Autophagy genes in myeloid cells counteract IFNγ-induced TNF-mediated cell death and fatal TNF-induced shock

Orvedahl, Anthony; McAllaster, Michael R.; Sansone, Amy; Dunlap, Bria F.; Desai, Chandni; Wang, Yating; Balce, Dale R.; Luke, Cliff J.; Lee, Sang‐Hyun; Orchard, Robert C.; Artyomov, Maxim N.; Handley, Scott A.; Doench, John G.; Silverman, Gary A.; Virgin, Herbert W.

doi:10.1073/pnas.1822157116

Cited by 35 publications

(40 citation statements)

References 91 publications

(109 reference statements)

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“…For analysis, read counts were log-normalized for each guide using the following formula: log-normalized reads per million for guide = log 2 ((# of reads for guide / total reads in condition x 1e6) +1). Log-normalized reads were averaged for each sample, and untreated average was subtracted from LLME treated average to achieve the log 2 fold changes for each sgRNA, which were then averaged to gene-level log 2 fold changes (https://github.com/mhegde/volcano_plots) as previously described (Table S6) (Orvedahl et al, 2019). The STARS program (https://portals.broadinstitute.org/gpp/public/software/stars) was used to obtain gene-level p values (Table S6) (Doench et al, 2016).…”

Section: Author Contributionsmentioning

confidence: 99%

TFEB Transcriptional Responses Reveal Negative Feedback by BHLHE40 and BHLHE41

et al. 2020

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Section: Author Contributionsmentioning

confidence: 99%

TFEB Transcriptional Responses Reveal Negative Feedback by BHLHE40 and BHLHE41

et al. 2020

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“…Autophagy has been since been described to play pivotal roles in a variety of different myeloid cell types. Many neutrophil functions have been linked to autophagy including differentiation (20), extracellular trap formation (21,22), and cytokine secretion and interaction (23,24). Eosinophils, important in allergic disease, have also been demonstrated to have diminished eosinophil extracellular trap formation (EET) when autophagy is inhibited (25).…”

Section: Introductionmentioning

confidence: 99%

Role of Autophagy in Lung Inflammation

2020

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Autophagy is a cellular recycling system found in almost all types of eukaryotic organisms. The system is made up of a variety of proteins which function to deliver intracellular cargo to lysosomes for formation of autophagosomes in which the contents are degraded. The maintenance of cellular homeostasis is key in the survival and function of a variety of human cell populations. The interconnection between metabolism and autophagy is extensive, therefore it has a role in a variety of different cell functions. The disruption or dysfunction of autophagy in these cell types have been implicated in the development of a variety of inflammatory diseases including asthma. The role of autophagy in non-immune and immune cells both lead to the pathogenesis of lung inflammation. Autophagy in pulmonary non-immune cells leads to tissue remodeling which can develop into chronic asthma cases with long term effects. The role autophagy in the lymphoid and myeloid lineages in the pathology of asthma differ in their functions. Impaired autophagy in lymphoid populations have been shown, in general, to decrease inflammation in both asthma and inflammatory disease models. Many lymphoid cells rely on autophagy for effector function and maintained inflammation. In stark contrast, autophagy deficient antigen presenting cells have been shown to have an activated inflammasome. This is largely characterized by a T H 17 response that is accompanied with a much worse prognosis including granulocyte mediated inflammation and steroid resistance. The cell specificity associated with changes in autophagic flux complicates its targeting for amelioration of asthmatic symptoms. Differing asthmatic phenotypes between T H 2 and T H 17 mediated disease may require different autophagic modulations. Therefore, treatments call for a more cell specific and personalized approach when looking at chronic asthma cases. Viral-induced lung inflammation, such as that caused by SARS-CoV-2, also may involve autophagic modulation leading to inflammation mediated by lung resident cells. In this review, we will be discussing the role of autophagy in non-immune cells, myeloid cells, and lymphoid cells for their implications into lung inflammation and asthma. Finally, we will discuss autophagy's role viral pathogenesis, immunometabolism, and asthma with insights into autophagic modulators for amelioration of lung inflammation.

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“…Besides using CRISPR/Cas9-based screening approaches together with a challenging virus, certain triggers of the innate immune system, e.g., endotoxins and cytokines, can also be used to study pathogen–host interactions with a focus on a particular pathway. This way, essential mediators of LPS signaling, IFN-γ-induced cell death, and DNA-damage responses occur during virus infection [ 120 , 121 , 122 ].…”

Section: Assay Design and Screening Formatmentioning

confidence: 99%

System-Based Approaches to Delineate the Antiviral Innate Immune Landscape

Krey

Babnis

Pichlmair

2020

Viruses

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Viruses pose substantial challenges for society, economy, healthcare systems, and research. Their distinctive pathologies are based on specific interactions with cellular factors. In order to develop new antiviral treatments, it is of central importance to understand how viruses interact with their host and how infected cells react to the virus on a molecular level. Invading viruses are commonly sensed by components of the innate immune system, which is composed of a highly effective yet complex network of proteins that, in most cases, mediate efficient virus inhibition. Central to this process is the activity of interferons and other cytokines that coordinate the antiviral response. So far, numerous methods have been used to identify how viruses interact with cellular processes and revealed that the innate immune response is highly complex and involves interferon-stimulated genes and their binding partners as functional factors. Novel approaches and careful experimental design, combined with large-scale, high-throughput methods and cutting-edge analysis pipelines, have to be utilized to delineate the antiviral innate immune landscape at a global level. In this review, we describe different currently used screening approaches, how they contributed to our knowledge on virus–host interactions, and essential considerations that have to be taken into account when planning such experiments.

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Autophagy genes in myeloid cells counteract IFNγ-induced TNF-mediated cell death and fatal TNF-induced shock

Cited by 35 publications

References 91 publications

TFEB Transcriptional Responses Reveal Negative Feedback by BHLHE40 and BHLHE41

TFEB Transcriptional Responses Reveal Negative Feedback by BHLHE40 and BHLHE41

Role of Autophagy in Lung Inflammation

System-Based Approaches to Delineate the Antiviral Innate Immune Landscape

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