Epigenetic regulation of immune cell functions during post-septic immunosuppression

Abstract

Studies in humans and animal models indicate that profound immunosuppression is one of the chronic consequences of severe sepsis. This immune dysfunction encompasses deficiencies in activation of cells in both the myeloid and lymphoid cell lineages. As a result, survivors of severe sepsis are at risk of succumbing to infections perpetrated by opportunistic pathogens that are normally controlled by a fully functioning immune system. Recent studies have indicated that epigenetic mechanisms may be one driving force behind this immunosuppression, through suppression of proinflammatory gene production and subsequent immune cell activation, proliferation and effector function. A better understanding of epigenetics and post-septic immunosuppression can improve our diagnostic tools and may be an important potential source of novel molecular targets for new therapies. This review will discuss important pathways of immune cell activation affected by severe sepsis, and highlight pathways of epigenetic regulation that may be involved in post-septic immunosuppression.

Figure 1

Overview of histone modifications and gene regulation events observed in myeloid cells associated with endotoxin shock and sepsis. Phenotypic outcomes associated with the indicated modification events are listed below each cell subtype.

Figure 2

Overview of histone modifications and gene regulation events observed in CD4⁺ T lymphocyte subsets following severe sepsis. Phenotypic outcomes are listed below the indicated modification events.

Figure 3

A schematic of the proposed feedback system between systemic inflammation and epigenetic imprinting of immune progenitor cells. In such a system, epigenetic modifications occur in progenitor cells during the acute phase of sepsis, resulting in re-seeding of tissues with daughter cells carrying similar histone modifications following recovery from sepsis.