Activation of MDL-1 (CLEC5A) on immature myeloid cells triggers lethal shock in mice

Abstract

Systemic inflammatory response syndrome (SIRS) is a potentially lethal condition, as it can progress to shock, multi-organ failure, and death. It can be triggered by infection, tissue damage, or hemorrhage. The role of tissue injury in the progression from SIRS to shock is incompletely understood. Here, we show that treatment of mice with concanavalin A (ConA) to induce liver injury triggered a G-CSF-dependent hepatic infiltration of CD11b + Gr-1 + Ly6G + Ly6C + immature myeloid cells that expressed the orphan receptor myeloid DAP12-associated lectin-1 (MDL-1; also known as CLEC5A). Activation of MDL-1 using dengue virus or an agonist MDL-1-specific antibody in the ConA-treated mice resulted in shock. The MDL-1 + cells were pathogenic, and in vivo depletion of MDL-1 + cells provided protection. Triggering MDL-1 on these cells induced production of NO and TNF-α, which were found to be elevated in the serum of treated mice and required for MDL-1-induced shock. Surprisingly, MDL-1-induced NO and TNF-α production required eNOS but not iNOS. Activation of DAP12, DAP10, Syk, PI3K, and Akt was critical for MDL-1-induced shock. In addition, Akt physically interacted with and activated eNOS. Therefore, triggering of MDL-1 on immature myeloid cells and production of NO and TNF-α may play a critical role in the pathogenesis of shock. Targeting the MDL-1/Syk/PI3K/Akt/eNOS pathway represents a potential new therapeutic strategy to prevent the progression of SIRS to shock.

Neonatal NET-inhibitory factor and related peptides inhibit neutrophil extracellular trap formation

“…We also examined the ability of NRPs to inhibit NETosis induced by other pathogens and found that CRISPP inhibited NET generation stimulated by dengue virus ( Figure 3D). Several viruses trigger NET deployment (43)(44)(45), but dengue, which interacts with ligands on myeloid cells (46), has not previously been reported as having this activity. To further explore the inhibitory activities of nNIF and NRPs, we examined heme, an endogenous damageassociated molecular pattern (DAMP) and toxin (47) that induced NETs in a murine model of sickle cell vasculopathy (17).…”

CLEC5A is critical for dengue virus–induced inflammasome activation in human macrophages

“…20 In addition, Cheung et al show that pretreatment of concanavalin A causes the accumulation of CLEC5A ϩ myeloid cells in liver, and incubation of DV with the CLEC5A ϩ myeloid cells causes massive secretion of NO and TNF-␣, whereas myeloid cells from CLEC5A Ϫ/Ϫ mice did not respond to DV infection under the same condition. 48 Thus, the CLEC5A ϩ GM-M subset may also play a critical role in the pathogenesis of DV infection. In contrast to IL-1␤, however, IL-18 is undetectable in both Clec5a ϩ/ϩ Stat1 Ϫ/Ϫ and Clec5a Ϫ/Ϫ Stat1 Ϫ/Ϫ mice after DV infection.…”

Do MDL-1+ cells play a broad role in acute inflammation?

“…Blocking DV interaction with MDL-1 reduces vascular leakage and shock in a mouse model of DSS (5). In this issue of the JCI, Cheung and colleagues provide new insights into the characteristics of MDL-1 + myeloid cells and their function in inflammation (6). These data could lead to new approaches for treating multiple conditions characterized by the progression of SIRS to shock and not just DSS.…”

“…In this scheme, release of both PMNs and MDL-1 + cells occurs in the bone marrow, under the influence of G-CSF (6). Upon entry into the bloodstream, MDL-1 + cells and PMNs traffic into the liver, which has been injured by injection of ConA.…”