Limitation of Deleterious iNOS-Expressing Interstitial Macrophages Is Dependent on Protective IL-1α and IL-17 in...

IL-1α, IL-1β, IFN-γ, IL-17 and the expression of inducible nitric oxide synthase (iNOS) enzyme by macrophages, which generate nitric oxide, are protective against tuberculosis, a disease caused by Mycobacterium tuberculosis. The severity of tuberculosis can be dependent on bacterial load and/or lung immunopathology. Tuberculosis is aggravated by existing comorbidities such as obesity. Obesity induces metabolic dysfunction, meta inflammation and dysbiosis, which increase the prevalence of respiratory diseases and worsen immunopathology. The deficiency of IL-1α (IL-1α^-/-) induces deleterious lung monocytic inflammation and functional activation of the adaptive immune response mediated by T cells during M. tuberculosis infection in non-obese mice. Although iNOS and IFN-γ have been described as protective in experimental tuberculosis, using a model of obesity induced by high-fat diet, we show here an increase in iNOS-expressing interstitial macrophages positively correlated with M. tuberculosis numbers in the lungs of IL-1α^-/- animals, followed by increased frequency of IFN-γ and decreased frequency of IL-17-producing T cells, showing that IFN-γ and iNOS contribute to immunopathology and pulmonary damage. The protective effect of IL-1α, characterised by reduction of lung immunopathology, is dependent on IL-17-producing CD4⁺ cells that negatively regulate iNOS expression on macrophages. Our data provide important implications for tuberculosis with existing obesity that aggravates lung immunopathology associated with an exacerbation of IFN-γ-producing and iNOS-expressing cells.