A novel role for myeloid cell-specific neuropilin 1 in mitigating sepsis

Abstract

Sepsis - typically caused by an uncontrolled and amplified host systemic inflammatory response to microbial infection - is a life-threatening complex clinical disorder and remains a major cause of infection-related deaths in the intensive care unit. Emerging evidence suggests that neuropilin 1 (Nrp1), an originally defined coreceptor for class 3 semaphorins and VEGF, plays important roles in the immune system; however, the function and regulation of macrophage Nrp1 in host immune defense against bacterial infection remain unknown. To address thisproblem,we generatedmyeloidcell-specificNrp1-knockout (Nrp1myel-KO) mice and applied 2 stringent animal models of sepsis: cecal ligation and puncture as well as intraperitoneal injection of LPS. Here, we reported thatmyeloid cell-specificNrp1-deficientmice exhibitedenhancedsusceptibility to cecal ligationand puncture- and LPS-induced sepsis, which correlated with significantly decreased survival rates and heightened levels of proinflammatory cytokines in both peritoneal lavage and serum. Mechanistically, LPS specifically attenuated the expression of Nrp1 in macrophages,whichwasmediated by TLR4-NF-κB p50 and -65 pathways. By using isolated primary macrophages, loss of Nrp1 consistently resulted in increased production of proinflammatory cytokines, including iNOS, TNF-α, and IL-6. Together, these findings demonstrate a novel role of macrophage Nrp1 in sepsis.