The balance between gasdermin D and STING signaling shapes the severity of schistosome immunopathology

Parisa Kalantari, Ilana Shecter, Jacob Hopkins, Andrea Pilotta Gois, Yoelkys Morales, Bijan F. Harandi, Shruti Sharma, Miguel J. Stadecker

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

There is significant disease heterogeneity among mouse strains infected with the helminth Schistosoma mansoni. Here, we uncover a unique balance in two critical innate pathways governing the severity of disease. In the low-pathology setting, parasite egg-stimulated dendritic cells (DCs) induce robust interferon (IFN)β production, which is dependent on the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) cytosolic DNA sensing pathway and results in a Th2 response with suppression of proinflammatory cytokine production and Th17 cell activation. IFNβ induces signal transducer and activator of transcription (STAT)1, which suppresses CD209a, a C-type lectin receptor associated with severe disease. In contrast, in the high-pathology setting, enhanced DC expression of the pore-forming protein gasdermin D (Gsdmd) results in reduced expression of cGAS/STING, impaired IFNβ, and enhanced pyroptosis. Our findings demonstrate that cGAS/STING signaling represents a unique mechanism inducing protective type I IFN, which is counteracted by Gsdmd.

Original languageEnglish (US)
Article numbere2211047120
JournalProceedings of the National Academy of Sciences of the United States of America
Volume120
Issue number13
DOIs
StatePublished - Mar 28 2023

All Science Journal Classification (ASJC) codes

  • General

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