Neutrophils activate macrophages for intracellular killing of Leishmania major through recruitment of TLR4 by neutrophil elastase.
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-alpha. 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.
Ribeiro-Gomes
Flavia L
FL
Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
Moniz-de-Souza
Maria Carolina A
MC
Alexandre-Moreira
Magna S
MS
Dias
Wagner B
WB
Lopes
Marcela F
MF
Nunes
Marise P
MP
Lungarella
Giuseppe
G
DosReis
George A
GA
D019264:Adoptive Transfer; D000818:Animals; D002478:Cells, Cultured; D018920:Coculture Techniques; D004789:Enzyme Activation / Q000276:immunology; D006801:Humans; D007424:Intracellular Fluid / Q000201:enzymology / Q000276:immunology* / Q000469:parasitology*; D018320:Leishmania major / Q000254:growth & development / Q000276:immunology*; D019272:Leukocyte Elastase / Q000378:metabolism / Q000502:physiology*; D008262:Macrophage Activation / Q000276:immunology; D008264:Macrophages / Q000201:enzymology / Q000276:immunology* / Q000469:parasitology* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000201:enzymology / Q000276:immunology* / Q000473:pathology / Q000637:transplantation; D021381:Protein Transport / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*