing Nie, Lijun Huang, Yonghong Liao, Yiheng Xing, Dongyang Wu, Ke Wang, Wenfeng Feng, Songtao Qi, Jun Pan, Binghui Qiu

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Abstract

The incidence of growth hormone deficiency (GHD) after subarachnoid hemorrhage (SAH) is significantly higher than that of other neuroendocrine disorders, but the mechanism is still elusive. We used mass spectrometry to identify differentially expressed proteins in cerebrospinal fluid samples from a well-characterized cohort of patients. A total of 683 proteins were identified, including 39 upregulated proteins in the GHD group. ADAM9 was most highly associated with GHD. In vivo, ADAM9 colocalized with M1 microglia markers, GH and cognitive ability of mice decreased significantly, and microglia secreted ADAM9 significantly. ADAM9 regulates pyroptosis of GHRH neurons by the Mad2L2-JNK-caspase-1 pathway. Sorafenib inhibits ADAM9 secretion by microglia and improves GH levels and the cognitive ability of mice. This study found that the crosstalk between GHRH neurons and neuroglial cells in the hypothalamic arcuate nucleus, i.e., microglia, is an essential factor in the formation of GHD in SAH. We propose that neutralization of ADAM9 production by microglia might be a potential therapy for GHD after SAH.

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在蛛网膜下腔出血中，源于小胶质细胞的ADAM9通过Mad2L2-JNK-caspase-1途径促进GHRH神经元的热解。

蛛网膜下腔出血（SAH）后生长激素缺乏症（GHD）的发病率明显高于其他神经内分泌疾病，但其发病机制仍难以捉摸。我们使用质谱技术鉴定了一组特征明确的患者脑脊液样本中差异表达的蛋白质。共鉴定出 683 种蛋白质，其中包括 39 种在 GHD 组中上调的蛋白质。ADAM9与GHD的关联度最高。在体内，ADAM9与M1小胶质细胞标志物共定位，小鼠的GH和认知能力显著下降，小胶质细胞显著分泌ADAM9。ADAM9通过Mad2L2-JNK-caspase-1通路调节GHRH神经元的热凋亡。索拉非尼可抑制小胶质细胞分泌 ADAM9，从而改善小鼠的 GH 水平和认知能力。这项研究发现，GHRH 神经元与下丘脑弓状核中的神经胶质细胞（即小胶质细胞）之间的串扰是 SAH 患者 GHD 形成的重要因素。我们认为，中和小胶质细胞产生的 ADAM9 可能是治疗 SAH 后 GHD 的一种潜在疗法。

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来源期刊

Journal of Neuroinflammation 医学-神经科学

CiteScore

15.90

自引率

3.20%

发文量

276

审稿时长

1 months

期刊介绍： The Journal of Neuroinflammation is a peer-reviewed, open access publication that emphasizes the interaction between the immune system, particularly the innate immune system, and the nervous system. It covers various aspects, including the involvement of CNS immune mediators like microglia and astrocytes, the cytokines and chemokines they produce, and the influence of peripheral neuro-immune interactions, T cells, monocytes, complement proteins, acute phase proteins, oxidative injury, and related molecular processes. Neuroinflammation is a rapidly expanding field that has significantly enhanced our knowledge of chronic neurological diseases. It attracts researchers from diverse disciplines such as pathology, biochemistry, molecular biology, genetics, clinical medicine, and epidemiology. Substantial contributions to this field have been made through studies involving populations, patients, postmortem tissues, animal models, and in vitro systems. The Journal of Neuroinflammation consolidates research that centers around common pathogenic processes. It serves as a platform for integrative reviews and commentaries in this field.