The lncRNA LUCAT1 is elevated in inflammatory disease and restrains inflammation by regulating the splicing and stability of NR4A2

Proceedings of the National Academy of Sciences, Год журнала: 2022, Номер 120(1)

Опубликована: Дек. 28, 2022

The nuclear long non-coding RNA LUCAT1 has previously been identified as a negative feedback regulator of type I interferon and inflammatory cytokine expression in human myeloid cells. Here, we define the mechanistic basis for suppression gene by LUCAT1. Using comprehensive identification RNA-binding proteins mass spectrometry well immunoprecipitation, important processing alternative splicing mRNAs LUCAT1-binding proteins. These included heterogeneous ribonucleoprotein C, M, A2B1. Consistent with this finding, cells lacking have altered selected immune genes. In particular, upon lipopolysaccharide stimulation, receptor 4A2 (NR4A2) was particularly affected. As consequence, NR4A2 reduced delayed NR4A2-deficient had elevated observations suggest that is induced to control stability NR4A2, which part responsible anti-inflammatory effect Furthermore, analyzed large cohort patients bowel disease asthma chronic obstructive pulmonary disease. these patients, levels were both diseases, positively correlated severity. Collectively, studies key molecular mechanism LUCAT1-dependent regulation through post-transcriptional highlighting its role

Язык: Английский

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The emerging role for metabolism in fueling neutrophilic inflammation

Immunological Reviews, Год журнала: 2022, Номер 314(1), С. 427 - 441

Опубликована: Ноя. 3, 2022

Neutrophils are a critical element of host defense and rapidly recruited to inflammatory sites. Such sites frequently limited in oxygen and/or nutrient availability, presenting metabolic challenge for infiltrating cells. Long believed be uniquely dependent on glycolysis, it is now clear that neutrophils possess far greater plasticity than previously thought, with the capacity generate energy stores utilize extracellular proteins fuel central carbon metabolism biosynthetic activity. Out-with cellular energetics, programs have also been implicated production their progenitors bone marrow compartment, activation neutrophil antimicrobial responses, cell survival signaling cascades, training innate immune response. Thus, understanding mechanisms by which processes sustain changes effector functions how these subverted disease states provides exciting new avenues treatment dysfunctional neutrophilic inflammation lacking clinical practice date.

Язык: Английский

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The Multi-Faceted Consequences of NRF2 Activation throughout Carcinogenesis

Molecules and Cells, Год журнала: 2023, Номер 46(3), С. 176 - 186

Опубликована: Март 1, 2023

The oxidative balance of a cell is maintained by the Kelch-like ECH-associated protein 1 (KEAP1)/nuclear factor erythroid 2-related 2 (NRF2) pathway.This cytoprotective pathway detoxifies reactive oxygen species and xenobiotics.The role KEAP1/NRF2 as pro-tumorigenic or anti-tumorigenic throughout stages carcinogenesis (including initiation, promotion, progression, metastasis) complex.This mini review focuses on key studies describing how affects cancer at different phases.The data compiled suggest that roles KEAP1/ NRF2 in are highly dependent context; specifically, model used (carcinogen-induced vs genetic), tumor type, stage cancer.Moreover, emerging suggests also important for regulating microenvironment its effects amplified either epigenetics response to co-occurring mutations.Further elucidation complexity this needed order develop novel pharmacological tools drugs improve patient outcomes.

Язык: Английский

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Itaconate-producing neutrophils regulate local and systemic inflammation following trauma

JCI Insight, Год журнала: 2023, Номер 8(20)

Опубликована: Сен. 14, 2023

Modulation of the immune response to initiate and halt inflammatory process occurs both at site injury as well systemically. Due evolving role cellular metabolism in regulating cell fate function, tendon injuries which undergo normal aberrant repair were evaluated by metabolic profiling determine its impact on healing outcomes. Metabolomics revealed an increasing abundance immunomodulatory metabolite itaconate with site. Subsequent single-cell RNA sequencing, molecular metabolomic validation identified a highly mature neutrophil subtype, not macrophages, primary producers following trauma. These itaconate-producing neutrophils inflammatory, producing cytokines that promote local fibrosis before cycling back bone marrow. In marrow, was shown alter hematopoiesis, skewing progenitor cells down myeloid lineages, thereby systemic inflammation. Therapeutically, exogenous found reduce inflammation, promoting tenogenic differentiation impairing vascularization disease ameliorating effects. results present intriguing for sensor inflammation induced injury, potentially production through delivery endogenously produced demonstrate therapeutic potential injury.

Язык: Английский

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Optimizing Spectronaut Search Parameters to Improve Data Quality with Minimal Proteome Coverage Reductions in DIA Analyses of Heterogeneous Samples

Journal of Proteome Research, Год журнала: 2024, Номер 23(6), С. 1926 - 1936

Опубликована: Май 1, 2024

Data-independent acquisition has seen breakthroughs that enable comprehensive proteome profiling using short gradients. As the coverage continues to increase, quality of data generated becomes much more relevant. Using Spectronaut, we show default search parameters can be easily optimized minimize occurrence false positives across different samples. an immunological infection model system demonstrate impact adjusting settings, analyzed Mus musculus macrophages and compared their spiked withCandida albicans. This experimental enabled identification "false positives" as Candida albicans peptides proteins should not present in musculus-only We reduced positive" identifications by 89% at peptide protein level, thereby considerably increasing data. also these incurred a moderate cost, only reducing overall number "true each biological replicate <6.7% both level. believe value our updated extends beyond two-organism analysis would great any DIA experiment analyzing heterogeneous populations cell types or tissues.

Язык: Английский

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