Host liver-derived extracellular vesicles deliver miR-142a-3p induces neutrophil extracellular traps via targeting WASL to block the development of Schistosoma japonicum

Abstract

Schistosomiasis is an important neglected tropical disease. Interactions between the host immune system and schistosomes are complex. Neutrophils contribute to clearance of large pathogens primarily by releasing neutrophil extracellular traps (NETs). However, the functional role of NETs in clearing schistosomes remains unclear. Herein, we report that extracellular vesicles (EVs) derived from the liver of Schistosoma japonicum-infected mice (IL-EVs) induce NET release by delivering miR-142a-3p to target WASL and block the development of S. japonicum. WASL knockout accelerated the formation of NETs that blocked further development of S. japonicum. miR-142a-3p and NETs upregulated the expression of CCL2, which recruits macrophages that block S. japonicum development. However, S. japonicum inhibited NET formation in wild-type mice by upregulating host interleukin-10 (IL-10) expression. In contrast, in WASL knockout mice, IL-10 expression was downregulated, and S. japonicum-mediated inhibition of NET formation was significantly reduced. IL-EV-mediated induction of NET formation is thus an anti-schistosome response that can be counteracted by S. japonicum. These findings suggest that IL-EV-mediated induction of NET formation plays a key role in schistosome infection and that WASL is a potential therapeutic target in schistosomiasis and other infectious diseases. Schistosomiasis is an important neglected tropical disease. Interactions between the host immune system and schistosomes are complex. Neutrophils contribute to clearance of large pathogens primarily by releasing neutrophil extracellular traps (NETs). However, the functional role of NETs in clearing schistosomes remains unclear. Herein, we report that extracellular vesicles (EVs) derived from the liver of Schistosoma japonicum-infected mice (IL-EVs) induce NET release by delivering miR-142a-3p to target WASL and block the development of S. japonicum. WASL knockout accelerated the formation of NETs that blocked further development of S. japonicum. miR-142a-3p and NETs upregulated the expression of CCL2, which recruits macrophages that block S. japonicum development. However, S. japonicum inhibited NET formation in wild-type mice by upregulating host interleukin-10 (IL-10) expression. In contrast, in WASL knockout mice, IL-10 expression was downregulated, and S. japonicum-mediated inhibition of NET formation was significantly reduced. IL-EV-mediated induction of NET formation is thus an anti-schistosome response that can be counteracted by S. japonicum. These findings suggest that IL-EV-mediated induction of NET formation plays a key role in schistosome infection and that WASL is a potential therapeutic target in schistosomiasis and other infectious diseases. IntroductionSchistosomiasis is a neglected tropical disease that affects 240 million people globally and causes 250,000 deaths annually.1Wendt G. Zhao L. Chen R. Liu C. O'Donoghue A.J. Caffrey C.R. Reese M.L. Collins J.J. A single-cell RNA-seq atlas of Schistosoma mansoni identifies a key regulator of blood feeding.Science. 2020; 369: 1644-1649https://doi.org/10.1126/science.abb7709Crossref PubMed Scopus (44) Google Scholar,2Liu S. Zhang X. Liu Y. Yuan X. Yang L. Zhang R. Wang X. Xu F. Zhu C. Early application of caffeine improves white matter development in very preterm infants.Respir. Physiol. Neurobiol. 2020; 281: 103495https://doi.org/10.1016/j.resp.2020.103495Crossref PubMed Scopus (10) Google Scholar Female Schistosoma japonicum worms live in the mesenteric veins of host organisms and produce numerous eggs, many of which are transported to the liver. Highly immunogenic substances released by these eggs elicit host immune responses, including granulomatous inflammation and fibrotic reactions. Schistosomes can flourish in the host despite the development of a pronounced immune response. Unfortunately, no schistosomiasis vaccines are available, and praziquantel is the only drug available for treatment. Therefore, a better understanding of how the immune system responds to schistosomes may facilitate the development of effective therapeutic strategies.In schistosomiasis, schistosomes evoke responses from many immune cells, including T helper cells, eosinophils, neutrophils, and macrophages, and induce chemokine release.3Chuah C. Jones M.K. Burke M.L. McManus D.P. Gobert and in PubMed Scopus Google Scholar Neutrophils are the immune and a role in Y. S. extracellular traps a host response to PubMed Scopus Google Scholar Neutrophils are to an important role in S. japonicum M.L. McManus D.P. Y. Jones M.K. Gobert expression of the in a of PubMed Scopus Google Scholar S. japonicum recruits and C. Chen Y. Y. Wang Y. Yang Y. Y. L. japonicum recruits and PubMed Scopus Google Scholar In schistosomiasis by S. to neutrophil and the granulomatous Y. Zhang Schistosoma japonicum formation in the PubMed Scopus Google Scholar Neutrophils are to of infection and the pathogens of PubMed Scopus Google Scholar neutrophil and clearance and host Scopus Google Scholar and the formation of neutrophil extracellular traps extracellular traps in and PubMed Scopus Google Scholar NETs are of and extracellular traps in and PubMed Scopus Google C. Y. Y. extracellular traps PubMed Scopus Google G. R. S. 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C. and are for development and PubMed Scopus Google Scholar is for in S. is for in PubMed Scopus Google Scholar of and in in the of S. of and in the response and in of PubMed Scopus Google Scholar However, the role of in the development and of remains that miR-142a-3p NET formation by which further development of S. japonicum and the of S. japonicum these we that WASL NET formation and the development of S. contribute significantly to the immune response macrophages are in the G. Interactions between macrophages and 2020; PubMed Scopus Google Scholar numerous macrophages to the of worms treatment. of CCL2, a for Zhang Zhang recruits to facilitate PubMed Scopus Google Scholar was upregulated miR-142a-3p that miR-142a-3p and NETs expression to macrophages to block further development of S. is of the of Female S. japonicum worms produce eggs that are transported to the and these eggs elicit host immune responses and fibrotic X. Y. X. Zhang C. Wang Y. Zhang by the PubMed Scopus Google Scholar of in are and in the C. Jones M.K. Burke M.L. McManus D.P. Gobert and in PubMed Scopus Google Scholar In we that miR-142a-3p to induce NET formation by further development of S. japonicum. causes in the liver to In schistosome macrophages in the of and may the of C. Jones M.K. Burke M.L. McManus D.P. Gobert and in PubMed Scopus Google Scholar that miR-142a-3p and NETs expression to macrophages and block further development of S. japonicum and host host immune system schistosomes to the host immune response and the schistosomes to and and immune of and 2020; PubMed Scopus Google Scholar we that S. japonicum inhibited NET and inhibited NET which may are upregulated schistosome the worms are However, the development of S. japonicum was blocked of in the of large of and NET These findings suggest that miR-142a-3p may be an important target for schistosome produce numerous that the host and of immune infection expression of and in to PubMed Scopus Google Scholar A that expression of primarily by schistosome eggs in IL-10 by and immune of and 2020; PubMed Scopus Google Scholar that a of S. significantly IL-10 in X. Yang F. 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However, S. japonicum response by upregulating host IL-10 expression. understanding of the that miR-142a-3p and WASL may be potential therapeutic for infectious schistosomiasis and and and mice from the WASL mice WASL by of by to S. japonicum from which from the of for and by the and of and to the for the and of of the of in and the from mice and mice and the and large and by in and for to in of the was for further by and by and In for in a and the for These a and for of to and for in an (EVs) and for in an was to the a and for was a of the and was by by a a and of in and in by and and for the and in for and in for blocked in for and and the was to in for an and and of mice and the a single-cell Neutrophils from the single-cell and and by for by the in and the macrophages Neutrophils and macrophages in a of for and was by an of was to a and for in an was and for in an Neutrophils for and the to was to and was to and for for for S. japonicum for S. japonicum for miR-142a-3p for for IL-10 for Neutrophils and S. japonicum worms in the an by of and and an and and an and and L. Y. Yang R. Zhang L. Zhu X. Liu Xu L. in extracellular vesicles liver by schistosomiasis 2020; PubMed Scopus Google Scholar In was from and the to the the an the to including target functional of expression expression and and of and and of was In was from by of liver and in to the was a was from of and a to the of CCL2, and was a the in and the in expression was to the for in a and and from the infection S. japonicum. expression in the liver was and of the and the of liver of of was of in was and in and released eggs and and for and worms a and was the was by liver of potential miR-142a-3p target and was to potential miR-142a-3p target for further by and in the of WASL and miR-142a-3p for was to the cells, and was an was to neutrophils, and macrophages in the of and to and the and blocked the IL-10 and and to the for an system of for NETs was for and NETs for are between between by and for NETs IntroductionSchistosomiasis is a neglected tropical disease that affects 240 million people globally and causes 250,000 deaths annually.1Wendt G. Zhao L. Chen R. Liu C. O'Donoghue A.J. Caffrey C.R. Reese M.L. Collins J.J. A single-cell RNA-seq atlas of Schistosoma mansoni identifies a key regulator of blood feeding.Science. 2020; 369: 1644-1649https://doi.org/10.1126/science.abb7709Crossref PubMed Scopus (44) Google Scholar,2Liu S. Zhang X. Liu Y. Yuan X. Yang L. Zhang R. Wang X. Xu F. Zhu C. Early application of caffeine improves white matter development in very preterm infants.Respir. Physiol. Neurobiol. 2020; 281: 103495https://doi.org/10.1016/j.resp.2020.103495Crossref PubMed Scopus (10) Google Scholar Female Schistosoma japonicum worms live in the mesenteric veins of host organisms and produce numerous eggs, many of which are transported to the liver. Highly immunogenic substances released by these eggs elicit host immune responses, including granulomatous inflammation and fibrotic reactions. Schistosomes can flourish in the host despite the development of a pronounced immune response. Unfortunately, no schistosomiasis vaccines are available, and praziquantel is the only drug available for treatment. Therefore, a better understanding of how the immune system responds to schistosomes may facilitate the development of effective therapeutic strategies.In schistosomiasis, schistosomes evoke responses from many immune cells, including T helper cells, eosinophils, neutrophils, and macrophages, and induce chemokine release.3Chuah C. Jones M.K. Burke M.L. McManus D.P. Gobert and in PubMed Scopus Google Scholar Neutrophils are the immune and a role in Y. S. extracellular traps a host response to PubMed Scopus Google Scholar Neutrophils are to an important role in S. japonicum M.L. McManus D.P. Y. Jones M.K. Gobert expression of the in a of PubMed Scopus Google Scholar S. japonicum recruits and C. Chen Y. Y. Wang Y. Yang Y. Y. L. japonicum recruits and PubMed Scopus Google Scholar In schistosomiasis by S. to neutrophil and the granulomatous Y. Zhang Schistosoma japonicum formation in the PubMed Scopus Google Scholar Neutrophils are to of infection and the pathogens of PubMed Scopus Google Scholar neutrophil and clearance and host Scopus Google Scholar and the formation of neutrophil extracellular traps extracellular traps in and PubMed Scopus Google Scholar NETs are of and extracellular traps in and PubMed Scopus Google C. Y. Y. extracellular traps PubMed Scopus Google G. R. S. S. plays a role in the of neutrophil extracellular PubMed Scopus Google Scholar of NETs of pathogens to further of NETs C. Y. Y. extracellular traps PubMed Scopus Google Scholar extracellular traps and and PubMed Scopus Google Scholar and Y. S. extracellular traps a host response to PubMed Scopus Google Scholar and NET release of the in and the can to S. G. extracellular traps and potential for 2020; Scopus Google NETs in and In that the the formation of in a in C. release of and neutrophil extracellular PubMed Scopus Google Scholar NETs in and in the F. A.J. R. extracellular traps in PubMed Scopus Google Scholar NETs may contribute to of by C. the of neutrophil extracellular PubMed Scopus Google Scholar induce the formation of NETs that the and facilitate by immune S. F. traps are and neutrophil and of PubMed Scopus Google Scholar a that S. G. L. host by a to neutrophil extracellular 2020; PubMed Scopus Google Scholar the NET formation in response to and the role of NETs in the of remains of in S. was in a of C. Jones M.K. Burke M.L. McManus D.P. Gobert and of Schistosoma formation for PubMed Scopus Google Scholar However, the role of and NETs in schistosome remains vesicles (EVs) are vesicles that large of and and in the of L. L. F. of in of extracellular vesicles from 2020; PubMed Scopus Google R. C. S. R. G. vesicles 2020; PubMed Scopus Google S. F. F. C. S. of extracellular vesicles by and and in and PubMed Scopus (10) Google Y. X. for and PubMed Scopus Google Scholar that an important role in are a of that expression the to the of target S. C. A of extracellular vesicles the of in PubMed Scopus Google L. Zhu S. Chen L. Liu X. R. Zhao L. Yang Y. Zhang G. Zhang S. of extracellular vesicles derived of a PubMed Scopus Google Y. Chen L. C. Y. Liu L. Y. Liu G. inhibition and 2020; PubMed Scopus Google L. C. S. R. L. Wang Y. to PubMed Scopus Google Scholar that of Schistosoma can for the and Zhu that derived from S. japonicum eggs S. Wang S. Y. X. Wang X. Zhang Y. of extracellular vesicles from the eggs of Schistosoma PubMed Scopus Google Scholar that derived from Schistosoma mansoni worms that host T helper Y. Y. Y. extracellular host T helper 2020; PubMed Scopus Google Scholar that in derived from Schistosoma eggs liver in S. japonicum L. Y. Yang R. Zhang L. Zhu X. Liu Xu L. in extracellular vesicles liver by schistosomiasis 2020; PubMed Scopus Google Scholar However, is the role of in we that derived from the liver of mice S. japonicum (IL-EVs) induce the formation of miR-142a-3p by plays a key role in IL-EV-mediated induction of NET formation of NETs block further development of S. japonicum in mice and the of However, S. japonicum is of NET formation by upregulating the expression of interleukin-10

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