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 5

DV-activated MDL-1+ cells produce NO and TNF-α in vitro, ex vivo, and in vivo.

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DV-activated MDL-1+ cells produce NO and TNF-α in vitro, ex vivo, and in...
(A and B) CD11b+ cells harvested from livers of ConA-treated WT and MDL-1–/– mice were plated and stimulated with (A) anti–MDL-1 mAb or (B) DV for 24 hours. NO and TNF-α in the conditioned media were measured. Data are mean ± SEM of triplicates and are representative of 3 independent experiments. *P < 0.05, ***P < 0.001 compared with naive cells from WT or stimulated cells from MDL-1–/– mice. (C and D) Precision-cut liver slices from ConA-treated WT or MDL-1–/– mice were plated and stimulated with (C) anti–MDL-1 mAb or (D) DV for 4 hours. NO and TNF-α in the conditioned media were measured. Data are mean ± SEM of triplicates and are representative of 2 independent experiments. *P < 0.05, ***P < 0.001 compared with naive liver slices from WT mice or stimulated liver slices from MDL-1–/– mice. (E and F) Serum from WT or MDL-1–/– mice treated with ConA, followed by (E) anti–MDL-1 mAb or (F) DV (n = 5), was collected. NO and TNF-α in the serum were measured. *P < 0.05, ***P < 0.001 compared with serum of IgG1-treated or naive mice.