Pyruvate dehydrogenase complex stimulation promotes immunometabolic homeostasis and sepsis survival
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
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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Research Article Immunology Infectious disease

Pyruvate dehydrogenase complex stimulation promotes immunometabolic homeostasis and sepsis survival

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 5

Dichloroacetate (DCA) treatment increases blood pressure and improves microvascular dysfunction.

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Dichloroacetate (DCA) treatment increases blood pressure and improves mi...
Septic animals were treated with DCA or vehicle 24 hours after cecal ligation and puncture (CLP) and assessed 6 hours after treatment. (A) Mean arterial pressure (MAP), measured via carotid artery cannulation, was significantly higher in CLP+ DCA vs. CLP+ vehicle group. (B) Mice treated with DCA (CLP+ DCA) or vehicle (CLP+ vehicle) were challenged with either normal saline (denoted as –LPS) or LPS (+LPS) i.p., and leukocyte and platelet adhesion were determined 4 hours later in the small intestine using intravital microscopy. CLP+ vehicle group did not show significant increase in leukocyte or platelet adhesion in response to LPS (+LPS) vs. normal saline (–LPS) stimulation and remained endotoxin tolerant. However, in CLP+ DCA groups, leukocyte and platelet adhesion increased significantly in response to LPS (vs. respective –LPS group), demonstrating endotoxin responsiveness. (C) E-selectin (left panel), ICAM1 (right panel) adhesion molecules, von Willebrand factor (VWF) endothelial marker, and nuclear DAPI staining show qualitatively increased E-selectin and ICAM1 expression in small intestinal tissue sections of CLP+ DCA vs. CLP+ vehicle group. IHC scale bar: 100 μm; A, n = 4 per group, t test. B, n = 5 in ±LPS vehicle and +LPS DCA, n = 4 in –LPS DCA. Assessed by 1-way ANOVA with Tukey post hoc multiple comparison test. C, n = 3. One exemplary result is shown. **P < 0.01; ***P < 0.001.