| 1 | Macrophage-specific inhibition of the histone demethylase JMJD3 decreases STING and pathologic inflammation in diabetic wound repair显示文摘Macrophage plasticity is critical for normal tissue repair following injury.In pathologic states such as diabetes,macrophage plasticity is impaired,and macrophages remain in a persistent proinflammatory state;however,the reasons for this are unknown.Here,using single-cell RNA sequencing of human diabetic wounds,we identified increased JMJD3 in diabetic wound macrophages,resulting in increased inflammatory gene expression.Mechanistically,we report that in wound healing,JMJD3 directs early macrophage-mediated inflammation via JAK1,3/STAT3 signaling.However,in the diabetic state,we found that IL-6,a cytokine increased in diabetic wound tissue at later time points post-injury,regulates JMJD3 expression in diabetic wound macrophages via the JAK1,3/STAT3 pathway and that this late increase in JMJD3 induces NFκB-mediated inflammatory gene transcription in wound macrophages via an H3K27me3 mechanism.Interestingly,RNA sequencing of wound macrophages isolated from mice with JMJD3-deficient myeloid cells(Jmjd3f/fLyz2Cre+)identified that the STING gene(Tmem173)is regulated by JMJD3 in wound macrophages.STING limits inflammatory cytokine production by wound macrophages during healing.However,in diabetic mice,its role changes to limit wound repair and enhance inflammation.This finding is important since STING is associated with chronic inflammation,and we found STING to be elevated in human and murine diabetic wound macrophages at late time points.Finally,we demonstrate that macrophage-specific,nanoparticle inhibition of JMJD3 in diabetic wounds significantly improves diabetic wound repair by decreasing inflammatory cytokines and STING.Taken together,this work highlights the central role of JMJD3 in tissue repair and identifies cell-specific targeting as a viable therapeutic strategy for nonhealing diabetic wounds. | Christopher O.Audu William J.Melvin Amrita D.Joshi Sonya J.Wolf Jadie Y.Moon Frank M.Davis Emily C.Barrett Kevin D.Mangum Hongping Deng Xianying Xing Rachel Wasikowski Lam C.Tsoi Sriganesh B.Sharma Tyler M.Bauer James Shadiow Matthew A.Corriere Andrea TObi Steven LKunkel Benjamin Levi Bethany BMoore Johann EGudjonsson Andrew MSmith Katherine A.Gallagher | 2022 | Cellular & Molecular Immunology2022，19，11： | 2 |
| 2 | Endothelin-1 activation in pediatric patients undergoing surgical coarctation of the aorta repair显示文摘AIM To determine endothelin-1(ET-1)concentration before and after surgical coarctectomy and evaluate its association with left ventricular geometric change.METHODSA prospective,cohort study of 24 patients aged 2 d to 10years with coarctation of the aorta undergoing surgical repair.A sub-cohort of patients with age<1 mo was classified as'neonates'.Echocardiograms were performed just prior to surgery and in the immediate post-op period to assess left ventricle mass index and relative wall thickness(RWT).Plasma ET-1 levels were assessed at both time points.Association between ET-1 levels and ventricular remodeling was assessed.RESULTSPatients<1 year demonstrated higher pre-op ET-1 than post-op(2.8 pg/m L vs 1.9 pg/m L,P=0.02).Conversely,patients>1 year had no change in ET-1 concentration before and after surgery(1.1 vs 1.4,NS).Pre-op,patients<1 year demonstrated significantly higher ET-1 than older children(2.8 vs 1.1,P=0.001).Post-op there was no difference between the age groups(1.9 vs 1.4,NS).Neither RWT nor left ventricle mass index(LVMI)varied from pre-op to post-op.The subset of neonates showed a strong positive correlation between pre-op ET-1 and RWT(r=0.92,P=0.001).Patients with ET-1>2 pg/m L preop demonstrated higher LVMI(65.7 g/m^(2.7) vs 38.5 g/m^(2.7),P=0.004)and a trend towards higher RWT(45%vs39%,P=0.07)prior to repair than those with lower ET-1concentration.CONCLUSIONET-1 concentration is significantly variable in the perioperative period surrounding coarctectomy.Older children and infants have different responses to surgical repair suggesting different mechanisms of activation. | Benjamin Steven Frank Tracy T Urban Suhong Tong Courtney Cassidy Max B Mitchell Christopher S Nichols Jesse A Davidson | 2017 | World Journal of Cardiology2017，9，12： | 2 |
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