Research On Pyroptosis In Hepatic Granulomatous Inflammation Induced By Schistosoma Japonicum Infection

In order to fight with the invasion of pathogens,body senses the danger signals and initiated a series of inflammation respond through the innate immune system.Emerging evidence show that pyroptosis contributes to immune defense against infectious diseases.Pyroptosis is a form of programed cell death mediated by gasdermin,which is activated by the inflammatory caspases,including human and mouse caspase-1,human caspase-4 and caspase-5,or mouse caspase-11.Caspases are activated at the platform of poly-protein complexes,called inflammasome.Canonical inflammasomes is composed of proteins including NOD-like receptors(NLRs)or the absent in melanoma 2(AIM)-like receptors(AIM2)as the sensor,where pro-caspase-1 is an executor,while apoptosis-associated speck like protein containing a caspase recruitment domain(ASC or Pycard)sometimes is an adapter.Activation of caspase-1 leads to production of pro-inflammatory cytokines IL-1β & IL-18 or pyroptosis.Caspase-11 itself can be a cytosolic PRR which senses cytosolic LPS,then leading to itself oligomerization and activation,finally cleave gasdermin D(GSDMD).Pore-formation by GSDMD causes cell swelling to rupture and release of pro-inflammatory cytokines including IL-1β and IL-18,as well as DAMPs.Consequently,inflammation is initiated and amplified rapidly.However,aberrant inflammation can make the immune system out of control and tissue damage more severe.Schistosoma japonicum(Sj)-induced schistosomiasis is a severe helminthic disease characterized by numerous eggs-induced granulomas in the liver and other organs.Granulomas consist of a tightly clusterd population of neutrophils,macrophages,lymphocytes and epithelioids.They arise in order to neutralize and clear the cytotoxixc products from egg,which is called soluble egg antigens(SEA).These granulomas can develop into severe fibrosis,then transfer into portal hypertension,which can lead to portal venous occlusive disease.The underlying mechanisms how body senses the dangerous components in SEA and initiates the cellular recruitment to lesions in liver infected by Schistosoma japonicum remain unclear.Considering the effect of pyproptosis,we reckon that pyroptosis is involved in the initiation and the developmet of hepatic granulomatous inflammation induced by soluble egg antigens of Schistosoma japonicum.In this study,we find that Caspase-1 and caspase-11 mediated GSDMD cleavage happens in the liver tissues of mice.The level of caspase-11 mediated GSDMD cleavage is the highest at week 5 post-Sj infection,while the level of caspase-1 cleavage keeps higher level in all time courses we tested.In vitro,single stimulation of SEA can induce the caspase-1/11 activation,IL-1β release and GSDMD cleavage in THP1-differentiated macrophages.And we showed that NLRP3 inflammasome contrubites to caspsase-1 executed GSDMD cleavage and IL-1β activation in mouse livers post Sj infection.Surprisingly,caspsase-4/11 are activated to cleave induced by single stimulation of SEA of Schistosoma japonicum without LPS.Taken together,our results indicate that pyproptosis may play a critical role in the initiation and the developmet of eggs-induced granulomatous inflammation in the liver infected by Schistosoma japonicum.And a new mechanism of caspase-11 activation induced by the component in SEA needs our further study.