Abstract
ABSTRACTThe innate immune response is the first line of defence against microbial infections. In Drosophila, two major pathways of the innate immune system (the Toll- and Imd-mediated pathways) induce the synthesis of antimicrobial peptides (AMPs) within the fat body. Recently, it has been reported that certain cationic AMPs exhibit selective cytotoxicity against human cancer cells; however, little is known about their anti-tumour effects. Drosophila mxcmbn1 mutants exhibit malignant hyperplasia in a larval haematopoietic organ called the lymph gland (LG). Here, using RNA-seq analysis, we found many immunoresponsive genes, including those encoding AMPs, to be upregulated in these mutants. Downregulation of these pathways by either a Toll or imd mutation enhanced the tumour phenotype of the mxc mutants. Conversely, ectopic expression of each of five different AMPs in the fat body significantly suppressed the LG hyperplasia phenotype in the mutants. Thus, we propose that the Drosophila innate immune system can suppress the progression of haematopoietic tumours by inducing AMP gene expression. Overexpression of any one of the five AMPs studied resulted in enhanced apoptosis in mutant LGs, whereas no apoptotic signals were detected in controls. We observed that two AMPs, Drosomycin and Defensin, were taken up by circulating haemocyte-like cells, which were associated with the LG regions and showed reduced cell-to-cell adhesion in the mutants. By contrast, the AMP Diptericin was directly localised at the tumour site without intermediating haemocytes. These results suggest that AMPs have a specific cytotoxic effect that enhances apoptosis exclusively in the tumour cells.
Highlights
Multicellular organisms have developed robust defence mechanisms to combat invading microbial pathogens that share the same environment
Malignant blood neoplasm phenotype appears in larvae hemizygous for mxcmbn1 mutation Previous studies demonstrated that mxcmbn1 hemizygotes showed hyperplasia of lymph glands (LG), a larval haematopoietic tissue, in which the precursors of haemocytes are abnormally increased in number
Ectopic induction of antimicrobial peptides (AMPs) in the fat body enhances apoptosis in the mxcmbn1 LG, but not in normal tissues To test the hypothesis that AMPs encoded by target genes of innate immune pathways are responsible for the suppressive effect on the development of the LG tumours in mxcmbn1 larvae, we examined whether the AMPs could stimulate apoptosis in the tumour cells
Summary
Multicellular organisms have developed robust defence mechanisms to combat invading microbial pathogens that share the same environment. A series of genetic analyses have demonstrated that the genes encoding these AMPs are regulated by two major innate immune signalling pathways (Buchon et al, 2014; Hoffmann and Reichhart, 2002; Tzou et al, 2002). One of these is the Toll-mediated pathway, which is activated mainly by fungi and Gram-positive bacteria (Lemaitre et al, 1997). The Toll pathway has a crucial role in the regulation of haemocyte proliferation in lymph glands (LG) and haemocyte density in haemolymph (Chiu et al, 2005; Qiu et al, 1998)
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