Epigenetic coordination of acute systemic inflammation: potential therapeutic targets

Abstract

Epigenetic reprogramming of thousands of genes directs the course of acute systemic inflammation, which is highly lethal when dysregulated during sepsis. No molecular-based treatments for sepsis are available. A new concept supports that sepsis is an immunometabolic disease and that loss of control of nuclear epigenetic regulator sirtuin 1 (SIRT-1), a NAD⁺ sensor directs immune and metabolic pathways during sepsis. SIRT-1, acting as homeostasis checkpoint, controls hyper- and hypo-inflammatory responses of sepsis at the microvascular interface, which disseminates inflammatory injury to cause multiple organ failure. Modifying SIRT-1 activity, which can prevent or treat established sepsis in mice, may provide a new way to treat sepsis by epigenetically restoring immunometabolic homeostasis.

Keywords::

• acute inflammation
• epigenetics
• immunometabolism
• leukocyte adhesion
• microvascular dysfunction
• sepsis
• SIRT-1

Acknowledgements

Part of images from Motifolio drawing toolkits (www.motifolio.com) were utilized in the figure preparation.

Financial & competing interests disclosure

This work was supported by NIH grants R01GM099807 (V Vachharajani), R01AI065791 (CE McCall), R01AI079144 (CE McCall). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Acute inflammation during sepsis kills millions annually. Currently, there is no treatment that targets sepsis pathophysiology.

• Epigenetic programming of thousands of genes decides the fate of the organism during acute inflammation including sepsis.

• Sepsis is an immunometabolic disease.

• Epigenetic regulator and homeostat SIRT-1 reprograms inflammatory and metabolic pathways during sepsis.

• Modifying SIRT-1 activity provides a new target for preventing early or treating late sepsis.

• SIRT-1 modulation may be the way to target pathophysiology of sepsis.

Notes