Cytosolic nucleic acid sensing as driver of critical illness: mechanisms and advances in therapy DOI Creative Commons

Z.C. Chen,

Rayk Behrendt,

Lennart Wild

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2025, Volume and Issue: 10(1)

Published: March 19, 2025

Abstract Nucleic acids from both self- and non-self-sources act as vital danger signals that trigger immune responses. Critical illnesses such acute respiratory distress syndrome, sepsis, trauma ischemia lead to the aberrant cytosolic accumulation massive release of nucleic are detected by antiviral innate receptors in endosome or cytosol. Activation for deoxyribonucleic ribonucleic triggers inflammation, a major contributor morbidity mortality critically ill patients. In past decade, there has been growing recognition therapeutic potential targeting acid sensing critical care. This review summarizes current knowledge ischemia. Given extensive research on common pathological conditions like cancer, autoimmune disorders, metabolic disorders aging, we provide comprehensive summary beyond illness offer insights may inform its role conditions. Additionally, discuss strategies specifically target sensing. By examining sources, sensor activation function, well impact regulating these pathways across various diseases, highlight driving illness.

Language: Английский

Epigenetic memory of coronavirus infection in innate immune cells and their progenitors DOI Creative Commons
Jin‐Gyu Cheong, Arjun Ravishankar, Siddhartha Sharma

et al.

Cell, Journal Year: 2023, Volume and Issue: 186(18), P. 3882 - 3902.e24

Published: Aug. 1, 2023

Language: Английский

Citations

142
Decoding Toll-like receptors: Recent insights and perspectives in innate immunity DOI Open Access
Taro Kawai,

Moe Ikegawa,

Daisuke Ori

et al.

Immunity, Journal Year: 2024, Volume and Issue: 57(4), P. 649 - 673

Published: April 1, 2024

Language: Английский

Citations

114
Interstitial macrophages are a focus of viral takeover and inflammation in COVID-19 initiation in human lung DOI Creative Commons
Ting-Hsuan Wu, Kyle J. Travaglini, Arjun Rustagi

et al.

The Journal of Experimental Medicine, Journal Year: 2024, Volume and Issue: 221(6)

Published: April 10, 2024

Early stages of deadly respiratory diseases including COVID-19 are challenging to elucidate in humans. Here, we define cellular tropism and transcriptomic effects SARS-CoV-2 virus by productively infecting healthy human lung tissue using scRNA-seq reconstruct the transcriptional program “infection pseudotime” for individual cell types. predominantly infected activated interstitial macrophages (IMs), which can accumulate thousands viral RNA molecules, taking over 60% transcriptome forming dense bodies while inducing host profibrotic (TGFB1, SPP1) inflammatory (early interferon response, CCL2/7/8/13, CXCL10, IL6/10) programs destroying architecture. Infected alveolar (AMs) showed none these extreme responses. Spike-dependent entry into AMs used ACE2 Sialoadhesin/CD169, whereas IM DC-SIGN/CD209. These results identify IMs as a prominent site takeover, focus inflammation fibrosis, suggest targeting CD209 prevent early pathology pneumonia. This approach be generalized any infection evaluate therapeutics.

Language: Английский

Citations

20
TLR8 escapes X chromosome inactivation in human monocytes and CD4+ T cells DOI Creative Commons
Ali Youness, Claire Cénac, Bérénice Faz-Lopez

et al.

Biology of Sex Differences, Journal Year: 2023, Volume and Issue: 14(1)

Published: Sept. 18, 2023

Human endosomal Toll-like receptors TLR7 and TLR8 recognize self non-self RNA ligands, are important mediators of innate immunity autoimmune pathogenesis. are, respectively, encoded by adjacent X-linked genes. We previously established that evades X chromosome inactivation (XCI) in female immune cells. Whether also XCI, however, has not yet been explored.

Language: Английский

Citations

26
The role of plasmacytoid dendritic cells (pDCs) in immunity during viral infections and beyond DOI Creative Commons

Clémence Ngo,

Clémence Garrec,

Elena Tomasello

et al.

Cellular and Molecular Immunology, Journal Year: 2024, Volume and Issue: 21(9), P. 1008 - 1035

Published: May 22, 2024

Abstract Type I and III interferons (IFNs) are essential for antiviral immunity act through two different but complimentary pathways. First, IFNs activate intracellular antimicrobial programs by triggering the upregulation of a broad repertoire viral restriction factors. Second, innate adaptive immunity. Dysregulation IFN production can lead to severe immune system dysfunction. It is thus crucial identify characterize cellular sources IFNs, their effects, regulation promote beneficial effects limit detrimental which depend on nature infected or diseased tissues, as we will discuss. Plasmacytoid dendritic cells (pDCs) produce large amounts all subtypes during infection. pDCs resistant infection many viruses, inhibiting evasion mechanisms viruses that target downstream responses. Therefore, considered control infections establishment protective A thorough bibliographical survey showed that, in most infections, despite being major producers, actually dispensable host resistance, achieved multiple depending tissue. Moreover, primary responses only transiently affected absence pDCs. More surprisingly, be some autoimmune diseases. This makes conservation vertebrate evolution an enigma raises outstanding questions about role not also other diseases under physiological conditions.

Language: Английский

Citations

18
Interferons and epigenetic mechanisms in training, priming and tolerance of monocytes and hematopoietic progenitors DOI
Bikash Mishra, Lionel B. Ivashkiv

Immunological Reviews, Journal Year: 2024, Volume and Issue: 323(1), P. 257 - 275

Published: April 3, 2024

Training and priming of innate immune cells involve preconditioning by PAMPs, DAMPs, and/or cytokines that elicits stronger induction inflammatory genes upon secondary challenge. Previous models distinguish training based whether activation returns to baseline prior Tolerance is a protective mechanism whereby potent stimuli induce refractoriness are important for memory responses protect against infection, efficacy vaccines, maintaining in state readiness; tolerance prevents toxicity from excessive activation. Dysregulation these processes can contribute pathogenesis autoimmune/inflammatory conditions, post-COVID-19 hyperinflammatory states, or sepsis-associated immunoparalysis. Training, priming, regulate similar "signature" such as TNF, IL6, IL1B utilize overlapping epigenetic mechanisms. We review how interferons (IFNs), best known activating JAK-STAT signaling interferon-stimulated genes, also play key role regulating training, via chromatin-mediated present new data on monocyte-to-macrophage differentiation modulates IFN-γ-mediated affects regulation AP-1 CEBP activity, attenuates superinduction genes. "training-priming continuum" model integrates IFN-mediated into current concepts about proposes central STAT1 IRF1.

Language: Английский

Citations

12
Regulation of type I and type III interferon induction in response to pathogen sensing DOI Creative Commons
Hossam Gewaid, Andrew Bowie

Current Opinion in Immunology, Journal Year: 2024, Volume and Issue: 87, P. 102424 - 102424

Published: April 1, 2024

Type I and III interferons (IFN-I IFN-III) have a central role in the early antimicrobial response against invading pathogens. Induction of IFN-Is IFN-IIIs arises due to sensing by pattern recognition receptors pathogen-associated molecular patterns (from micro-organisms) or damage-associated (DAMPs; produced host cells). Here, we review recent developments on how IFN-I IFN-III expression is stimulated different pathogens signalling pathways leading IFN induction are tightly regulated. We also summarise growing knowledge that lead severe acute respiratory syndrome coronavirus 2.

Language: Английский

Citations

10
Macrophage phagocytosis of SARS-CoV-2-infected cells mediates potent plasmacytoid dendritic cell activation DOI Creative Commons
Obdulio García-Nicolás,

Aurélie Godel,

Gert Zimmer

et al.

Cellular and Molecular Immunology, Journal Year: 2023, Volume and Issue: 20(7), P. 835 - 849

Published: May 30, 2023

Abstract Early and strong interferon type I (IFN-I) responses are usually associated with mild COVID-19 disease, whereas persistent or unregulated proinflammatory cytokine severe disease outcomes. Previous work suggested that monocyte-derived macrophages (MDMs) resistant unresponsive to SARS-CoV-2 infection. Here, we demonstrate upon phagocytosis of SARS-CoV-2-infected cells, MDMs activated secrete IL-6 TNF. Importantly, in turn mediate activation plasmacytoid dendritic cells (pDCs), leading the secretion high levels IFN-α Furthermore, pDC promoted production by MDMs. This kind was dependent on direct integrin-mediated cell‒cell contacts involved stimulation TLR7 STING signaling pathways. Overall, present study describes a novel potent pathway is linked macrophage-mediated clearance infected cells. These findings suggest infection rate may lead exaggerated responses, which contribute tissue damage disease.

Language: Английский

Citations

24
Dexamethasone attenuates interferon-related cytokine hyperresponsiveness in COVID-19 patients DOI Creative Commons
Job J. Engel, Caspar I. van der Made, Nick Keur

et al.

Frontiers in Immunology, Journal Year: 2023, Volume and Issue: 14

Published: Aug. 8, 2023

Dexamethasone improves the survival of COVID-19 patients in need supplemental oxygen therapy. Although its broad immunosuppressive effects are well-described, immunological mechanisms modulated by dexamethasone hospitalized with remain to be elucidated.We combined functional assays and an omics-based approach investigate vitro vivo plasma peripheral blood mononuclear cells (PBMCs) patients.Hospitalized eligible for therapy were recruited from general care ward between February July, 2021. Whole transcriptomic targeted proteomic analyses performed before after starting treatment. PBMCs isolated healthy individuals stimulated inactivated SARS-CoV-2 ex presence or absence transcriptome cytokine responses assessed.Dexamethasone efficiently inhibited SARS-CoV-2-induced expression chemokines cytokines at transcriptional protein level. treatment resulted down-regulation genes related type I II interferon (IFN) signaling whole immune cells. In addition, attenuated circulating concentrations secreted interferon-stimulating gene 15 (ISG15) pro-inflammatory correlating disease severity lethal outcomes, such as tumor necrosis factor (TNF), interleukin-6 (IL-6), chemokine ligand 2 (CCL2), C-X-C motif 8 (CXCL8), 10 (CXCL10). that multiple pathogens Toll-like receptor (TLR) ligands, responses.We describe anti-inflammatory impact on pathways contributing hyperresponsiveness observed severe manifestations COVID-19, including I/II IFN signaling. could have adverse mild symptoms inhibiting early stages disease, whereas it exhibits beneficial clinical phenotypes diminishing hyperresponsiveness.

Language: Английский

Citations

23
Modulation of type I interferon responses potently inhibits SARS-CoV-2 replication and inflammation in rhesus macaques DOI
Elise G. Viox, Timothy N. Hoang, Amit A. Upadhyay

et al.

Science Immunology, Journal Year: 2023, Volume and Issue: 8(85)

Published: July 28, 2023

Type I interferons (IFN-I) are critical mediators of innate control viral infections but also drive the recruitment inflammatory cells to sites infection, a key feature severe coronavirus disease 2019. Here, IFN-I signaling was modulated in rhesus macaques (RMs) before and during acute SARS-CoV-2 (severe respiratory syndrome 2) infection using mutated IFN-α2 (IFN-modulator; IFNmod), which has previously been shown reduce binding endogenous IFN-I. IFNmod treatment uninfected RMs observed induce modest up-regulation only antiviral IFN-stimulated genes (ISGs); however, SARS-CoV-2–infected RMs, reduced both ISGs. resulted potent reduction loads vitro Calu-3 vivo bronchoalveolar lavage (BAL), upper airways, lung, hilar lymph nodes RMs. Furthermore, potently cytokines, chemokines, CD163 + MRC1 − macrophages BAL expression Siglec-1 on circulating monocytes. In pathogenesis attenuated pathways inflammasome activation stress response infection. Using an intervention targeting IFN-α IFN-β pathways, this study shows that, whereas early restrains replication, uncontrolled critically contributes inflammation moderate model

Language: Английский

Citations

20