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.

Major trauma induces innate immune suppression, yet the underlying mechanisms are poorly understood. Resistin is an immunosuppressive molecule that is systemically elevated post-injury. However, its role in trauma-induced immune dysfunction and clinical outcomes is poorly defined. Here, we acquired blood samples from 147 adult trauma patients (≤1, 4–12, 48–72 h post-injury) and 95 burns patients (days 1, 3, 7, 14, 28 post-burn). We measured plasma resistin concentrations, studied resistin gene expression in peripheral blood mononuclear cells (PBMCs) and neutrophils, and measured resistin production by lipopolysaccharide (LPS)-challenged whole blood leukocytes. To identify potential novel triggers of resistin secretion by immune cells, we examined the effect that stimulation with mitochondrial-derived damage-associated molecular patterns (mtDAMPs) had on resistin production by neutrophils isolated from healthy donors. We also treated neutrophils, from healthy donors, and THP-1 cells with resistin prior to stimulation with Phorbol 12-myristate-13-acetate (PMA) or LPS to study its effects on reactive oxygen species (ROS) and cytokine production, respectively. Injured patients presented with significantly elevated circulating resistin concentrations and increased resistin gene expression in PBMCs and neutrophils. LPS and mtDAMP stimulation promoted resistin secretion by whole blood leukocytes and neutrophils. Plasma resistin concentrations were negatively associated with PMA-induced ROS generation by neutrophils, and LPS-induced cytokine production by monocytes. Resistin-treated THP-1 cells and neutrophils exhibited impaired functional responses upon secondary stimulation with LPS or PMA, respectively. Trauma patients who developed multiple organ dysfunction syndrome (MODS) presented with significantly elevated resistin concentrations, which at 48–72 h post-injury showed good performance as a predictor of post-traumatic MODS (AUROC, 0.796). Hyperresistinemia is an immediate and persistent feature of the inflammatory response to injury that may contribute to the development of innate immune dysfunction.

Platelet activation is energy-dependent and associated with a hyperglycolytic phenotype, yet the role of key glycolytic enzymes remains unclear. We investigated the role of platelet hexokinases (HK1 and HK2) in regulating thrombin- and convulxin-stimulated bioenergetics, functions, and hemostasis using pharmacological inhibitors 2-deoxyglucose (2DG; pan-HK) and 3-bromopyruvate (3BP; HK2-preferential). Platelet activation increased HK activity, with convulxin producing a stronger response than thrombin. Using 2DG and 3BP, we found that activation-induced glucose uptake, glycolytic ATP production, and glycolysis were dependent on both HK isoforms. Platelet aggregation was reduced but not abolished by HK inhibition, indicating that platelet function is underpinned by metabolic flexibility. Integrin activation and pro-coagulant platelet formation were suppressed by both inhibitors. In contrast, α-granule secretion markers (CD62P, CD40L), platelet spreading, and convulxin-induced reactive oxygen species (ROS) generation were more sensitive to 3BP, suggesting a prominent role for HK2 in secretion, outside-in signaling, and ROS regulation. In vitro thrombus formation over collagen was significantly reduced by both inhibitors. In addition, HKs play a pivotal role in the regulation of in vivo hemostasis with increased bleeding time in mice treated with HK inhibitor. These findings identify HK as a central regulator of platelet metabolism and function, with distinct contributions of HK isoforms to specific platelet responses.