tetano
Editor, Senior Moderator
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[SUP] #[/SUP][SUP] 1 [/SUP], Jeong Seok Lee[SUP] #[/SUP][SUP] 2 [/SUP], Jae-Hoon Ko[SUP] #[/SUP][SUP] 3 [/SUP], Seunghee Hong[SUP] 4 [/SUP], Sang Taek Oh[SUP] 5 [/SUP], Seongkyun Choi[SUP] 5 [/SUP], Kyong Ran Peck[SUP] 6 [/SUP], Ji Hun Yang[SUP] 7 [/SUP], Seok Chung[SUP] 8 9 [/SUP], Sung-Han Kim[SUP] 10 [/SUP], Yeon-Sook Kim[SUP] 11 [/SUP], Eui-Cheol Shin[SUP] 12 13 [/SUP]
Affiliations
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.
. 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[SUP] #[/SUP][SUP] 1 [/SUP], Jeong Seok Lee[SUP] #[/SUP][SUP] 2 [/SUP], Jae-Hoon Ko[SUP] #[/SUP][SUP] 3 [/SUP], Seunghee Hong[SUP] 4 [/SUP], Sang Taek Oh[SUP] 5 [/SUP], Seongkyun Choi[SUP] 5 [/SUP], Kyong Ran Peck[SUP] 6 [/SUP], Ji Hun Yang[SUP] 7 [/SUP], Seok Chung[SUP] 8 9 [/SUP], Sung-Han Kim[SUP] 10 [/SUP], Yeon-Sook Kim[SUP] 11 [/SUP], Eui-Cheol Shin[SUP] 12 13 [/SUP]
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.