6533b7d3fe1ef96bd1260206
RESEARCH PRODUCT
IL-33/ST2 pathway regulates neutrophil migration and predicts outcome in patients with severe alcoholic hepatitis.
Sébastien DharancyLine-carolle Ntandja-wandjiPhilippe MathurinRamon BatallerJulie DemaretDoumet Georges HelouMassih NingarhariElodie DrumezEmilie GantierAxel PérianinAxel PérianinAxel PérianinLaurent DubuquoyFlorent ArtruFrançois MaggiottoSylvie Chollet-martinJean-paul Pais De BarrosGuillaume LassaillyJulien LabreucheMohammed Bou SalehAlexandre Louvetsubject
Male0301 basic medicineAlcoholic liver diseaseCirrhosisPolymorphonuclear neutrophilsNeutrophils[SDV.MHEP.PHY] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO]ApoptosisGastroenterologyReceptors Interleukin-8BLiver disease0302 clinical medicineCell MovementLiver Cirrhosis AlcoholicProspective StudiesCXC chemokine receptorsReceptorCells CulturedMigrationMiddle AgedPrognosisRecombinant Proteins3. Good healthCirrhosisAlcoholic hepatitis;Cirrhosis;Infection;Interleukin-33;Migration;Polymorphonuclear neutrophilsFemale030211 gastroenterology & hepatologyAlcoholic hepatitisInfectionSignal TransductionAdultmedicine.medical_specialtyAlcoholic hepatitisSepsis03 medical and health sciencesInternal medicinemedicine[SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO]Humanscardiovascular diseasesAgedHepatologyHepatitis Alcoholicbusiness.industrymedicine.diseaseInterleukin-33Interleukin-1 Receptor-Like 1 Proteinnervous system diseasesInterleukin 33030104 developmental biologyCase-Control StudiesbusinessFollow-Up Studiesdescription
Background & Aims Severe alcoholic hepatitis (SAH) is associated with a high risk of infection. The IL-33/ST2 pathway is involved in sepsis control but data regarding its role in alcohol-related liver disease (ALD) are lacking. We aimed to characterize the role of IL-33/ST2 in the polymorphonuclear neutrophils (PMNs) of patients with ALD and SAH. Methods Serum and circulating neutrophils were collected from patients with SAH, alcoholic cirrhosis and healthy controls. We quantified IL-33/ST2 pathway activity and CXCR2 at baseline and after exposure to IL-33. We also determined the migration capacity of PMNs. Results The decoy receptor of IL-33 (soluble ST2 [sST2]) was increased in SAH vs. cirrhosis and controls, demonstrating the defect in this pathway during ALD. The sST2 level was associated with response to treatment, 2-month survival, infection-free survival and probability of infection in SAH. Endotoxemia was weakly correlated with sST2. GRK2, a negative regulator of CXCR2, was overexpressed in PMNs of patients with SAH and cirrhosis and was decreased by IL-33. CXCR2 levels on PMNs were lower in SAH vs. cirrhosis and controls. Treatment with IL-33 partially restored CXCR2 expression in SAH and cirrhosis. PMN migration upon IL-8 was lower in patients with SAH and cirrhosis vs. controls. Treatment with IL-33 partially restored migration in those with SAH and cirrhosis. Interestingly, the migration capacity of PMNs and the response to IL-33 were enhanced in responders to corticosteroids (Lille Conclusion The IL33/ST2 pathway is defective in SAH and predicts outcome. This defect is associated with decreased CXCR2 expression on the surface of PMNs and lower migration capacity, which can be corrected by IL-33, especially in patients responding to steroids. These results suggest that IL-33 has therapeutic potential for SAH and its infectious complications. Lay summary The neutrophils of patients with severe alcoholic hepatitis are associated with a defect in the IL-33/ST2 pathway. This defect is associated with lower migration capacities in neutrophils and a higher probability of getting infected. Administration of IL-33 to the neutrophils at least partly restores this defect and may be effective at reducing the risk of infection in patients with severe alcoholic hepatitis.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2020-06-01 |