title: 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: Discovery Research, Merck Research Laboratories, Palo Alto, California, USA. ricky.cheung@utoronto.ca
authors: Ricky
authors: R
authors: Cheung
authors: Fran
authors: F
authors: Shen
authors: Joseph H
authors: JH
authors: Phillips
authors: Mandy J
authors: MJ
authors: McGeachy
authors: Daniel J
authors: DJ
authors: Cua
authors: Paul G
authors: PG
authors: Heyworth
authors: Robert H
authors: RH
authors: Pierce
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation; D003208:Concanavalin A / Q000633:toxicity; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D006801:Humans; D007113:Immunity, Innate; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D037181:Lectins, C-Type / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D008099:Liver / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018448:Models, Immunological; D022423:Myeloid Cells / Q000276:immunology* / Q000473:pathology; D009569:Nitric Oxide / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D011971:Receptors, Immunologic / Q000378:metabolism; D019595:Severe Dengue / Q000209:etiology; D012769:Shock / Q000209:etiology* / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D000072377:Syk Kinase; D018746:Systemic Inflammatory Response Syndrome / Q000209:etiology / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C509772:Clec5a protein, mouse; C492355:Hcst protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D037181:Lectins, C-Type; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D014409:Tumor Necrosis Factor-alpha; C484963:Tyrobp protein, mouse; D003208:Concanavalin A; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496317:Nos2 protein, mouse; C496315:Nos3 protein, mouse; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606897:Syk protein, mouse; D051057:Proto-Oncogene Proteins c-akt