Role of IL 1α in obesity and tuberculosis comorbidity

Author(s)

Vinícius Bottura Apolloni

• Document type: Master's Dissertation
• Press: Ribeirão Preto.
• Institution: Universidade de São Paulo (USP). Faculdade de Medicina de Ribeirão Preto (PCARP/BC)
• Defense date: 2024-04-12

Examining board members

Vania Luiza Deperon Bonato; Alessandra D'Almeida Filardy; Maria Regina D'Imperio Lima

• Advisor: Vania Luiza Deperon Bonato

Abstract

Tuberculosis (TB) is the second infectious disease that causes the greater number of deaths in the world; around 1.6 million people die annually from this disease. A characteristic of severe cases of TB is the exacerbation of lung inflammation induced by CD4+ IFN-γ + cells. Obesity is a comorbidity that may be associated with severe cases of TB and increases the concentration of IFN-γ in the lungs. Our hypothesis is that the alarmin IL-1α, a pro-inflammatory cytokine from the IL-1 family, exacerbates lung inflammation and the progression of infection in obesity and TB comorbidity. The objective of this study was to investigate the role of IL-1α in the comorbidity of obesity and TB. We confirmed previous results from our group, and, unlike the initial hypothesis, we showed that IL-1α plays a protective role, rather than deleterious, in the comorbidity of obesity and TB. Obese mice, fed a High Fat Diet, treated with a monoclonal antibody against IL-1α (HFD+mAb IL-1α) exhibited increased bacterial load and inflammation in the lungs compared to the untreated obese group (non-treated HFD group). The HFD+mAb IL-1α group showed an increase in interstitial macrophages that expressed iNOS (CD11b+ SiglecFiNOS+ cells) and monocytes in the lungs (CD11b+ Ly6C+ and CD11b+ Ly6C+ CCR2+ cells), and a decrease in the population of CD4+ IL-17+ T cells compared to the HFD group left untreated. The reduction in the Th17 population was associated with an increase in HIF-1α. Obese mice deficient for IL-1α (IL-1α-/-) treated with rIL-1α (HFD+rIL-1α group) showed decreased bacterial load and inflammation in the lungs compared to the obese IL-1α group-/- left untreated (untreated HFD IL-1α-/- group). The IL-1α-/- HFD+rIL-1α group showed a reduction in interstitial and alveolar macrophages that expressed iNOS. Furthermore, we found a reduction in the populations of monocytes and CD4+ IFN-γ+ T cells, and an increase in CD4+ IL-17+ T cells compared to the untreated group. The higher the expression of iNOS by macrophages was correlated with the greater bacterial load in the lungs. The higher the expression of RORγt was correlated with the lower the expression of HIF-1α in the lungs. Bone marrow-derived macrophages infected with Mycobacterium tuberculosis and treated with recombinant IL17 exhibited reduced bacterial load, and reduction of HIF-1α and iNOS expression. Obese mice deficient for IL-17R (IL-17R-/-) treated with rIL-1α (IL-17R-/- HFD+rIL1α) showed an increase in interstitial and alveolar macrophages expressing iNOS compared to obese WT mice treated with rIL-1α (WT HFD+rIL-1α). We also found higher bacterial loads in the lungs of IL-17R-/- HFD+rIL-1α compared to WT HFD+rIL1α. In conclusion, our results show a protective role for IL-1α in comorbidity obesity and TB and show that the HIF-1α-iNOS axis is negatively regulated by IL-17. (AU)

• FAPESP's process: 22/03974-5 - The role of IL-1a in obesity and tuberculosis comorbidity
• Grantee: Vinicius Bottura Apolloni
• Support Opportunities: Scholarships in Brazil - Master