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Neutrophils Activate Macrophages for Intracellular Killing of Leishmania major through Recruitment of TLR4 by Neutrophil Elastase¹

Flavia L. Ribeiro-Gomes^*, Maria Carolina A. Moniz-de-Souza^*, Magna S. Alexandre-Moreira^*, Wagner B. Dias^*, Marcela F. Lopes^*, Marise P. Nunes, Giuseppe Lungarella and George A. DosReis^2,*

^* Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil, and Institute for Investigation in Immunology (iii), Millenium Institutes, Brazil; Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil; and Department of Physiopathology and Experimental Medicine, University of Siena, Siena, Italy

We investigated the role of neutrophil elastase (NE) in interactions between murine inflammatory neutrophils and macrophages infected with the parasite Leishmania major. A blocker peptide specific for NE prevented the neutrophils from inducing microbicidal activity in macrophages. Inflammatory neutrophils from mutant pallid mice were defective in the spontaneous release of NE, failed to induce microbicidal activity in wild-type macrophages, and failed to reduce parasite loads upon transfer in vivo. Conversely, purified NE activated macrophages and induced microbicidal activity dependent on secretion of TNF-. Induction of macrophage microbicidal activity by either neutrophils or purified NE required TLR4 expression by macrophages. Injection of purified NE shortly after infection in vivo reduced the burden of L. major in draining lymph nodes of TLR4-sufficient, but not TLR4-deficient mice. These results indicate that NE plays a previously unrecognized protective role in host responses to L. major 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 Brazilian National Research Council, Rio de Janeiro State Science Foundation, Programa de Núcleos de Excelência, Institute for Investigation in Immunology, Millenium Institutes, Brazilian Ministry of Science and Technology, John Simon Guggenheim Memorial Foundation, Howard Hughes Medical Institute (Grant 55003669), and by Ministero dell’ Istruzione, Università e Ricerca, Rome, Italy (Grant 2006069824).

² Address correspondence and reprint requests to Dr. George A. DosReis, Programa de Imunobiologia, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Centro de Ciências da Saúde Bloco G, Ilha do Fundão, Rio de Janeiro, Brazil. E-mail address: gdosreis{at}biof.ufrj.br

³ Abbreviations used in this paper: NE, neutrophil elastase; DFO, deferoxamine; SLPI, secretory leukocyte protease inhibitor; AAT, ₁ anti-trypsin; MeOSuc-AAPV-CMK, methoxysuccinyl-Ala-Ala-Pro-Val-chloromethylketone; WT, wild type.