The immune suppressive properties of damage associated molecular patterns in the setting of sterile traumatic injury

Abstract

Associated with the development of hospital-acquired infections, major traumatic injury results in an immediate and persistent state of systemic immunosuppression, yet the underlying mechanisms are poorly understood. Detected in the circulation in the minutes, days and weeks following injury, damage associated molecular patterns (DAMPs) are a heterogeneous collection of proteins, lipids and DNA renowned for initiating the systemic inflammatory response syndrome. Suggesting additional immunomodulatory roles in the post-trauma immune response, data are emerging implicating DAMPs as potential mediators of post-trauma immune suppression. Discussing the results of in vitro, in vivo and ex vivo studies, the purpose of this review is to summarise the emerging immune tolerising properties of cytosolic, nuclear and mitochondrial-derived DAMPs. Direct inhibition of neutrophil antimicrobial activities, the induction of endotoxin tolerance in monocytes and macrophages, and the recruitment, activation and expansion of myeloid derived suppressor cells and regulatory T cells are examples of some of the immune suppressive properties assigned to DAMPs so far. Crucially, with studies identifying the molecular mechanisms by which DAMPs promote immune suppression, therapeutic strategies that prevent and/or reverse DAMP-induced immunosuppression have been proposed. Approaches currently under consideration include the use of synthetic polymers, or the delivery of plasma proteins, to scavenge circulating DAMPs, or to treat critically-injured patients with antagonists of DAMP receptors. However, as DAMPs share signalling pathways with pathogen associated molecular patterns, and pro-inflammatory responses are essential for tissue regeneration, these approaches need to be carefully considered in order to ensure that modulating DAMP levels and/or their interaction with immune cells does not negatively impact upon anti-microbial defence and the physiological responses of tissue repair and wound healing.

Keywords: critical care; damage associated molecular patterns; immunosuppression; innate immunity; trauma.

Figure 1

Theoretical model of a HMGB-1 and resistin-induced vicious cycle of immunosuppression in the setting of sterile injury. Passively released from damaged/necrotic tissue, the nuclear-derived damage associated molecular pattern high mobility group box-1 (HMGB-1) modulates the functions of innate and adaptive immune cells. Via binding to the pathogen recognition receptors toll like receptor-4 (TLR-4), and receptor for advanced glycation end products (RAGE), HMGB-1 directly inhibits neutrophil anti-microbial functions and enhances the suppressive activities of regulatory T cells and myeloid derived suppressor cells (MDSCs). Monocytes activated by HMGB-1 secrete resistin, an inducer of endotoxin tolerance, and a negative regulator of neutrophil chemotaxis and reactive oxygen species (ROS) production. In a self-perpetuating feedback loop, resistin, through TLR-4 signalling, promotes the secretion of HMGB-1 by monocytes, culminating in a localised immune suppressive environment at the site of tissue injury. IL-10, Interleukin-10; LPS, Lipopolysaccharide. Figure was generated at Biorender.com.

Figure 2

Proposed therapeutic strategies for treating damage associated molecular pattern (DAMP)-induced immunosuppression. Two therapeutic approaches under consideration for preventing and/or reversing DAMP-induced immunosuppression are to scavenge circulating DAMPs or to inhibit their activation of immune cells. Restoring circulating levels of hemopexin (Hpx), a heme scavenging protein whose plasma concentrations are reduced post-injury, may help combat heme-induced suppression of neutrophil anti-microbial functions, whilst the use of microfiber meshes or nucleic acid scavenging polymers (NASPs) to reduce the systemic load of circulating mtDNA and HMGB-1 could alleviate the post-trauma impairments reported in monocyte and neutrophil function. Showing promise in in vitro studies, blocking DAMP-induced activation of neutrophils through the use of toll-like receptor-9 (TLR-9) or formyl peptide receptor-1 (FPR-1) antagonists prevents the induction of functional tolerance to subsequent secondary stimulation with inflammatory agonists or microbial-derived proteins. HMGB-1, High mobility group box-1, mtDNA, Mitochondrial-derived DNA; mtFPs, Mitochondrial-derived N-formylated peptides; RAGE, Receptor for advanced glycation end products; ROS, Reactive oxygen species; TLR, Toll-like receptor. Figure was were generated at Biorender.com.