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

Abstract

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- and LPS-induced increases in MTAL TNF-α production. The suppressive effect of MPLA on TNF-α was mediated through activation of a phosphatidylinositol 3-kinase-dependent pathway that inhibits MyD88-dependent ERK activation. This likely involves MPLA-phosphatidylinositol 3-kinase-mediated induction of Tollip, which negatively regulates the MyD88-ERK pathway by inhibiting activation of IL-1 receptor-associated kinase 1. These regulatory mechanisms are similar to those previously shown to mediate the effect of MPLA to prevent sepsis-induced inhibition of MTAL [Formula: see text] 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.

• Authors: Bruns A Watts 3rd, Esther Tamayo, Edward R Sherwood, David W Good
• Journal: American journal of physiology. Renal physiology (Am J Physiol Renal Physiol) Vol. 319 Issue 1 Pg. F8-F18 (07 01 2020) ISSN: 1522-1466 [Electronic] United States
• PMID: 32421349 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Cytokines
• Lipid A
• Lipopolysaccharides
• Myeloid Differentiation Factor 88
• monophosphoryl lipid A

Topics

• Animals
• Cytokines (metabolism)
• Kidney Medulla (drug effects, metabolism)
• Lipid A (analogs & derivatives, pharmacology)
• Lipopolysaccharides (pharmacology)
• Loop of Henle (drug effects, metabolism)
• Male
• Mice
• Mice, Knockout
• Myeloid Differentiation Factor 88 (genetics, metabolism)
• Sepsis (metabolism)
• Signal Transduction (drug effects)