Chemerin Exacerbates Pulmonary Inflammation in Type 2 Diabetes and Mycobacterium Tuberculosis Infection Comorbidity

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.