Sphingosine-1-phosphate Receptor-1 Agonist Averts the De Novo Generation of Autoreactive T-cells in Murine Acute Graft-versus-Host Disease.
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ABSTRACT:
SUBMITTER: Vollmer M
PROVIDER: S-EPMC8274799 | biostudies-literature | 2021 Aug
REPOSITORIES: biostudies-literature
Publications
Sphingosine-1-phosphate Receptor-1 Agonist Averts the De Novo Generation of Autoreactive T-cells in Murine Acute Graft-versus-Host Disease.
Vollmer Madeleine M Smith Philip P Bucher Christoph C Krenger Werner W Jeker Lukas T LT
HemaSphere 20210713 8
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Project description:BackgroundSphingosine-1-phosphate (S1P) is a bioactive sphingolipid produced by mast cells (MCs) on cross-linking of their high-affinity receptors for IgE by antigen that can amplify MC responses by binding to its S1P receptors. An acute MC-dependent allergic reaction can lead to systemic shock, but the early events of its development in lung tissues have not been investigated, and S1P functions in the onset of allergic processes remain to be examined.ObjectiveWe used a highly specific neutralizing anti-S1P antibody (mAb) and the sphingosine-1-phosphate receptor 2 (S1PR2) antagonist JTE-013 to study the signaling contributions of S1P and S1PR2 to MC- and IgE-dependent airway allergic responses in mice within minutes after antigen challenge.MethodsAllergic reaction was triggered by a single intraperitoneal dose of antigen in sensitized mice pretreated intraperitoneally with anti-S1P, isotype control mAb, JTE-013, or vehicle before antigen challenge.ResultsKinetics experiments revealed early pulmonary infiltration of mostly T cells around blood vessels of sensitized mice 20 minutes after antigen exposure. Pretreatment with anti-S1P mAb inhibited in vitro MC activation, as well as in vivo development of airway infiltration and MC activation, reducing serum levels of histamine, cytokines, and the chemokines monocyte chemoattractant protein 1/CCL2, macrophage inflammatory protein 1α/CCL3, and RANTES/CCL5. S1PR2 antagonism or deficiency or MC deficiency recapitulated these results. Both in vitro and in vivo experiments demonstrated MC S1PR2 dependency for chemokine release and the necessity for signal transducer and activator of transcription 3 activation.ConclusionActivation of S1PR2 by S1P and downstream signal transducer and activator of transcription 3 signaling in MCs regulate early T-cell recruitment to antigen-challenged lungs through chemokine production.
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