Macrophages induce neutrophil apoptosis through membrane TNF, a process amplified by Leishmania major

Neutrophils are recruited to the site of parasite inoculation within a few hours of infection with the protozoan parasite Leishmania major. In C57BL/6 mice, which are resistant to infection, neutrophils are cleared from the site of s.c. infection within 3 days, whereas they persist for at least 10 days in susceptible BALB/c mice. In the present study, we investigated the role of macrophages (M Phi) in regulating neutrophil number. Inflammatory cells were recruited by i.p. injection of either % starch or L major promastigotes. Neutrophils were isolated and cultured in the presence of increasing numbers of M Phi. Extent of neutrophil apoptosis positively correlated with the number of M Phi added. This process was strictly dependent on TNF because M Phi from TNF-deficient mice failed to induce neutrophil apoptosis. Assays using M Phi derived from membrane TNF knock-in mice or cultures in Transwell chambers revealed that contact with M Phi was necessary to induce neutrophil apoptosis, a process requiring expression of membrane TNF. L. major was shown to exacerbate M Phi-induced apoptosis of neutrophils, but BALB/c M Phi were not as potent as C57BL/6 M Phi in this induction. Our results emphasize the importance of M Phi-induced neutrophil apoptosis, and membrane TNF in the early control of inflammation.