Activation of MDL-1 (CLEC5A) on immature myeloid cells triggers lethal shock in mice
Ricky Cheung, … , Paul G. Heyworth, Robert H. Pierce
Ricky Cheung, … , Paul G. Heyworth, Robert H. Pierce
Published October 17, 2011
Citation Information: J Clin Invest. 2011;121(11):4446-4461. https://doi.org/10.1172/JCI57682.
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Research Article

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.

Authors

Ricky Cheung, Fran Shen, Joseph H. Phillips, Mandy J. McGeachy, Daniel J. Cua, Paul G. Heyworth, Robert H. Pierce

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Figure 2

G-CSF is important for MDL-1–mediated shock.

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G-CSF is important for MDL-1–mediated shock. (A) Serum and liver homogen...
(A) Serum and liver homogenates were obtained from mice treated with ConA for the indicated times (n = 5), and G-CSF levels were quantitated by Luminex. *P < 0.05, **P < 0.01 compared with 0-hour time point. (B) Mice were pretreated with anti–G-CSF neutralizing antibodies (n = 5) or IgG1 (n = 3) prior to administration of ConA, followed by anti–MDL-1 mAb, and survival was monitored. **P < 0.01 compared with IgG1. (C) Blood and livers were collected from the mice represented in B, and G-CSF levels in the serum and liver homogenates were measured to evaluate the efficiency of G-CSF neutralization. **P < 0.01, ***P < 0.001 compared with IgG1. (D) Liver sections collected from the mice represented in B were immunostained with anti–MDL-1 mAb, and positively stained cells were quantitated (n = 5). ***P < 0.001 compared with IgG1.