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

[tetano]

Exp Mol Med


. 2023 Mar 20.
doi: 10.1038/s12276-023-00964-8. Online ahead of print.
Corticosteroids reduce pathologic interferon responses by downregulating STAT1 in patients with high-risk COVID-19


Hyun-Woo Jeong ^{# 1} , Jeong Seok Lee ^{# 2} , Jae-Hoon Ko ^{# 3} , Seunghee Hong ⁴ , Sang Taek Oh ⁵ , Seongkyun Choi ⁵ , Kyong Ran Peck ⁶ , Ji Hun Yang ⁷ , Seok Chung ^{8 9} , Sung-Han Kim ¹⁰ , Yeon-Sook Kim ¹¹ , Eui-Cheol Shin ^{12 13}



Affiliations

• PMID: 36941461
• DOI: 10.1038/s12276-023-00964-8

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.