慢性IFNα治疗诱导白细胞生成,血浆琥珀酸增加和免疫细胞代谢重接线

IF 3.7 4区 医学 Q2 CELL BIOLOGY Cellular immunology Pub Date : 2023-08-01 DOI:10.1016/j.cellimm.2023.104741
Anjali S. Yennemadi , Gráinne Jameson , Mary Glass , Carolina De Pasquale , Joseph Keane , Massimiliano Bianchi , Gina Leisching
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引用次数: 0

摘要

尽管临床上有效,IFNα的作用,无论是内源性还是通过治疗性递送,仍然知之甚少。这一研究差距的标志是易感个体出现的一系列不同的显著副作用,如神经精神后果、自身免疫现象和感染并发症。我们假设这些并发症至少部分是由细胞代谢失调引起的。雄性Wistar大鼠每周用170000IU/kg人重组IFNα-2a或BSA/生理盐水(0.9%NaCl)处理三次,持续三周。从切除的股骨中分离骨髓(BM)免疫细胞,使用安捷伦海马技术进行糖酵解速率和线粒体功能评估。通过流式细胞术评估免疫细胞群的频率,以确定血液和骨髓中是否发生了白细胞生成变化。还测定了血浆乳酸和琥珀酸的水平。BMDM如上所述进行代谢评估,以及它们对抗原刺激(iH37Rv)的代谢反应。我们观察到,来自IFN处理的大鼠的BM免疫细胞表现出高代谢状态(基础OCR/GlycoPER增加),线粒体代谢呼吸减少,非线粒体OCR增加。流式细胞术结果显示,血液中未成熟粒细胞(RP1-SSChi CD45lo)增加,血浆中琥珀酸盐水平增加。来自IFN处理的大鼠的BMDM在分化后保留了高代谢表型,并且在细菌刺激后未能诱导糖酵解和线粒体呼吸的增加。这项工作首次证明了IFNα治疗在诱导与炎症、白细胞生成和对细菌刺激的缺陷反应相关的高代谢免疫特征方面的作用。
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Chronic IFNα treatment induces leukopoiesis, increased plasma succinate and immune cell metabolic rewiring

Although clinically effective, the actions of IFNα, either produced endogenously or by therapeutic delivery, remain poorly understood. Emblematic of this research gap is the disparate array of notable side effects that occur in susceptible individuals, such as neuropsychiatric consequences, autoimmune phenomena, and infectious complications. We hypothesised that these complications are driven at least in part by dysregulated cellular metabolism. Male Wistar rats were treated with either 170,000 IU/kg human recombinant IFNα-2a or BSA/saline (0.9% NaCl) three times per week for three weeks. Bone marrow (BM) immune cells were isolated from the excised femurs for glycolytic rate and mitochondrial function assessment using Agilent Seahorse Technology. Frequencies of immune cell populations were assessed by flow cytometry to determine whether leukopoietic changes had occurred in both blood and BM. Plasma levels of lactate and succinate were also determined. BMDMs were metabolically assessed as above, as well as their metabolic response to an antigenic stimulus (iH37Rv). We observed that BM immune cells from IFN-treated rats exhibit a hypermetabolic state (increased basal OCR/GlycoPER) with decreased mitochondrial metabolic respiration and increased non-mitochondrial OCR. Flow cytometry results indicated an increase in immature granulocytes (RP1- SSChi CD45lo) only in the blood, together with increased succinate levels in the plasma. BMDMs from IFN-treated rats retained the hypermetabolic phenotype after differentiation and failed to induce a step-up in glycolysis and mitochondrial respiration after bacterial stimulation. This work provides the first evidence of the effects of IFNα treatment in inducing hypermetabolic immune features that are associated with markers of inflammation, leukopoiesis, and defective responses to bacterial stimulation.

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来源期刊
Cellular immunology
Cellular immunology 生物-免疫学
CiteScore
8.20
自引率
2.30%
发文量
102
审稿时长
30 days
期刊介绍: Cellular Immunology publishes original investigations concerned with the immunological activities of cells in experimental or clinical situations. The scope of the journal encompasses the broad area of in vitro and in vivo studies of cellular immune responses. Purely clinical descriptive studies are not considered. Research Areas include: • Antigen receptor sites • Autoimmunity • Delayed-type hypersensitivity or cellular immunity • Immunologic deficiency states and their reconstitution • Immunologic surveillance and tumor immunity • Immunomodulation • Immunotherapy • Lymphokines and cytokines • Nonantibody immunity • Parasite immunology • Resistance to intracellular microbial and viral infection • Thymus and lymphocyte immunobiology • Transplantation immunology • Tumor immunity.
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