title: IL-4/IL-13-mediated polarization of renal macrophages/dendritic cells to an M2a phenotype is essential for recovery from acute kidney injury.
abstract: Cytokines IL-4 and IL-13 play important roles in polarization of macrophages/dendritic cells to an M2 phenotype, which is important for recovery from acute kidney injury. Both IL-4 and IL-13 activate JAK3/STAT6 signaling. In mice with diphtheria toxin receptor expression in proximal tubules (selective injury model), a relatively selective JAK3 inhibitor, tofacitinib, led to more severe kidney injury, delayed recovery from acute kidney injury, increased inflammatory M1 phenotype markers and decreased reparative M2 phenotype markers of macrophages/dendritic cells, and development of more severe renal fibrosis after diphtheria toxin administration. Similarly, there was delayed recovery and increased tubulointerstitial fibrosis in these diphtheria toxin-treated mice following tamoxifen-induced deletion of both IL-4 and IL-13, with increased levels of M1 and decreased levels of M2 markers in the macrophages/dendritic cells. Furthermore, deletion of IL-4 and IL-13 led to a decrease of tissue reparative M2a phenotype markers but had no effect on anti-inflammatory M2c phenotype markers. Deletion of IL-4 and IL-13 also inhibited recovery from ischemia-reperfusion injury in association with increased M1 and decreased M2 markers and promoted subsequent tubulointerstitial fibrosis. Thus, IL-4 and IL-13 are required to effectively polarize macrophages/dendritic cells to an M2a phenotype and to promote recovery from acute kidney injury.
authors.affiliation: Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA; Vanderbilt Center for Kidney Disease, Vanderbilt University School of Medicine, Nashville, Tennessee, USA. Electronic address: mingzhi.zhang@vanderbilt.edu.
authors.forename: Ming-Zhi
authors.initials: MZ
authors.lastname: Zhang
authors.affiliation: Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.affiliation: Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors.forename: Yinqiu
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors.forename: Aolei
authors.initials: A
authors.lastname: Niu
authors.affiliation: Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors.forename: Suwan
authors.initials: S
authors.lastname: Wang
authors.affiliation: Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors.forename: Chenhang
authors.initials: C
authors.lastname: Zou
authors.affiliation: Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA; Vanderbilt Center for Kidney Disease, Vanderbilt University School of Medicine, Nashville, Tennessee, USA; Department of Veterans Affairs, Nashville, Tennessee, USA. Electronic address: ray.harris@vanderbilt.edu.
authors.forename: Raymond C
authors.initials: RC
authors.lastname: Harris
mesh_terms: D058186:Acute Kidney Injury / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D000066670:Cell Plasticity; D003713:Dendritic Cells / Q000378:metabolism* / Q000473:pathology; D004167:Diphtheria Toxin; D004195:Disease Models, Animal; D005355:Fibrosis; D005838:Genotype; D066257:Heparin-binding EGF-like Growth Factor / Q000235:genetics / Q000378:metabolism; D018793:Interleukin-13 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015847:Interleukin-4 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D053616:Janus Kinase 3 / Q000378:metabolism; D007668:Kidney / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D008297:Male; D057507:Mice, 129 Strain; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D010641:Phenotype; D020127:Recovery of Function; D015427:Reperfusion Injury / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D050800:STAT6 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors
chemical_list: D004167:Diphtheria Toxin; D066257:Heparin-binding EGF-like Growth Factor; D018793:Interleukin-13; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D015847:Interleukin-4; C507935:Jak3 protein, mouse; D053616:Janus Kinase 3
keywords: STAT6; ischemia-reperfusion; macrophage polarization; tofacitinib