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 November 1, 2011; First 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 1

Recruitment and activation of MDL-1+ cells led to lethal shock in mice.

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Recruitment and activation of MDL-1+ cells led to lethal shock in mice. ...
(A) C57BL/6 mice were injected with inflammation probe after ConA treatment and monitored for inflammation (left panel). After in vivo imaging, mice were sacrificed and livers were excised for ex vivo imaging (right panel). p, photons; sr, steradians. (B) Mice were treated with ConA for the indicated times (n = 5), and liver sections were stained with anti–MDL-1 mAb. The inset shows high magnification of MDL-1+ cells. Scale bars: 10 μm. (C) Quantitation of MDL-1+ cells in B. *P < 0.05, ***P < 0.001 compared with 0 hours. (D and E) MDL-1–/– and WT mice were treated with ConA, followed by (D) DV or (E) anti–MDL-1 mAb (n = 5), and survival was monitored. *P < 0.05, **P < 0.01 compared with WT. (F) Mice were treated with ConA, followed by the indicated doses of anti–MDL-1 mAb (n = 3), and survival was monitored. (G) Mice were treated with ConA, followed by IgG1 (n = 20), anti–MDL-1 agonist (n = 23), or antagonist (n = 5) mAb, and survival was monitored. ***P < 0.001 compared with IgG1.