Corrêa Giseli Furlan, Martins Núbia Sabrina, Cipriano Ualter Guilherme, Gembre Ana Flávia, Rodrigues Daniel, Apolloni Vinícius Bottura, Zambelli Ramalho Leandra Naira, de Campos Fraga-Silva Thais Fernanda, Tostes Rita, Bonato Vânia Luiza Deperon
Basic and Applied Immunology Program, Ribeirao Preto Medical School, University of Sao Paulo, 3900 Bandeirantes Ave., Ribeirao Preto, SP, Brazil.
Department of Biochemistry and Immunology, Ribeirao Preto Medical School, University of Sao Paulo, São Paulo, SP, Brazil.
Inflammation. 2025 Aug 22. doi: 10.1007/s10753-025-02343-z.
The adipokine chemerin is increased in the serum of individuals with obesity and type 2 diabetes. Patients with type 2 diabetes exhibit a threefold increased risk of developing tuberculosis, are more refractory to tuberculosis treatment and display more severe forms of the disease. Patients with type 2 diabetes and tuberculosis exhibit a dysfunctional immunological response characterized by a higher frequency of peripheral Th1 and Th17 cells, increased concentrations of pro- and anti-inflammatory cytokines, and a reduced microbicidal capacity compared to subjects affected exclusively by tuberculosis. In the present study, we investigated whether chemerin exerts a pro- or anti-inflammatory effect on macrophages in vitro and its role in the lungs of normoglycemic or hyperglycemic (obese plus type 2 diabetes) mice infected with Mycobacterium tuberculosis. Bone marrow-derived macrophages (BMDM) cultured with hyperglycemic medium and infected with M. tuberculosis secreted increased IL-6 and reduced IL-10 concentrations following chemerin treatment. BMDM from obese (fed with high-fat diet, HFD), non-diabetic mice were also pro-inflammatory, while BMDM from obese and diabetic mice (db/db) showed no significant difference compared to BMDM from normoglycemic mice (db/+). In vivo, db/db mice exhibited an increase of bacterial load and an exacerbated pulmonary immunopathology. Treatment of infected db/db mice with CCX832 chemerin receptor (ChemR23) antagonist significantly reduced pulmonary inflammation with no effect on bacterial load. Our findings show that blocking chemerin receptors may represent an adjuvant therapeutic strategy to mitigate pulmonary immunological response-mediated pathology accentuated by type 2 diabetes in active tuberculosis.
脂肪因子chemerin在肥胖和2型糖尿病患者的血清中水平升高。2型糖尿病患者患结核病的风险增加了两倍，对结核病治疗更具耐药性，且病情表现更为严重。与仅患结核病的患者相比，2型糖尿病合并结核病的患者表现出免疫反应功能失调，其特征为外周Th1和Th17细胞频率更高、促炎和抗炎细胞因子浓度增加以及杀菌能力降低。在本研究中，我们调查了chemerin在体外对巨噬细胞是发挥促炎还是抗炎作用，以及它在感染结核分枝杆菌的血糖正常或高血糖（肥胖加2型糖尿病）小鼠肺部中的作用。用高血糖培养基培养并感染结核分枝杆菌的骨髓来源巨噬细胞（BMDM）在接受chemerin处理后，分泌的IL-6增加，IL-10浓度降低。来自肥胖（喂食高脂饮食，HFD）的非糖尿病小鼠的BMDM也具有促炎作用，而来自肥胖和糖尿病小鼠（db/db）的BMDM与血糖正常小鼠（db/+）的BMDM相比无显著差异。在体内，db/db小鼠的细菌载量增加，肺部免疫病理学加重。用CCX832 chemerin受体（ChemR23）拮抗剂治疗感染的db/db小鼠可显著减轻肺部炎症，但对细菌载量无影响。我们的研究结果表明，阻断chemerin受体可能是一种辅助治疗策略，以减轻2型糖尿病在活动性结核病中加剧的肺部免疫反应介导的病理变化。
