title: Reactive oxygen species and IRF1 stimulate IFNα production by proximal tubules during ischemic AKI.
abstract: We previously reported that expression of the transcription factor interferon regulatory factor 1 (IRF1) is an early, critical maladaptive signal expressed by renal tubules during murine ischemic acute kidney injury (AKI). We now show that IRF1 mediates signals from reactive oxygen species (ROS) generated during ischemic AKI and that these signals ultimately result in production of α-subtypes of type I interferons (IFNαs). We found that genetic knockout of the common type I IFN receptor (IFNARI-/-) improved kidney function and histology during AKI. There are major differences in the spatial-temporal production of the two major IFN subtypes, IFNβ and IFNαs: IFNβ expression peaks at 4 h, earlier than IFNαs, and continues at the same level at 24 h; expression of IFNαs also increases at 4 h but continues to increase through 24 h. The magnitude of the increase in IFNαs relative to baseline is much greater than that of IFNβ. We show by immunohistology and study of isolated cells that IFNβ is produced by renal leukocytes and IFNαs are produced by renal tubules. IRF1, IFNαs, and IFNARI were found on the same renal tubules during ischemic AKI. Furthermore, we found that ROS induced IFNα expression by renal tubules in vitro. This expression was inhibited by small interfering RNA knockdown of IRF1. Overexpression of IRF1 resulted in the production of IFNαs. Furthermore, we found that IFNα stimulated production of maladaptive proinflammatory CXCL2 by renal tubular cells. Altogether our data support the following autocrine pathway in renal tubular cells: ROS > IRF1 > IFNα > IFNARI > CXCL2.
authors: Department of Pediatrics, Nephrology Division, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors: Pamela D
authors: PD
authors: Winterberg
authors: Yanxia
authors: Y
authors: Wang
authors: Keng-Mean
authors: KM
authors: Lin
authors: John R
authors: JR
authors: Hartono
authors: Glenn T
authors: GT
authors: Nagami
authors: Xin J
authors: XJ
authors: Zhou
authors: John M
authors: JM
authors: Shelton
authors: James A
authors: JA
authors: Richardson
authors: Christopher Y
authors: CY
authors: Lu
mesh_terms: D058186:Acute Kidney Injury / Q000378:metabolism*; D000818:Animals; D019898:Autocrine Communication; D054426:Chemokine CXCL2 / Q000378:metabolism*; D004195:Disease Models, Animal; D050856:Interferon Regulatory Factor-1 / Q000494:pharmacology*; D016898:Interferon-alpha / Q000096:biosynthesis*; D007687:Kidney Tubules, Proximal / Q000378:metabolism; D007962:Leukocytes / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D017382:Reactive Oxygen Species / Q000494:pharmacology*; D053633:Receptor, Interferon alpha-beta / Q000378:metabolism; D015427:Reperfusion Injury / Q000378:metabolism*
chemical_list: D054426:Chemokine CXCL2; C404915:Cxcl2 protein, mouse; D050856:Interferon Regulatory Factor-1; D016898:Interferon-alpha; C494258:Irf1 protein, mouse; D017382:Reactive Oxygen Species; D053633:Receptor, Interferon alpha-beta
keywords: AKI; innate immunity; type I interferon
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