LECT2 protects mice against bacterial sepsis by activating macrophages via the CD209a receptor

Leukocyte cell–derived chemotaxin 2 (LECT2) is a multifunctional cytokine and reduced plasma levels were found in patients with sepsis. However, precise functions and mechanisms of LECT2 remain unclear. The aim of the present study was to determine the role of LECT2 in modulating immune responses using mouse sepsis models. We found that LECT2 treatment improved outcome in mice with bacterial sepsis. Macrophages (MΦ), but not polymorphonuclear neutrophils, mediated the beneficial effect of LECT2 on bacterial sepsis. LECT2 treatment could alter gene expression and enhance phagocytosis and bacterial killing of MΦ in vitro. CD209a was identified to specifically interact with LECT2 and mediate LECT2-induced MΦ activation. CD209a-expressing MΦ was further confirmed to mediate the effect of LECT2 on sepsis in vivo. Our data demonstrate that LECT2 improves protective immunity in bacterial sepsis, possibly as a result of enhanced MΦ functions via the CD209a receptor. The modulation of MΦ functions by LECT2 may serve as a novel potential treatment for sepsis.Sepsis is defined as infection with systemic inflammatory reaction syndrome and can be the result of injury, burn, pancreatitis, surgery, and other disease states (Levy et al., 2003). More than half of sepsis cases are caused by infection with bacteria, among which the most important pathogens include Escherichia coli and Pseudomonas aeruginosa (Annane et al., 2005). Sepsis remains the leading cause of death in critically ill patients worldwide, despite modern advances in critical care. Macrophages (MΦ) are the key component of the innate immune system, forming a bridge between innate and adaptive immunity by producing a myriad of cytokines, and phagocytosing and presenting antigens to the immune system, responses which are severely impaired in septic patients (Hotchkiss and Karl, 2003). Thus, MΦ are a potentially important therapeutic target in sepsis (Anderson et al., 2012).Leukocyte cell–derived chemotaxin 2 (LECT2) is a multifunctional factor originally identified as a neutrophil chemotactic protein (Yamagoe et al., 1996), consisting of 151 amino acids and three intramolecular disulfide bonds. It is produced in the liver and secreted into the blood. LECT2 is involved in many pathological conditions, such as renal amyloidosis (Benson et al., 2008), hepatocarcinogenesis (Ong et al., 2011), and severe liver injury (Saito et al., 2004). Most recently, plasma LECT2 levels were found to be down-regulated in septic patients (Ando et al., 2012), suggesting a relationship between LECT2 and sepsis. However, precise functions and mechanisms of LECT2 in sepsis remain unclear. C-type lectin receptors (CLRs) perform multiple functions in myeloid cells, including MΦ (Kang et al., 2003; Osorio and Reis e Sousa, 2011). CD209, pattern recognition receptors belonging to the CLR superfamily, can not only recognize exogenous carbohydrate ligands to provide innate resistance to microbial infection (Robinson et al., 2006) but also bind to endogenous self-ligands to maintain immune homeostasis (García-Vallejo and van Kooyk, 2009). For example, SIGN-R1(CD209b) in spleen MΦ can capture pneumococcal capsular polysaccharide to activate complement system through an unusual C3 activation pathway (Kang et al., 2006).In this study, we determined that LECT2 treatment improved survival in septic mice via the increased phagocytic ability, bactericidal activity, and beneficial cytokine production of MΦ. These effects were mediated through CD209a. Moreover, CD209a-expressing MΦ mediated the effect of LECT2 on sepsis. Collectively, our data suggest that LECT2 plays a potentially important role in MΦ activation and for the treatment of sepsis.