A obesidade altera a resposta de macrófagos à L. major em camundongos C57BL/6

Abstract

In previous studies conducted by our group, we showed that mice with obesity and infected with L. major had more ulcerated lesions compared to lean mice after eight weeks of infection. Additionally, their peritoneal macrophages were more susceptible to infection in vitro. In this present study, we aimed to investigate the effect of obesity on the immune response of macrophages to L. major infection in C57BL/6 mice. Firstly, we compared macrophages derived from the bone marrow of control and obese mice that were infected in vitro under different stimuli. Macrophages from obese mice infected with L. major showed a higher infection index, produced less nitric oxide and presented a higher arginase activity compared to macrophages from lean animals. We also observed that macrophages from obese mice were more permissive to L. major infection when stimulated to differentiate into M1 or M2 profiles. To evaluate the participation of macrophages in vivo and the innate immune response, mice with or without obesity were subjected to intradermal infection with 2x105 L. major metacyclic. Obese mice had more severe lesions and higher parasitic burden up to 98 days after infection. Flow cytometry analysis of cells in the ear revealed that obese mice had a lower frequency of neutrophils in the early stages of infection. After 8 weeks, when the lesion in obese mice was more severe, these animals presented a higher frequency of resident CD206+ macrophages. The increase in resident macrophages occurred in relation to monocytes, dendritic cells, and CD11c+ macrophages when compared to healthy mice. Additionally, we observed that obese mice had a higher frequency of CD206+ macrophages in the spleen, liver, and adipose tissue, regardless of infection. In the ear, this increase happens only in the presence of the parasite. Finally, we demonstrated that CCR2-/- animals, which mainly have resident macrophages in the lesion, had a more severe lesion when compared to C57BL/6 controls, and obesity potentialized the severity of the lesion. Therefore, bone marrow-derived macrophages from C57BL/6 mice with obesity have an impaired inflammatory response, allowing for greater L. major survival. Furthermore, our data suggest that obesity may impair the immune response to L. major. The increase in CD206+ macrophage frequency in the ear is consistent with a more severe prognosis of infection.