Hao Doudou, Luo Yanggan, Liao Hanjing, Lu Zihan, Huang Manjing, Du Meng, Zhu Zhixiang, Wu Qing
School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China.
School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China; Modern Research Center for Traditional Chinese Medicine, Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China.
Int Immunopharmacol. 2024 Dec 25;143(Pt 3):113568. doi: 10.1016/j.intimp.2024.113568. Epub 2024 Nov 2.
Timely treatment of acute inflammatory diseases induced by bacteria or fungi is essential to prevent infectious damage. Baricitinib is an inhibitor of Janus kinases (JAKs) which was approved to treat rheumatoid arthritis, atoptic dermatitis, and alopecia areata. It is also known that JAKs play important roles in innate immunity and inflammatory response. In this study, we investigated the regulatory effects of baricitinib on the activation of macrophages and neutrophils and its therapeutic effects on acute peritonitis and systemic inflammatory response syndrome (SIRS). In addition, we also studied its anti-inflammatory mechanisms by transcriptome and immunoblotting analyses. The results showed that baricitinib inhibited the expression and secretion of multiple inflammatory factors in macrophages induced by multiple Toll-like receptor (TLR) agonists. Baricitinib also moderately suppressed superoxide release of neutrophils stimulated by TLR agonists. In zymosan-induced acute peritonitis, baricitinib significantly reduced the infiltration of neutrophils into peritoneal cavity and the production of inflammatory factors in peritoneal cavity. In addition, baricitinib also slightly decreased the production of inflammatory factors in SIRS. Transcriptome analysis revealed that baricitinib markedly inhibited the mRNA transcription of many interferon-inducible genes, antiviral immune-related genes, transcription factors in JAKs-STATs signaling pathways, inflammatory factors, chemokines, colony-stimulating factor, and immunoglobulin receptors in macrophages induced by lipopolysaccharide (LPS). Furthermore, immunoblotting analysis showed that baricitinib selectively inhibited the phosphorylation of STAT1 and STAT3 in macrophages stimulated by LPS, and almost completely blocked the phosphorylation of STAT1 and STAT3 induced by IFN-γ and IL-6. Collectively, baricitinib can moderately inhibit the activation of macrophages and superoxide production of neutrophils, and exert anti-inflammatory effects by blocking JAKs-STATs signaling pathways, and has potential to be developed into therapeutic drug for acute inflammatory diseases, especially local ones.
及时治疗由细菌或真菌引起的急性炎症性疾病对于预防感染性损伤至关重要。巴瑞替尼是一种 Janus 激酶（JAKs）抑制剂，已被批准用于治疗类风湿性关节炎、特应性皮炎和斑秃。已知 JAKs 在先天免疫和炎症反应中发挥重要作用。在本研究中，我们研究了巴瑞替尼对巨噬细胞和中性粒细胞活化的调节作用及其对急性腹膜炎和全身炎症反应综合征（SIRS）的治疗作用。此外，我们还通过转录组和免疫印迹分析研究了其抗炎机制。结果表明，巴瑞替尼抑制多种 Toll 样受体（TLR）激动剂诱导的巨噬细胞中多种炎症因子的表达和分泌。巴瑞替尼还适度抑制 TLR 激动剂刺激的中性粒细胞超氧化物释放。在酵母聚糖诱导的急性腹膜炎中，巴瑞替尼显著减少中性粒细胞向腹腔的浸润以及腹腔中炎症因子的产生。此外，巴瑞替尼还略微降低了 SIRS 中炎症因子的产生。转录组分析显示，巴瑞替尼显著抑制脂多糖（LPS）诱导的巨噬细胞中许多干扰素诱导基因、抗病毒免疫相关基因、JAKs-STATs 信号通路中的转录因子、炎症因子、趋化因子、集落刺激因子和免疫球蛋白受体的 mRNA 转录。此外，免疫印迹分析表明，巴瑞替尼选择性抑制 LPS 刺激的巨噬细胞中 STAT1 和 STAT3 的磷酸化，几乎完全阻断 IFN-γ 和 IL-6 诱导的 STAT1 和 STAT3 的磷酸化。总体而言，巴瑞替尼可适度抑制巨噬细胞的活化和中性粒细胞的超氧化物产生，并通过阻断 JAKs-STATs 信号通路发挥抗炎作用，有潜力开发成为治疗急性炎症性疾病，尤其是局部炎症性疾病的治疗药物。
