JAK1/2 Regulates Synergy Between Interferon Gamma and Lipopolysaccharides in Microglia

IF 5.2 3区 医学 Q1 NEUROSCIENCES Journal of Neuroimmune Pharmacology Pub Date : 2024-04-20 DOI:10.1007/s11481-024-10115-z
Alexander P. Young, Eileen M. Denovan-Wright
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Abstract

Microglia, the resident immune cells of the brain, regulate neuroinflammation which can lead to secondary neuronal damage and cognitive impairment under pathological conditions. Two of the many molecules that can elicit an inflammatory response from microglia are lipopolysaccharide (LPS), a component of gram-negative bacteria, and interferon gamma (IFNγ), an endogenous pro-inflammatory cytokine. We thoroughly examined the concentration-dependent relationship between LPS from multiple bacterial species and IFNγ in cultured microglia and macrophages. We measured the effects that these immunostimulatory molecules have on pro-inflammatory activity of microglia and used a battery of signaling inhibitors to identify the pathways that contribute to the microglial response. We found that LPS and IFNγ interacted synergistically to induce a pro-inflammatory phenotype in microglia, and that inhibition of JAK1/2 completely blunted the response. We determined that this synergistic action of LPS and IFNγ was likely dependent on JNK and Akt signaling rather than typical pro-inflammatory mediators such as NF-κB. Finally, we demonstrated that LPS derived from Escherichia coli, Klebsiella pneumoniae, and Akkermansia muciniphila can elicit different inflammatory responses from microglia and macrophages, but these responses could be consistently prevented using ruxolitinib, a JAK1/2 inhibitor. Collectively, this work reveals a mechanism by which microglia may become hyperactivated in response to the combination of LPS and IFNγ. Given that elevations in circulating LPS and IFNγ occur in a wide variety of pathological conditions, it is critical to understand the pharmacological interactions between these molecules to develop safe and effective treatments to suppress this process.

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JAK1/2调控小胶质细胞中γ干扰素与脂多糖之间的协同作用
小胶质细胞是大脑的常驻免疫细胞,可调节神经炎症,在病理条件下可导致继发性神经元损伤和认知障碍。在能引起小胶质细胞炎症反应的众多分子中,有两种分子是脂多糖(LPS)和γ干扰素(IFNγ),前者是革兰氏阴性细菌的一种成分,后者是一种内源性促炎细胞因子。我们深入研究了培养小胶质细胞和巨噬细胞中多种细菌的 LPS 与 IFNγ 之间的浓度依赖关系。我们测量了这些免疫刺激分子对小胶质细胞促炎活性的影响,并使用一系列信号抑制剂来确定导致小胶质细胞反应的途径。我们发现,LPS 和 IFNγ 相互协同作用,诱导小胶质细胞产生促炎表型,而抑制 JAK1/2 则会完全减弱这种反应。我们确定 LPS 和 IFNγ 的这种协同作用可能依赖于 JNK 和 Akt 信号,而不是 NF-κB 等典型的促炎介质。最后,我们证明了来自大肠埃希菌、肺炎克雷伯氏菌和阿克曼粘菌的 LPS 可引起小胶质细胞和巨噬细胞的不同炎症反应,但使用 JAK1/2 抑制剂芦可替尼(ruxolitinib)可持续阻止这些反应。总之,这项研究揭示了小胶质细胞可能在 LPS 和 IFNγ 的共同作用下过度激活的机制。鉴于循环中LPS和IFNγ的升高发生在多种病理情况下,因此了解这些分子之间的药理相互作用对于开发安全有效的治疗方法来抑制这一过程至关重要。
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来源期刊
CiteScore
13.60
自引率
0.00%
发文量
18
审稿时长
6-12 weeks
期刊介绍: The aims of the Journal of Neuroimmune Pharmacology are to promote the dissemination, interest, and exchange of new and important discoveries for the pharmacology and immunology of the nervous system. The aims parallel that of the Society on NeuroImmune Pharmacology by increasing the fundamental understanding of neurologic and neuropsychiatric disorders affected by the immune system or vice versa and towards pharmacologic measures that lead, either to a better understanding of disease mechanisms, or by improving disease outcomes. The scope of JNIP includes all primary works and reviews into the etiology, prevention, and treatment of neuroimmune and nervous system diseases affected by disordered immunity. Original studies serving to define neuroimmune modulation of environmental or endogenous cues such as toxins and drugs of abuse, hormones, and cytokines are welcome. JNIP will serve as a reliable source of interdisciplinary information bridging the fields of pharmacology, immunology, and neuroscience.
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