Monophosphoryl lipid A pretreatment suppresses sepsis- A nd LPS-induced proinflammatory cytokine production in the medullary thick ascending limb

Bruns A. Watts, Esther Tamayo, Edward R. Sherwood, David W. Good

Research output: Contribution to journalArticle

Abstract

Monophosphoryl lipid A pretreatment suppresses sepsis- A nd LPS-induced proinflammatory cytokine production in the medullary thick ascending limb. Am J Physiol Renal Physiol 319: F8-F18, 2020. First published May 18, 2020; doi:10.1152/ajprenal.00178.2020.-Sepsis is the leading cause of acute kidney injury in critically ill patients. Tumor necrosis factor-α (TNF-α) has been implicated in the pathogenesis of septic kidney injury; however, the sites and mechanisms of renal TNF-α production during sepsis remain to be defined. In the present study, we showed that TNF-α expression is increased in medullary thick ascending limbs (MTALs) of mice with sepsis induced by cecal ligation and puncture. Treatment with lipopolysaccharide (LPS) for 3 h in vitro also increased MTAL TNF-α production. Sepsis and LPS increased MTAL TNF-α expression through activation of the myeloid differentiation factor 88 (MyD88)-IL-1 receptor-associated kinase 1-ERK signaling pathway. Pretreatment with monophosphoryl lipid A (MPLA), a nontoxic immunomodulator that protects against bacterial infection, eliminated the sepsis- A nd LPS-induced increases in MTAL TNF-α production. The suppressive effect of MPLA on TNF-α was mediated through activation of a phosphatidylinositol 3-kinasedependent pathway that inhibits MyD88-dependent ERK activation. This likely involves MPLA-phosphatidylinositol 3-kinasemediated induction of Tollip, which negatively regulates the MyD88-ERK pathway by inhibiting activation of IL-1 receptorassociated kinase 1. These regulatory mechanisms are similar to those previously shown to mediate the effect of MPLA to prevent sepsis-induced inhibition of MTAL HCO3 absorption. These results identify the MTAL as a site of local TNF-α production in the kidney during sepsis and identify molecular mechanisms that can be targeted to attenuate renal TNF-α expression. The ability of MPLA pretreatment to suppress MyD88-dependent ERK signaling in the MTAL during sepsis has the dual beneficial effects of protecting tubule transport functions and attenuating harmful proinflammatory responses.

Original languageEnglish (US)
Pages (from-to)F8-F18
JournalAmerican Journal of Physiology - Renal Physiology
Volume319
Issue number1
DOIs
StatePublished - Jul 2020

Keywords

  • Kidney
  • Lipopolysaccharide
  • Monophosphoryl lipid A
  • Sepsis
  • Tumor necrosis factor-α

ASJC Scopus subject areas

  • Physiology
  • Urology

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