Corticosteroids reduce pathologic interferon responses by downregulating STAT1 in patients with high-risk COVID-19

Hyun Woo Jeong, Jeong Seok Lee, Jae Hoon Ko, Seunghee Hong, Sang Taek Oh, Seongkyun Choi, Kyong Ran Peck, Ji Hun Yang, Seok Chung, Sung Han Kim, Yeon Sook Kim, Eui Cheol Shin

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

Abstract

We do not yet understand exactly how corticosteroids attenuate hyperinflammatory responses and alleviate high-risk coronavirus disease 2019 (COVID-19). We aimed to reveal the molecular mechanisms of hyperinflammation in COVID-19 and the anti-inflammatory effects of corticosteroids in patients with high-risk COVID-19. We performed single-cell RNA sequencing of peripheral blood mononuclear cells (PBMCs) from three independent COVID-19 cohorts: cohort 1 was used for comparative analysis of high-risk and low-risk COVID-19 (47 PBMC samples from 28 patients), cohort 2 for longitudinal analysis during COVID-19 (57 PBMC samples from 15 patients), and cohort 3 for investigating the effects of corticosteroid treatment in patients with high-risk COVID-19 (55 PBMC samples from 13 patients). PBMC samples from healthy donors (12 PBMC samples from 12 donors) were also included. Cohort 1 revealed a significant increase in the proportion of monocytes expressing the long noncoding RNAs NEAT1 and MALAT1 in high-risk patients. Cohort 2 showed that genes encoding inflammatory chemokines and their receptors were upregulated during aggravation, whereas genes related to angiogenesis were upregulated during improvement. Cohort 3 demonstrated downregulation of interferon-stimulated genes (ISGs), including STAT1, in monocytes after corticosteroid treatment. In particular, unphosphorylated STAT-dependent ISGs enriched in monocytes from lupus patients were selectively downregulated by corticosteroid treatment in patients with high-risk COVID-19. Corticosteroid treatment suppresses pathologic interferon responses in monocytes by downregulating STAT1 in patients with high-risk COVID-19. Our study provides insights into the mechanisms underlying COVID-19 aggravation and improvement and the effects of corticosteroid treatment.

Original languageEnglish
Pages (from-to)653-664
Number of pages12
JournalExperimental and Molecular Medicine
Volume55
Issue number3
DOIs
Publication statusPublished - 2023 Mar

Bibliographical note

Funding Information:
This work is supported by the Samsung Science and Technology Foundation under project number SSTF-BA1402-51 (E.C.S.), the NRF grant funded by the MSIT (2021M3E5E3080744; S.C.), and the Starting growth Technological R&D Program (TIPS Program, No. S3136588) funded by the Ministry of SMEs and Startups (MSS, Republic of Korea) in 2021. This work was also supported by BD Biosciences (San Jose, CA, USA), Einocle Inc. (Seoul, Republic of Korea) and Next & Bio Inc. (Seoul, Republic of Korea).

Publisher Copyright:
© 2023, The Author(s).

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry

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