重组人IgG1 Fc六聚体在内源性K/BxN类风湿性关节炎小鼠模型中对中性粒细胞功能的调节

IF 2.9 4区 医学 Q2 PHARMACOLOGY & PHARMACY
Pharmacology Pub Date : 2023-01-01 DOI:10.1159/000528780
Ruqayyah J Almizraq, Kayluz Frias Boligan, Bonnie J B Lewis, Selena Cen, Heather Whetstone, Rolf Spirig, Fabian Käsermann, Ian K Campbell, Stephan von Gunten, Donald R Branch
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引用次数: 3

摘要

中性粒细胞是类风湿关节炎K/BxN小鼠模型中的关键细胞类型,在关节炎的进展中起着至关重要的作用。它们很容易被免疫复合物(ic)激活,通过它们的FcγRs释放IL-1β和其他细胞因子,这些细胞因子诱导软骨破坏。中性粒细胞也释放中性粒细胞活性趋化因子,以自分泌的方式招募自己,使组织永久破坏。中性粒细胞中fc - γ - r的表达对ic的识别至关重要。方法:在本研究中,由于重组IgG1 Fc六聚体(rFc-µTP-L309C)与Fcγ rs的高亲和性结合,我们研究了重组IgG1 Fc六聚体(rFc-µTP-L309C)对内源性慢性关节炎K/BxN小鼠模型中性粒细胞的潜在抗炎作用。每隔一天皮下注射200 mg/kg rFc-µTP-L309C和人血清白蛋白(HSA)作为对照。每天监测小鼠踝关节以产生临床评分。免疫组织学评价中性粒细胞浸润,TUNEL评价细胞凋亡。ELISA法检测IL-1β。结果:rFc-µTP-L309C治疗,而不是HSA治疗,能够显著改善K/BxN小鼠的关节炎。发现踝关节有明显的中性粒细胞浸润,但rFc-µTP-L309C治疗后中性粒细胞浸润明显减少。rFc-µTP-L309C对中性粒细胞死亡和凋亡无显著影响。中性粒细胞浸润减少与趋化因子介导的迁移无关。在rFc-µTP-L309C处理的小鼠中,IL-1β明显减少。结论:内源性K/BxN小鼠类风湿关节炎模型的改善部分可以通过抑制关节中性粒细胞浸润和IL-1β的产生来解释。鉴于观察到的对中性粒细胞的抑制特性,rFc-µTP-L309C可能是治疗自身免疫性和炎症性疾病的潜在候选药物,其中中性粒细胞是参与发病的主要细胞类型。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Modulation of Neutrophil Function by Recombinant Human IgG1 Fc Hexamer in the Endogenous K/BxN Mouse Model of Rheumatoid Arthritis.

Modulation of Neutrophil Function by Recombinant Human IgG1 Fc Hexamer in the Endogenous K/BxN Mouse Model of Rheumatoid Arthritis.

Modulation of Neutrophil Function by Recombinant Human IgG1 Fc Hexamer in the Endogenous K/BxN Mouse Model of Rheumatoid Arthritis.

Modulation of Neutrophil Function by Recombinant Human IgG1 Fc Hexamer in the Endogenous K/BxN Mouse Model of Rheumatoid Arthritis.

Introduction: Neutrophils are a pivotal cell type in the K/BxN mouse model of rheumatoid arthritis and play an essential role in the progression of the arthritis. They are readily activated by immune complexes (ICs) via their FcγRs to release IL-1β in addition to other cytokines, which are inducing cartilage destruction. Neutrophils also release neutrophil-active chemokines to recruit themselves in an autocrine manner to perpetuate tissue destruction. FcγR-expression on neutrophils is of crucial importance for the recognition of ICs.

Methods: In this study, due to its high avidity for binding to FcγRs, we investigated the potential anti-inflammatory effect of a recombinant IgG1 Fc hexamer (rFc-µTP-L309C) on neutrophils in the K/BxN mouse model of endogenously generated chronic arthritis. 200 mg/kg rFc-µTP-L309C and human serum albumin (HSA), used as controls, were administered subcutaneously every other day. Mouse ankle joints were monitored daily to generate a clinical score. Immunohistology was used to evaluate neutrophil infiltration and TUNEL to assess apoptosis. ELISA was used to measure IL-1β.

Results: Treatment with rFc-µTP-L309C, but not HSA, was able to significantly ameliorate the arthritis in the K/BxN mice. Significant neutrophil infiltration into the ankle joint was found, but treatment with rFc-µTP-L309C resulted in significantly less neutrophil infiltration. There was no significant influence of rFc-µTP-L309C on neutrophil death or apoptosis. Less neutrophil infiltration could not be correlated to chemokine-mediated migration. Significantly less IL-1β was measured in mice treated with rFc-µTP-L309C.

Conclusion: In the endogenous K/BxN mouse model of rheumatoid arthritis, amelioration can be explained in part by inhibition of neutrophil infiltration into the joints as well as inhibition of IL-1β production. Given the observed inhibitory properties on neutrophils, rFc-µTP-L309C may be a potential therapeutic candidate to treat autoimmune and inflammatory conditions in which neutrophils are the predominant cell type involved in pathogenesis.

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来源期刊
Pharmacology
Pharmacology 医学-药学
CiteScore
5.60
自引率
0.00%
发文量
52
审稿时长
6-12 weeks
期刊介绍: ''Pharmacology'' is an international forum to present and discuss current perspectives in drug research. The journal communicates research in basic and clinical pharmacology and related fields. It covers biochemical pharmacology, molecular pharmacology, immunopharmacology, drug metabolism, pharmacogenetics, analytical toxicology, neuropsychopharmacology, pharmacokinetics and clinical pharmacology. In addition to original papers and short communications of investigative findings and pharmacological profiles the journal contains reviews, comments and perspective notes; research communications of novel therapeutic agents are encouraged.
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