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Leukotrienes Are Essential for the Control of Leishmania amazonensis Infection and Contribute to Strain Variation in Susceptibility¹

Carlos H. Serezani^2,*,, Joao H. Perrela^*, Momtchilo Russo^*, Marc Peters-Golden and Sonia Jancar^*

^* Department of Immunology, Institute of Biomedical Science IV, University of São Paulo, São Paulo, Brazil; and Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Medical School, University of Michigan, Ann Arbor, MI 48109

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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Fundação de Amparo a Pesquisa do Estado de São Paulo; Conselho Nacional de Desenvolvimento Científico e Tecnológico (Brazil); and National Institutes of Health HL HL-058897.

² Address correspondence and reprint requests to Dr. Carlos Henrique Serezani, University of Michigan Health System, 6301 Medical Science Research Building III, Box 0642, 1150 West Medical Center Drive, Ann Arbor, MI 48109-0642. E-mail address: cserezan{at}med.umich.edu

³ Abbreviations used in this paper: LT, leukotriene; 5-LO, 5-lipoxygenase; FLAP, 5-LO-activating protein; cysLT, cysteinyl LT; iNOS, inducible NO synthase; KO, knockout; WT, wild type.