Early interleukin 6 production by leukocytes during ischemic acute kidney injury is regulated by TLR4

Jianlin Chen, John R. Hartono, Reji John, Michael Bennett, Xin Jin Zhou, Yanxia Wang, Qingqing Wu, Pamela D. Winterberg, Glenn T. Nagami, Christopher Y. Lu

Research output: Contribution to journalArticlepeer-review

41 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)504-515
Number of pages12
JournalKidney international
Volume80
Issue number5
DOIs
StatePublished - Sep 1 2011

Keywords

  • Acute kidney injury
  • Acute renal failure
  • Inflammation
  • Ischemia-reperfusion
  • Ischemic renal failure

ASJC Scopus subject areas

  • Nephrology

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