title: Early interleukin 6 production by leukocytes during ischemic acute kidney injury is regulated by TLR4.
abstract: Although leukocytes infiltrate the kidney during ischemic acute kidney injury (AKI) and release interleukin 6 (IL6), their mechanism of activation is unknown. Here, we tested whether Toll-like receptor 4 (TLR4) on leukocytes mediated this activation by interacting with high-mobility group protein B1 (HMGB1) released by renal cells as a consequence of ischemic kidney injury. We constructed radiation-induced bone marrow chimeras using C3H/HeJ and C57BL/10ScNJ strains of TLR4 (-/-) mice and their respective TLR4 (+/+) wild-type counterparts and studied them at 4 h after an ischemic insult. Leukocytes adopted from TLR4 (+/+) mice infiltrated the kidneys of TLR4 (-/-) mice, and TLR4 (-/-) leukocytes infiltrated the kidneys of TLR4 (+/+) mice but caused little functional renal impairment in each case. Maximal ischemic AKI required both radiosensitive leukocytes and radioresistant renal parenchymal and endothelial cells from TLR4 (+/+) mice. Only TLR4 (+/+) leukocytes produced IL6 in vivo and in response to HMGB1 in vitro. Thus, following infiltration of the injured kidney, leukocytes produce IL6 when their TLR4 receptors interact with HMGB1 released by injured renal cells. This underscores the importance of TLR4 in the pathogenesis of ischemic AKI.
authors.affiliation: Division of Nephrology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390-8856, USA.
authors.forename: Jianlin
authors.initials: J
authors.lastname: Chen
authors.forename: John R
authors.initials: JR
authors.lastname: Hartono
authors.forename: Reji
authors.initials: R
authors.lastname: John
authors.forename: Michael
authors.initials: M
authors.lastname: Bennett
authors.forename: Xin Jin
authors.initials: XJ
authors.lastname: Zhou
authors.forename: Yanxia
authors.initials: Y
authors.lastname: Wang
authors.forename: Qingqing
authors.initials: Q
authors.lastname: Wu
authors.forename: Pamela D
authors.initials: PD
authors.lastname: Winterberg
authors.forename: Glenn T
authors.initials: GT
authors.lastname: Nagami
authors.forename: Christopher Y
authors.initials: CY
authors.lastname: Lu
mesh_terms: D058186:Acute Kidney Injury / Q000276:immunology* / Q000473:pathology; D000818:Animals; D001853:Bone Marrow; D002634:Chemotaxis, Leukocyte; D024243:HMGB1 Protein / Q000378:metabolism; D015850:Interleukin-6 / Q000096:biosynthesis*; D007511:Ischemia; D007668:Kidney; D007962:Leukocytes / Q000378:metabolism* / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D051197:Toll-Like Receptor 4 / Q000502:physiology*
chemical_list: D024243:HMGB1 Protein; D015850:Interleukin-6; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4