Dados do Trabalho

Título

NATURAL PPAR-γ AGONISTS, DOWNREGULATE THE IMMUNE RESPONSE AND INCREASE THE KILLING OF L. braziliensis BY MACROPHAGES FROM CUTANEOUS LEISHMANIASIS PATIENTS

Introdução

Cutaneous leishmaniasis (CL) is an infectious disease caused by parasites of the genus Leishmania, characterized by the presence of ulcerated lesions on the skin. CL lesions present an intense inflammatory reaction with the predominance of lymphocytes and mononuclear phagocytes. Furthermore, few parasites are observed. High levels of TNF and IL-1β observed at lesion site of these individuals, is associated with tissue damage and lesion development. Eicosapentaenoic (EPA) and docosahexaenoic (DHA) polyunsaturated fatty acids of omega 3 family are known to be natural ligands of wide variety receptors such free fatty acid receptor 4 (FFAR4) and gamma peroxosomal proliferator-activated receptor (PPAR-γ). The activation theses receptors resulting in actions that inhibition of NF-κβ.

Objetivo(s)

Our aim was to evaluate the role of EPA and DHA in regulating the inflammatory response observed in CL patients.

Material e Métodos

The gene expression of PPARG, NF-κβ, IL-1β, IL-6, TNF, ALOX5, ELOVL 1-7 and FADS 1, 2, 6 were determined by RNAseq in skin lesion of CL patients and health skin. PBMC and biopsies were obtained from CL patients and cultured for 72 hours in the presence or absence of soluble Leishmania antigen (SLA), GW9662 (PPAR-γ inhibitor), AH7614 (FFAR4 inhibitor), EPA and DHA for 72 hours. Macrophages were infected with L. braziliensis and treated with EPA and DHA for 2, 48 or 72h. Levels of TNF, IL-6, IL-1β and LTB4 were determined by ELISA.

Resultados e Conclusão

We observed that the genes NF-κβ, IL-1β, IL-6, TNF and ALOX5 were increased in patient’s lesions, whereas the PPARG, ELOVL and FADS genes was suppressed when compared to healthy skin. In addition, we found that the PPAR-y gene was negatively correlated with the NF-κβ, IL-1β and IL-6. However, EPA and DHA negatively regulated the production of IL-6, TNF and IL-1β, but increased production of LTB4 in PBMC and resident cells of lesions. The neutralization of FFAR4 in PBMC do not modify effects EPA and DHA in immune response. However, the neutralization of PPAR-y abolished the modulatory effects on the production of TNF, IL-6 and IL-1β, and maintained a greater release of LTB4. Surprisingly, EPA and DHA increased LTB4 production by macrophages infected with Leishmania decreasing the percentage of infected cells and the number of amastigotes within these cells. Our results show that EPA/DHA decrease in vitro inflammatory response and enhance parasite killing in CL, and may serve as adjuvant therapy in CL.

Palavras-chave

PPAR-y, OMEGA 3, EPA, DHA, Cutaneous leishmaniasis