IL-7Suppresses Macrophages Apoptosis Bypass BCL-2Protein Family

Schistosomiasis is a parasitic disease caused by several species of trematodes(platyhelminth infection, or "flukes"), a parasitic worm of the genus Schistosoma.Eggs laid by the female worms trapped in the liver will cause severe hepaticgranulomas, progress of which will allow the development of fibrosis and finally leadto portal hypertension, and the patients will suffer from disablement and the loss ofself-care ability, they may even die at last. As the major antigen-presenting cells ingranulomas, macrophages play essential role in the occurrence and developmen of thegranulomas, first of all, macrophages engulf schistosome egg antigens and processthe antigens before presenting them to CD4+T cells, and thus activate T cell immuneresponse to produce abundance cytokines and chemokines which will initiategranuloma response; secondly, after exposure to the egg antigens, macrophagesthemselves will secrete cytokines and chemokines and together with T cells to recruitmultiple cells include macrophages, eosnophils, neutrophils and fibrocytes to formgranulomas by wrapping the eggs, whats more, as a component of the granulomas,macrophages are about30%of all the cells in granulomas. Macrophages are suchimportant cells for the development of hepatic granulomas, so it is logical for us tospeculate that the apoptosis of macrophages will markedly impact the development ofthe hepatic granulomas and thereby influence the pathopoiesis of schistosomeinfection.Our research proved that schistosome infection would induce apoptosis in macrophages, however, we noticed that although the absolute numbers of apoptoticmacrophages apparently increased after schistosome infection, the total numbers ofmacrophages obviously increased and the percentages of apoptotic macrophagesdistinctly decreased, so what contributed to the decreased percentages of apoptoticmacrophages? We found that, cytokine IL-7was dramatically induced to increase thetotal numbers of macrophages by preventing the apoptosis of them. The increasedmacrophages thereby lead to the enhancement of hepatic granulomas, which maycontribute to the Immune pathological damage in liver.Immediately after that we further explored the mechanisms of the prevention ofmacrophages apoptosis by IL-7. Results turned out that IL-7could signal through theIL-7R(consists of α chain, CD127, and γ chain, CD132) expressed on macrophages toprevent the apoptosis of macrophages and the apoptosis induced by soluble eggantigen(SEA). The function of increasing numbers of macrophages by IL-7was notinfluenced by the changes of macrophages proliferation after IL-7treatment.Different from previous studies which declared that IL-7prevents T cell apoptosis byup-regulating anti-apoptotic members and down-regulating pro-apoptotic members ofBCL-2protein family, our study found that IL-7prevented macrophages apoptosisindependent of BCL-2protein family. The pro-apoptotic members of BCL-2proteinfamily(BAX,BAK) works through promoting the release of cytochrome C andSmac/Diablo from mitochondria to activate caspases and promote apoptosis, whilethe anti-apoptotic members(BCL-2,BCL-XL) works on the contrary. However, BCL-2protein family can still promote or prevent cell apoptosis independent of caspases.This research found that IL-7could prevent macrophages apoptosis independent ofcaspases(but we could not rule out the impact of caspase-dependent pathway yet),and schistosome infection and the egg antigen induced macrophages apoptosis wereindependent of BCL-2protein family and caspases which could be prevented by IL-7 through the same way. Finally, our research indicated that SEA may inducedmacrophages apoptosis by induction of macrophages autophagy, while IL-7justinhibited macrophages autophagy to prevent macrophages apoptosis.In a word, this research observed for the first time that IL-7could also preventapoptosis of immunocytes (macrophages) other than T cells. And we innovativelyfound that mechanisms underlying in the preventing apoptotic role of IL-7onmacrophages were independent of caspases while through inhibiting autophagy,which was different from previous studies. These results dramatically expanded theexisting reorganization of the preventing apoptotic function of IL-7, and can apply asclinical supervision for the control of hepatic granulomas in schistosomiasis.