A microbiota tem papel essencial na ativação de macrófagos e na resposta imune durante infecção cutânea por Leishmania major

Abstract

The microbiota plays a central role in immune system development, maturation and activation of immune cells. Due to the influence of the microbiota on the immune system, the commensal microorganisms can play a direct role in the immune response against pathogens. Germ free animals (GF), which do not have an associated microbiota, can be more resistant or more susceptible than conventional (CV) animals, which have the complete associated microbiota. The resistance or susceptibility are dependent on the pathogens that elicit the infection. The microbiota is important for in vivo elimination of Leishmania major, because GF Swiss/NIH mice are susceptible to the infection, regardless their capacity to polarize a Th1 immune response as the CV mice. The aim of our work is to better understand the mechanisms that might explain the susceptibility of GF mice even in a context of a Th1 immune response. We hypothesize that macrophages, relevant host cells for L. major, might present an impairment in their classic activation allowing the parasite growth. In our work we showed that GF and CV animals presented similar lymphoid infiltrate and the chronic lesions with a higher parasite load is associated with a higher quantity of infected myeloid cells. Macrophages are cells that present a broad spectrum of activation dependent on endogenous and exogenous stimuli, including microbial stimuli. Our data show that the absence of microbiota exacerbates the alternative activation profile, characterized by the YM1, FIZZ1 and arginase I expression, as well as the regulatory activation profile, characterized by IL-10 and SPHK1. On the other hand, macrophages derived from GF mice showed an impaired classical activation phenotype as they produce less IL-12, TNF, reactive oxygen species and nitric oxide.. During in vivo infection, the GF mice present a lower parasite elimination capacity, because in the lesion of GF animals there were lesser iNOS+ macrophages. This enzyme is responsible for the production of nitric oxide, the microbicidal molecule responsible for the elimination of the intracellular parasite. The differences found for the activation of macrophages in vitro and their response in vivo may explain the fact that CV animals control the lesion and the GF animals are not.