Leukotrienes Are Essential for the Control ofLeishmania amazonensisInfection and Contribute to Strain Variation in Susceptibility

Abstract

Leukotrienes (LTs) are known to be produced by macrophages when challenged with Leishmania, but it is not known whether these lipid mediators play a role in host defense against this important protozoan parasite. In this study, we investigated the involvement of LTs in the in vitro and in vivo response to Leishmania amazonensis infection in susceptible (BALB/c) and resistant (C3H/HePAS) mice. Pharmacologic or genetic deficiency of LTs resulted in impaired leishmanicidal activity of peritoneal macrophages in vitro. In contrast, addition of LTB4 increased leishmanicidal activity and this effect was dependent on the BLT1 receptor. LTB4 augmented NO production in response to L. amazonensis challenge, and studies with a NO synthesis inhibitor revealed that NO was critical for the enhancement of macrophage leishmanicidal activity. Interestingly, macrophages from resistant mice produced higher levels of LTB4 upon L. amazonensis challenge than did those from susceptible mice. In vivo infection severity, as assessed by footpad swelling following s.c. promastigote inoculation, was increased when endogenous LT synthesis was abrogated either pharmacologically or genetically. Taken together, these results for the first time reveal an important role for LTB4 in the protective response to L. amazonensis, identify relevant leishmanicidal mechanisms, and suggest that genetic variation in LTB4 synthesis might influence resistance and susceptibility patterns to infection.

Leukotriene B4 Modulates P2X7 Receptor–MediatedLeishmania amazonensisElimination in Murine Macrophages

“…Other works have shown that apoptosis triggered after activation of the P2X7 receptor is dependent on PLA 2 and 5-LO (24). Based on these findings and on data indicating that LTB 4 reduces the parasitic load of infected macrophages (20), we examined whether the ATPe-induced release of LTB 4 requires the P2X7 receptor. Our data demonstrate that ATP was able to induce LTB 4 production.…”

“…Serezani and coworkers (20) demonstrated that 5-LO participates in the elimination of L. amazonensis. Therefore, we investigated the importance of 5-LO in reducing the parasite load triggered by ATPe.…”

“…The activation of LTs synthesis occurs during bacterial, fungal, viral, and protozoa infection in animal and humans models (19). LTB 4 is essential for controlling infection with L. amazonensis (20). Thus, we hypothesized that P2X7 receptor activation by ATPe might cause LTB 4 synthesis and release and cause the elimination of L. amazonensis from macrophages.…”

Análise da atividade de CD100 na modulação da ativação de macrófagos e sua infectividade por Leishmania (Leishmania) amazonensis.

“…major (AFONSO e SCOTT, 1993), e os mecanismos que determinam maior sucesso no combate à infecção não estão completamente esclarecidos (SEREZANI et al, 2006 …”

Avaliação da participação de mediadores lipídicos nas infecções experimentais induzidas por diferentes isolados de Mycobacterium tuberculosis de humanos

“…LTs regulam a resposta imune protetora, quer seja do padrão T H 1 ou do T H 2, em infecções como aquelas por K. pneumoniae [61] , H. capsulatum [54] , Strongyloides venezuelensis [68] , Leishmania amazonensis [69] . Neste contexto, mostramos que a infecção pelo Mtb induz produção de LTB 4 nos pulmões, persistente até pelo menos 60 dias após a infecção, sendo esta importante para o desenvolvimento de resposta protetora do hospedeiro [70] .…”