Тhe role of the IL-33/ST2 axis in the immunopathogenesis of experimental acute gastric injury

[I. F. Ćorović]

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Peptička ulkusna bolest predstavlja značajan globalni zdravstveni problem zbog visoke učestalosti i ozbiljnih kliničkih komplikacija. Bolje razumevanje inflamacijskih puteva koji učestvuju u oštećenju sluznice želuca može otvoriti nove mogućnosti za ciljane terapijske intervencije. Eksperimentalna manipulacija IL- 33/ST2 osovine pokazala je da može uticati na tok inflamacije i oštećenja epitela u gastrointestinalnom traktu. Cilj studije je da se ispita efekat delecije ST2 na različite tokove inflamacije i mehanizme ćelijske smrti u eksperimentalnom modelu akutnog oštećenja želuca. Akutno oštećenje želuca izazvano je jednokratnom primenom 80% etanola oralnom gavažom kod miševa sa nedostatkom gena za ST2 i miševa čistog soja BALB/c. Nakon indukcije oštećenja sprovedena je makroskopska i p atohistološka procena intenziteta tkivnog oštećenja. Analiziran je uticaj delecije ST2 na modulaciju imunskog odgovora i puteva ćelijske smrti u oštećenom tkivu želuca, dok je rekombinantni mišji IL-33 aplikovan u ciljnim grupama radi funkcionalne potvrde. Delecija ST2 ublažava akutno oštećenje želuca kod miševa inhibicijom NF- κB i NLRP3 signalnih puteva u tkivu želuca, što je praćeno smanjenom infiltracijom ćelija urođene i stečene imunosti, kao i sniženom produkcijom proinflamacijskih citokina. Takođe, delecija ST2 ograničava apoptozu epitelnih ćelija, dok primena rekombinantnog IL-33 pogoršava oštećenje sluznice želuca, potvrđujući patogenu ulogu IL-33/ST2 osovine. Dobijeni rezultati ukazuju da nedostatak ST2 gena ublažava akutno oštećenje želuca i ciljanje IL-33/ST2 osovine predstavlja potencijalno obećavajuću strategiju za lečenje peptične ulkusne bolesti želuca.

Peptic ulcer disease represents a significant global health problem due to its high prevalence and serious clinical complications. A better understanding of the inflammatory pathways involved in gastric mucosal injury may open new opportunities for targeted therapeutic interventions. Experimental manipulation of the IL-33/ST2 axis has been shown to influence the course of inflammation and epithelial damage in the gastrointestinal tract. The aim of this study was to investigate the effect of ST2 deletion on different inflammatory pathways and mechanisms of cell death in an experimental model of acute gastric injury. Acute gastric injury was induced by a single oral gavage of 80% ethanol in wild-type and ST2-deficient BALB/c mice. Following injury induction, macroscopic and histopathological assessments of tissue damage severity were performed. The impact of ST2 deletion on immune response modulation and cell death pathways in damaged gastric tissue was analyzed, while recombinant murine IL-33 was administered to selected groups for functional validation. ST2 deletion attenuated acute gastric injury in mice by inhibiting NF-κB and NLRP3 signaling in gastric tissue, which was accompanied by reduced infiltration of innate and adaptive immune cells and decreased production of pro-inflammatory cytokines. In addition, ST2 deletion limited epithelial cell apoptosis, whereas administration of recombinant IL-33 exacerbated gastric mucosal damage, confirming the pathogenic role of the IL-33/ST2 axis. These findings indicate that ST2 deficiency alleviates acute gastric injury and that targeting the IL-33/ST2 axis represents a promising strategy for the treatment of peptic ulcer disease.

IL-33/ST2 osovina, akutno oštećenje želuca, NF-κB, NLRP3 inflamazom, ćelijska smrt.

IL-33/ST2 axis, аcute gastric injury, NF-κB, NLRP3 inflammasome, cell death.

616.33-002.1-092-097(043.3)

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