IL-37 Suppresses M1 Macrophage Polarization Through The Notch1 And NF-κB Pathways To Attenuate The Progression Of Aortic Valve Calcification

PART1 Interleukin 37 suppresses M1 macrophage polarization through the Notchl and nuclear factor kappa B pathwaysMacrophage-orchestrated chronic inflammation plays an important role in cardiovascular disease,including accelerating the development of calcific aortic valve disease(CAVD).M1 and M2 macrophage polarization imbalances can alter intensity of inflammatory responses.Recombinant human interleukin 37(IL-37)could be involved in regulating immune cell function to attenuate inflammation.This study aimed to identify IL-37 specifically modulates M1 polarization and investigate the underlying mechanism.Compared with normal aortic valves,there are more M1 macrophages accumulation and less IL-37 expression in calcific aortic valves,which may indicate a negative relationship between IL-37 and M1 polarization.THP-1 cells could differentiate into resting macrophages with phorbol-12-myristate-13-acetate(PMA)and then polarize into M1 macrophages following the treatment with lipopolysaccharide(LPS)and interferon gamma(IFN-γ).In vitro,recombinant human IL-37 attenuated the expression of inducible nitric oxide synthase(iNOS),CD11c,IL-6 and monocyte chemoattractant protein 1(MCP-1)in Ml but augmented the expression of CD206 and IL-10 in M2.The suppression of M1 polarization was associated with the inhibition of the activation of the nuclear factor kappa B(NF-κB)and Notchl signaling pathways.These results demonstrated that IL-37 inhibited the macrophages polarizing into M1 type via the inhibition of the Notchl and nuclear factor kappa B pathways.In summary,IL-37 could be a potential therapeutic candidate for progressive CAVD by modulating M1 polarization and its orchestrated inflammation.PART2 Correlation between the plasma level of interleukin-37 and peri-operative factors in patients undergoing cardiac surgeryUntil now,The level of plasma IL-37 after cardiac surgery has not been studied.The purpose of this study was to monitor the plasma level of IL-37 in patients after cardiac surgery and to evaluate the relationship between plasma level of IL-37 and clinical factors,biochemical laboratory indexes.We measured the postoperative the plasma level of IL-37,the clinical indexes and biochemical test results before and after the operation,and analyzed the correlation between the plasma level of IL-37 and various peri-operative factors.The variables related to IL-37 included body surface area,body weight,postoperative platelet count,preoperative history of CKD,serum creatinine and cystatin-c before and after operation,cardiothoracic ratio,BMI,postoperative EF,postoperative use of natriuretic peptide,intraoperative or postoperative erythrocyte infusion,WBC on the first day after operation,mechanical ventilation time,and hospitalization days.The level of IL-37 can be used as a predictor of cardiac function,postoperative mechanical ventilation time and hospital stay in patients,and a predictor of postoperative renal insufficiency in cardiac the patients undergoing cardiac surgery.