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Transcriptional reprogramming from innate immune functions to a pro-thrombotic signature by monocytes in COVID-19.

ABSTRACT: Although alterations in myeloid cells have been observed in COVID-19, the specific underlying mechanisms are not completely understood. Here, we examine the function of classical CD14⁺ monocytes in patients with mild and moderate COVID-19 during the acute phase of infection and in healthy individuals. Monocytes from COVID-19 patients display altered expression of cell surface receptors and a dysfunctional metabolic profile that distinguish them from healthy monocytes. Secondary pathogen sensing ex vivo leads to defects in pro-inflammatory cytokine and type-I IFN production in moderate COVID-19 cases, together with defects in glycolysis. COVID-19 monocytes switch their gene expression profile from canonical innate immune to pro-thrombotic signatures and are functionally pro-thrombotic, both at baseline and following ex vivo stimulation with SARS-CoV-2. Transcriptionally, COVID-19 monocytes are characterized by enrichment of pathways involved in hemostasis, immunothrombosis, platelet aggregation and other accessory pathways to platelet activation and clot formation. These results identify a potential mechanism by which monocyte dysfunction may contribute to COVID-19 pathology.

SUBMITTER: Maher AK

PROVIDER: S-EPMC9791976 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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Transcriptional reprogramming from innate immune functions to a pro-thrombotic signature by monocytes in COVID-19.

Maher Allison K AK Burnham Katie L KL Jones Emma M EM Tan Michelle M H MMH Saputil Rocel C RC Baillon Laury L Selck Claudia C Giang Nicolas N Argüello Rafael R Pillay Clio C Thorley Emma E Short Charlotte-Eve CE Quinlan Rachael R Barclay Wendy S WS Cooper Nichola N Taylor Graham P GP Davenport Emma E EE Dominguez-Villar Margarita M

Nature communications 20221226 1

Although alterations in myeloid cells have been observed in COVID-19, the specific underlying mechanisms are not completely understood. Here, we examine the function of classical CD14<sup>+</sup> monocytes in patients with mild and moderate COVID-19 during the acute phase of infection and in healthy individuals. Monocytes from COVID-19 patients display altered expression of cell surface receptors and a dysfunctional metabolic profile that distinguish them from healthy monocytes. Secondary pathog ...[more]

PMID: 36572683

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Project description:IkB proteins regulate the inhibition and activation of NF-kB transcription factor complexes. While classical IkB proteins keep NF-kB complexes inactive in the cytoplasm, atypical IkB proteins act on activated NF-kB complexes located in the nucleus. Most of the knowledge regarding the function of IkB proteins has been collected in vitro, while far less is known regarding their impact on activation and regulation of immune responses during in vivo infections. Combining in vivo Listeria monocytogenes (Lm) infection with comparative ex vivo transcriptional profiling of the hepatic response to the pathogen we observed that in contrast to wild type mice that mounted a robust inflammatory response, IkBNS-deficiency was generally associated with a transcriptional repression of innate immune responses. Whole tissue transcriptomics revealed a pronounced IkBNS-dependent (Nfkbid gene) reduction of myeloid cell-associated transcripts in the liver together with an exceptionally high Nfkbid promoter activity uncovered in Ly6C-high inflammatory monocytes prompted us to further characterized the specific contribution of IkBNS in the inflammatory response of monocytes to the infectious agent. Indeed, Ly6C-high monocytes primed during Lm infection in the absence of IkBNS displayed a blunted response compared to wild type-derived Ly6C-high monocytes as evidenced by the reduced early expression of hallmark transcripts of monocyte-driven inflammation such as Il-6, Nos2 and Il1-β. Strikingly, altered monocyte activation in IkBNS-deficient mice was associated with an exceptional resistance against Lm infection and protection was associated with a strong reduction in immunopathology in Lm target organs. Of note, mice lacking IkBNS exclusively in myeloid cells failed to resist Lm infection, indicating that the observed effect was not monocyte intrinsic but monocyte extrinsic. While serum cytokine-profiling did not discover obvious differences between wild type and IkBNS -/- mice for most of the analyzed mediators, IL-10 was virtually undetectable in IkBNS-deficient mice, both in the steady state and following Lm infection. Together, we show here a crucial role for IkBNS during Lm infection with IkBNS-deficient mice showing an overall blunted pro-inflammatory immune response attributed to a reduced pro-inflammatory signature in Ly6C-high monocytes. Reduced immunopathology and complete protection of mice against an otherwise lethal Lm infection identified IkBNS as molecular driver of inflammation in listeriosis.

Project description:IκB proteins regulate the inhibition and activation of NF-κB transcription factor complexes. While classical IκB proteins keep NF-κB complexes inactive in the cytoplasm, atypical IκB proteins act on activated NF-κB complexes located in the nucleus. Most of the knowledge regarding the function of IκB proteins has been collected in vitro, while far less is known regarding their impact on activation and regulation of immune responses during in vivo infections. Combining in vivo Listeria monocytogenes (Lm) infection with comparative ex vivo transcriptional profiling of the hepatic response to the pathogen we observed that in contrast to wild type mice that mounted a robust inflammatory response, IκBNS-deficiency was generally associated with a transcriptional repression of innate immune responses. Whole tissue transcriptomics revealed a pronounced IκBNS-dependent reduction of myeloid cell-associated transcripts in the liver together with an exceptionally high Nfkbid promoter activity uncovered in Ly6Chigh inflammatory monocytes prompted us to further characterize the specific contribution of IκBNS in the inflammatory response of monocytes to the infectious agent. Indeed, Ly6Chigh monocytes primed during Lm infection in the absence of IκBNS displayed a blunted response compared to wild type-derived Ly6Chigh monocytes as evidenced by the reduced early expression of hallmark transcripts of monocyte-driven inflammation such as Il6, Nos2 and Il1β. Strikingly, altered monocyte activation in IκBNS-deficient mice was associated with an exceptional resistance against Lm infection and protection was associated with a strong reduction in immunopathology in Lm target organs. Of note, mice lacking IκBNS exclusively in myeloid cells failed to resist Lm infection, indicating that the observed effect was not monocyte intrinsic but monocyte extrinsic. While serum cytokine-profiling did not discover obvious differences between wild type and IκBNS -/- mice for most of the analyzed mediators, IL-10 was virtually undetectable in IκBNS-deficient mice, both in the steady state and following Lm infection. Together, we show here a crucial role for IκBNS during Lm infection with IκBNS-deficient mice showing an overall blunted pro-inflammatory immune response attributed to a reduced pro-inflammatory signature in Ly6Chigh monocytes. Reduced immunopathology and complete protection of mice against an otherwise fatal Lm infection identified IκBNS as molecular driver of inflammation in listeriosis.

Dataset Information

Transcriptional reprogramming from innate immune functions to a pro-thrombotic signature by monocytes in COVID-19.

Publications

Transcriptional reprogramming from innate immune functions to a pro-thrombotic signature by monocytes in COVID-19.

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