Sepsis is a deadly inflammatory syndrome caused by an exaggerated immune response to infection. Much has been focused on host response to pathogens mediated through the interaction of pathogen-associated molecular patterns (PAMPs) and pattern recognition receptors (PRRs). PRRs are also activated by host nuclear, mitochondrial, and cytosolic proteins, known as damage-associated molecular patterns (DAMPs) that are released from cells during sepsis. Some well described members of the DAMP family are extracellular cold-inducible RNA-binding protein (eCIRP), high mobility group box 1 (HMGB1), histones, and adenosine triphosphate (ATP). DAMPs are released from the cell through inflammasome activation or passively following cell death. Similarly, neutrophil extracellular traps (NETs) are released from neutrophils during inflammation. NETs are webs of extracellular DNA decorated with histones, myeloperoxidase, and elastase. Although NETs contribute to pathogen clearance, excessive NET formation promotes inflammation and tissue damage in sepsis. Here, we review DAMPs and NETs and their crosstalk in sepsis with respect to their sources, activation, release, and function. A clear grasp of DAMPs, NETs and their interaction is crucial for the understanding of the pathophysiology of sepsis and for the development of novel sepsis therapeutics.

PW is an inventor of patent applications (WO/2010/120726 and 61/881.798) covering the fundamental concept of targeting cold-inducible RNAbinding protein for the treatment of inflammatory diseases, licensed by TheraSource LLC. PW is a cofounder of TheraSource LLC.

Although microRNAs regulate mRNA expression intracellularly, they are often released into the circulation in inflammatory diseases. During sepsis, secreted extracellular cold-inducible RNAbinding protein (eCIRP) acts as a damage-associated molecular pattern (DAMP), inducing tissue damage by elevating inflammatory cytokines and chemokines. Here, we report that the circulating microRNA 130b-3p inhibits eCIRP-mediated sterile and cecal ligation and puncture (CLP)-induced non-sterile inflammation. We find that levels of miR-130b-3p are increased in the serum of septic mice and patients and that it strongly interacts with recombinant murine (rm) CIRP in vitro and with eCIRP in the serum of septic mice in vivo. Combining a miR-130b-3p mimic with rmCIRP significantly decreases TNF-a release by macrophages compared to only rmCIRP-treated cells. This combined treatment also dose-dependently decreases the affinity of rmCIRP with its receptor TLR4/ MD2. Finally, injection of a miR-130b-3p mimic significantly reduces rmCIRP-or CLP-induced systemic inflammation and acute lung injury in mice. These data show that extracellular miR-130b-3p functions as a novel endogenous inhibitor of eCIRP and point to an innovative therapeutic approach to treat inflammatory diseases.