Sepsis is a complex immune disorder that is characterized by systemic hyperinflammation. counterparts. Collectively these findings suggest that galectin-9 functions as a novel alarmin by augmenting the inflammatory response AMG-47a in sepsis development during pulmonary infection. Introduction Systemic hyperinflammation is the underlying cause of many immune inflammatory diseases including sepsis. Despite more than three decades of active research severe sepsis and septic shock remain major healthcare challenges with a mortality rate of 20-50% and no effective therapy [1]. During sepsis overwhelming and sustained release of pro- as well as anti-inflammatory cytokines termed cytokine storm causes extensive tissue damage and wide-spread cell death eventually resulting in death. Despite the identification of cytokine circuitry as major determinants of mortality pro-inflammatory cytokine blockade has been ineffective as therapy for sepsis. This indicates the involvement of additional mediators that are likely acting AMG-47a as regulators and/or perpetuators of this AMG-47a hyper inflammatory response. Alarmins are evolutionarily conserved endogenous molecules that perform homeostatic functions when contained within cellular compartments [2]. However under pathological conditions these molecules can be released either passively from dead cells or actively via non-classical secretion pathways [3]. Once in the extracellular milieu they exhibit immune modulatory properties such as induction of pro-inflammatory cytokines immune cell chemotaxis and regulation of cell death [2]. In fact a sustained and excessive release of alarmins has been shown to contribute to pathogenesis of several sterile as well as infectious inflammatory conditions [4 5 Pertaining to their ability to impact innate immune cells such as macrophages dendritic cells and neutrophils alarmins also represent a crucial link between innate and adaptive immune responses and hence an attractive therapeutic target for complex disorders such as sepsis. Francisella is a highly virulent bacterial pathogen that causes an acute lethal disease called tularemia in humans and mice. Although there are strain-dependent differences in the initial mechanisms involved [6 7 our studies have shown that pulmonary infection of mice with fully virulent as well as the AMG-47a murine model organism (F.n.) leads to development of severe sepsis characterized by hyperinflammation T cell depletion and extensive cell death in systemic organs [8-10]. As pulmonary infections are a major cause of sepsis [11] we are using a murine inhalation model of F.n. infection to understand DPP4 the mechanism/s responsible for pulmonary infection-induced sepsis development. A recent report of an F.n. outbreak in a correctional facility suggests that this strain may be more virulent to humans than initially surmised supporting its relevance as a model strain to understand pathogenesis [12]. Furthermore studies from our and other laboratories have shown that extensive tissue damage and wide-spread cell death is a hallmark of Francisella infection regardless of the bacterial strain [9 13 14 Additionally our studies show that Francisella infected macrophages are defective in clearance of dead cells a process termed efferocytosis leading to accumulation of these dead cells and their progression to secondary necrosis [15]. It is thus likely that alarmins released from these dead or dying cells contribute to the inflammatory response culminating in sepsis development during respiratory infection with Francisella. We and others have reported an alarmin-mediated regulation of the inflammatory response during pulmonary infections [16-18]. However in a complex immune disorder like sepsis which is an interplay of several host immune pathways such as the coagulation system complement cascade and even the autonomic nervous system [19] several alarmins may be involved at the intersections of these pathways. Thus identification of additional alarmins will present therapeutic targets that may have more tangible translational potential when used in combination. Galectins mammalian β-galactoside binding lectins are emerging as potent immune regulators in a variety of pathological processes including inflammation autoimmunity fibrosis and cancer [20 21 Curiously some galectins (galectin-1 and -3) have been shown to be secreted in the extracellular milieu via a nonclassical.