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Pyruvate dehydrogenase complex stimulation promotes immunometabolic homeostasis and sepsis survival
Charles E. McCall, … , Peter W. Stacpoole, Vidula Vachharajani
Charles E. McCall, … , Peter W. Stacpoole, Vidula Vachharajani
Published August 9, 2018
Citation Information: JCI Insight. 2018;3(15):e99292. https://doi.org/10.1172/jci.insight.99292.
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Research Article Immunology Infectious disease

Pyruvate dehydrogenase complex stimulation promotes immunometabolic homeostasis and sepsis survival

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Abstract

Limited understanding of the mechanisms responsible for life-threatening organ and immune failure hampers scientists’ ability to design sepsis treatments. Pyruvate dehydrogenase kinase 1 (PDK1) is persistently expressed in immune-tolerant monocytes of septic mice and humans and deactivates mitochondrial pyruvate dehydrogenase complex (PDC), the gate-keeping enzyme for glucose oxidation. Here, we show that targeting PDK with its prototypic inhibitor dichloroacetate (DCA) reactivates PDC; increases mitochondrial oxidative bioenergetics in isolated hepatocytes and splenocytes; promotes vascular, immune, and organ homeostasis; accelerates bacterial clearance; and increases survival. These results indicate that the PDC/PDK axis is a druggable mitochondrial target for promoting immunometabolic and organ homeostasis during sepsis.

Authors

Charles E. McCall, Manal Zabalawi, Tiefu Liu, Ayana Martin, David L. Long, Nancy L. Buechler, Rob J. W. Arts, Mihai Netea, Barbara K. Yoza, Peter W. Stacpoole, Vidula Vachharajani

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Figure 6

Dichloroacetate (DCA) treatment repolarizes effector and repressor immune cell responses in the spleen.

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Dichloroacetate (DCA) treatment repolarizes effector and repressor immun...
To examine the effect of pyruvate dehydrogenase kinase (PDK) inhibition on immune polarity, we used flow cytometry to analyze isolated splenocytes for CD4+ T cells and CD11c+ DCs obtained from post–cecal ligation and puncture (CLP) mice with or vehicle (CLP+ vehicle) vs. DCA (CLP+ DCA) treatment. Isolated splenocytes were assayed 6 hours after DCA/vehicle treatments and compared with SHAM control. The proportion of total CD4+ cells among total splenocytes was significantly lower in both the sepsis groups (CLP+ vehicle and CLP+ DCA) and was unaffected by DCA (A). The proportion of CD25+FoxP3+CD4+ Tregs were not significantly higher in CLP+ vehicle group vs. SHAM, while the proportion of CD25+FoxP3+CD4+ cells in the CLP+ DCA group was significantly lower vs. CLP+ vehicle group (B). Sepsis also induced an increase in the frequency of CD11c+ cells in CLP+ vehicle vs. SHAM group, and this trend was not affected by DCA (C). However, sepsis caused a marked fall in IL-12+CD11c+ cell frequency in CLP+ vehicle vs. SHAM group and a significant increase in IL-12+CD11c+ cells vs. CLP+ vehicle group (D). A, SHAM n = 9, CLP n = 14, CLP+ DCA n = 13; B, SHAM n = 5, CLP n = 5, CLP+ DCA n = 3; C, SHAM n = 2, CLP n = 4, CLP+ DCA n = 5; D, SHAM n = 2, CLP n = 4, CLP+ DCA n = 5. Assessed by 1-way ANOVA with Sidak’s post hoc multiple comparisons. *P < 0.05.

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