ABSTRACT
Acute immune responses with excess production of cytokines, lipid/chemical mediators, or coagulation factors, often result in lethal damage. In addition, the innate immune system utilizes multiple types of receptors that recognize neurotransmitters as well as pathogen-associated molecular patterns, making immune responses complex and clinically unpredictable. We here report an innate immune and adrenergic link inducing lethal levels of platelet-activating factor. Injecting mice with toll-like receptor (TLR) 4 ligand lipopolysaccharide (LPS), cell wall N-glycans of Candida albicans, and the α2-adrenergic receptor (α2-AR) agonist medetomidine induces lethal damage. Knocking out the C-type lectin Dectin-2 prevents the lethal damage. In spleen, large amounts of platelet-activating factor (PAF) are detected, and knocking out lysophospholipid acyltransferase 9 (LPLAT9/LPCAT2), which encodes an enzyme that converts inactive lyso-PAF to active PAF, protects mice from the lethal damage. These results reveal a linkage/crosstalk between the nervous and the immune system, possibly inducing lethal levels of PAF.
Subject(s)
Platelet Activating Factor , Animals , Platelet Activating Factor/metabolism , Mice , Mice, Knockout , Mice, Inbred C57BL , Lipopolysaccharides , Candida albicans , Immunity, Innate , Male , 1-Acylglycerophosphocholine O-Acyltransferase/metabolism , 1-Acylglycerophosphocholine O-Acyltransferase/genetics , Toll-Like Receptor 4/metabolism , Toll-Like Receptor 4/genetics , Adrenergic alpha-2 Receptor Agonists/pharmacologyABSTRACT
Severe infection often causes a septic cytokine storm followed by immune exhaustion/paralysis. Not surprisingly, many pathogens are equipped with various anti-inflammatory mechanisms. Such mechanisms might be leveraged clinically to control septic cytokine storms. Here we show that N-glycan from pathogenic C. albicans ameliorates mouse sepsis through immunosuppressive cytokine IL-10. In a sepsis model using lipopolysaccharide (LPS), injection of the N-glycan upregulated serum IL-10, and suppressed pro-inflammatory IL-1ß, TNF-α and IFN-γ. The N-glycan also improved the survival of mice challenged by LPS. Analyses of structurally defined N-glycans from several yeast strains revealed that the mannose core is key to the upregulation of IL-10. Knocking out the C-type lectin Dectin-2 abrogated the N-glycan-mediated IL-10 augmentation. Furthermore, C. albicans N-glycan ameliorated immune exhaustion/immune paralysis after acute inflammation. Our results suggest a strategy where the immunosuppressive mechanism of one pathogen can be applied to attenuate a severe inflammation/cytokine storm caused by another pathogen.
Subject(s)
Candida albicans/immunology , Candidiasis/immunology , Cell Wall/immunology , Cytokines/immunology , Membrane Glycoproteins/immunology , Polysaccharides/immunology , Sepsis/immunology , Animals , Candida albicans/metabolism , Candidiasis/metabolism , Candidiasis/microbiology , Cell Wall/metabolism , Cells, Cultured , Cytokines/metabolism , Dendritic Cells/immunology , Dendritic Cells/metabolism , Disease Models, Animal , Host-Pathogen Interactions , Interferon-gamma/immunology , Interferon-gamma/metabolism , Interleukin-10/immunology , Interleukin-10/metabolism , Interleukin-1beta/immunology , Interleukin-1beta/metabolism , Lectins, C-Type/genetics , Lectins, C-Type/metabolism , Macrophages/immunology , Macrophages/metabolism , Membrane Glycoproteins/metabolism , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Knockout , Polysaccharides/metabolism , Sepsis/metabolism , Sepsis/microbiology , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , Time Factors , Tumor Necrosis Factor-alpha/immunology , Tumor Necrosis Factor-alpha/metabolismABSTRACT
The formation of benzocyclobutenol derivatives by intramolecular cyclizations of o-acylbenzyllithiums is described. Treatment of o-(trialkylsilylmethyl)phenyl ketones with lithium diisopropylamide (LDA) followed by quenching of the resulting benzylic carbanions with chlorotrialkylsilane resulted in stereoselective formation of the corresponding 1-trialkylsiloxy-2-(trialkylsilyl)benzocyclobutenes in good yields. Subsequently, o-acyl-m-methoxybenzyllithiums were found to work well in cyclization to benzocyclobuten-1-ol derivatives. The reaction of 2-benzoyl-3,4,5-trimethoxybenzyllithium, generated in situ by deprotonation of 6-methyl-2,3,4-trimethoxybenzophenone with LDA, with chlorotrimethylsilane afforded the corresponding 1-(trimethylsiloxy)benzocyclobutene. Cyclization of 2-pivaloyl-3-methoxybenzyllithiums, generated in situ from tert-butyl 2-methyl-6-methoxyphenyl ketones upon deprotonation with LDA, proceeded spontaneously even at -78 degrees C to give the corresponding benzocyclobuten-1-ols. We also describe the results of thermal isomerization of these 1-trimethylsiloxy-2-(trialkylsilyl)benzocyclobutenes.
ABSTRACT
Vinyl sulfoxides (PhSOCR(1)=CHR(2): R(1) = H, Me, or Ph; R(2) = H or Me) were treated with (dialkylamino)magnesium reagents, generated in situ from the reaction of EtMgBr with secondary amines (R(3)R(4)NH: R(3) = Et, i-Pr, or Bn; R(4) = Me, Et, or i-Pr) in refluxing Et(2)O for 1 h, and stirring at room-temperature overnight gave the corresponding symmetrical beta-(dialkylamino) dithioacetals [(PhS)(2)CR(1)CHR(2)NR(3)R(4)] in 24-84% yields. When the (diethylamino)magnesium reagent was treated with appropriate thiols (RSH; R = p-ClC(6)H(4) or Bn) prior to the interaction with phenyl vinyl sulfoxide, the corresponding unsymmetrical beta-(diethylamino) dithioacetals [(PhS)(RS)CHCH(2)NEt(2)] were produced in 63-67% yields.
