bims-aditis 2022-01-30 papers

Issue of 2022–01–30
seven papers selected by
Matthew C. Sinton, University of Glasgow

Cell Biol Int. 2022 Jan 23.

IL-17 in intervertebral disc degeneration: mechanistic insights and therapeutic implications.

Jing-Hua Tan, Ze-Peng Li, Lu-Lu Liu, Hao Liu, Jing-Bo Xue.

Intervertebral disc degeneration (IDD) serves as an independent risk factor for lower back pain and is closely associated with spinal musculoskeletal disorders including lumbar disc herniation, radiculopathy and myelopathy. Interleukin-17 (IL-17), also named IL-17A, is a critical signature cytokine of T helper 17 cells. Upon binding to the IL-17 receptor A/C heterodimeric complex, IL-17 can trigger multiple signal transduction pathways to stimulate gene transcription and increase mRNA stability. IL-17 expression is significantly increased in degenerative disc tissue and shows a positive correlation with disease severity. IL-17 has been shown to accelerate the development of IDD by promoting extracellular matrix degradation, enhancing inflammatory response, inducing neoangiogenesis, and inhibiting nucleus pulposus cell autophagy and proliferation. Targeting IL-17 represents a novel and promising approach for therapeutic intervention of IDD. In this review, we summarized the recent progression about the role of IL-17 in IDD and highlighted its therapeutic implications. This article is protected by copyright. All rights reserved.

Keywords: IDD; IL-17; angiogenesis; extracellular matrix; inflammation

DOI: https://doi.org/10.1002/cbin.11767

Immunometabolism. 2021 ;pii: e220002. [Epub ahead of print]4(1):

T Regulatory Cells in the Visceral Adipose Tissues.

Allen N Fooks, Louise M D'Cruz.

CD4+ Foxp3+ T regulatory cells (Tregs) residing in the visceral adipose tissues (VAT) have profound effects on local and systemic metabolism. Although many of the molecular characteristics of VAT resident Tregs have been identified, how these cells promote metabolic homeostasis is still unclear. Several new publications help to illuminate the molecular mechanisms that underpin VAT resident Treg function and will be discussed here.

Keywords: Tregs; adipose tissue; metabolism; obesity

DOI: https://doi.org/10.20900/immunometab20220002

Nat Commun. 2022 Jan 26. 13(1): 528

Neutrophil extracellular traps and their histones promote Th17 cell differentiation directly via TLR2.

Alicia S Wilson, Katrina L Randall, Jessica A Pettitt, Julia I Ellyard, Antje Blumenthal, Anselm Enders, Benjamin J Quah, Tobias Bopp, Christopher R Parish, Anne Brüstle.

Neutrophils perform critical functions in the innate response to infection, including through the production of neutrophil extracellular traps (NETs) - web-like DNA structures which are extruded from neutrophils upon activation. Elevated levels of NETs have been linked to autoimmunity but this association is poorly understood. By contrast, IL-17 producing Th17 cells are a key player in various autoimmune diseases but are also crucial for immunity against fungal and bacterial infections. Here we show that NETs, through their protein component histones, directly activate T cells and specifically enhance Th17 cell differentiation. This modulatory role of neutrophils, NETs and their histones is mediated downstream of TLR2 in T cells, resulting in phosphorylation of STAT3. The innate stimulation of a specific adaptive immune cell subset provides an additional mechanism demonstrating a direct link between neutrophils, NETs and T cell autoimmunity.

DOI: https://doi.org/10.1038/s41467-022-28172-4

Bio Protoc. 2021 Dec 20. 11(24): e4265

A Method to Induce Brown/Beige Adipocyte Differentiation from Murine Preadipocytes.

Andréa Livia Rocha, Beatriz Alves Guerra, Jeremie Boucher, Marcelo A Mori.

Adipocytes exhibit different morphological and functional characteristics, depending on their anatomical location, developmental origin, and stimulus. While white adipocytes tend to accumulate energy as triglycerides, brown and beige adipocytes tend to direct carbon sources to fuel thermogenesis. White and beige adipocytes originate from common progenitor cells, which are distinct from brown adipocyte precursors. Having a method to study white vs. beige vs. brown adipocyte differentiation may help to unveil the mechanisms driving distinct adipogenic programs. Preadipocytes can be cultured and differentiated in vitro using a combination of compounds to stimulate adipogenesis. Here, we describe and compare protocols designed to stimulate adipocyte differentiation and induce brown/beige-like or white-like characteristics in differentiating adipocytes. The protocols consist in exposing murine preadipocytes to pharmacological stimuli aimed at triggering adipogenesis and inducing (or not) a thermogenic gene expression program. After 8 days of differentiation with a pro-browning cocktail, immortalized preadipocytes isolated from interscapular brown fat (9B cells) or inguinal white fat (9W cells) from the same mouse expressed higher levels of brown/beige adipocyte markers (e.g., Ucp1) and pan-adipocyte differentiation markers (e.g., Pparg, Cebpa and aP2) when compared to the same cells differentiated with a cocktail that lacked brown/beige adipogenic inducers (i.e., rosiglitazone, T3, and indomethacin). Consistent with a higher thermogenic potential of brown vs. beige adipocytes, differentiated 9B cells expressed higher Ucp1 levels than differentiated 9W cells. This simple protocol may help researchers to understand mechanisms of adipogenesis and how adipocytes become thermogenic.

Keywords: Adipocyte differentiation; Beige adipocytes; Brown adipocytes; Preadipocytes; Thermogenesis

DOI: https://doi.org/10.21769/BioProtoc.4265

J Lipid Res. 2022 Jan 20. pii: S0022-2275(22)00005-0. [Epub ahead of print] 100172

Lipid droplet-mitochondria coupling via Perilipin 5 augments respiratory capacity but is dispensable for FA oxidation.

Benedikt Kien, Stephanie Kolleritsch, Natalia Kunowska, Christoph Heier, Gabriel Chalhoub, Anna Tilp, Heimo Wolinski, Ulrich Stelzl, Guenter Haemmerle.

Disturbances in lipid homeostasis can cause mitochondrial dysfunction and lipotoxicity. Perilipin 5 (PLIN5) decorates intracellular lipid droplets (LD) in oxidative tissues and controls triacylglycerol (TG) turnover via its interactions with Adipose triglyceride lipase (ATGL) and the ATGL co-activator Comparative gene identification-58 (CGI-58). Furthermore, PLIN5 anchors mitochondria to the LD membrane via the outermost part of the carboxyl-terminus. However, the role of this LD-mitochondria coupling (LDMC) in cellular energy catabolism is less established. In this study, we investigated the impact of PLIN5-mediated LDMC in comparison to disrupted LDMC on cellular TG homeostasis, FA oxidation, mitochondrial respiration and protein interaction. To do so, we established PLIN5 mutants deficient in LDMC whilst maintaining normal interactions with key lipolytic players. Radiotracer studies with cell lines stably overexpressing wild type or truncated PLIN5 revealed that LDMC has no significant impact on FA esterification upon lipid loading or TG catabolism during stimulated lipolysis. Moreover, we demonstrated that LDMC exerts a minor if any role in mitochondrial FA oxidation. In contrast, LDMC significantly improved the mitochondrial respiratory capacity and metabolic flexibility of lipid-challenged cardiomyocytes, which was corroborated by LDMC-dependent interactions of PLIN5 with mitochondrial proteins involved in mitochondrial respiration, dynamics and cristae organization. Taken together, this study suggests that PLIN5 preserves mitochondrial function by adjusting FA supply via the regulation of TG hydrolysis and that LDMC is a vital part of mitochondrial integrity.

Keywords: Adipose-triglyceride lipase; Comparative gene identification-58; Lipid droplets; PLIN5; cardiovascular disease; fatty acid oxidation; lipid droplet-mitochondria coupling; lipolysis; lipotoxicity; mitochondrial respiration

DOI: https://doi.org/10.1016/j.jlr.2022.100172

Antioxid Redox Signal. 2022 Jan 24.

Circadian control of mitochondria in ROS homeostasis.

Volha Mezhnina, Oghogho P Ebeigbe, Allan Poe, Roman V Kondratov.

SIGNIFICANCE: Mitochondria produce most of the cellular ATP through the process of oxidative phosphorylation. Energy metabolism in the mitochondria is associated with the production of reactive oxygen species (ROS). Excessive ROS production leads to oxidative stress and compromises cellular physiology. Energy metabolism in the mitochondria depends on nutrient flux and cellular metabolic needs, which are in turn connected with the feeding/fasting cycle. In animals, the feeding/fasting cycle is controlled by the circadian clock that generates 24-hour rhythms in behavior, metabolism and signaling. Recent Advances. Here, we discuss the role of the circadian clock and rhythms in mitochondria on ROS homeostasis. Circadian clock is involved in mitochondrial ROS production and detoxification through control of nutrient flux and oxidation, uncoupling, antioxidant defense and mitochondrial dynamics.
CRITICAL ISSUES: Little is known on molecular mechanisms of circadian control of mitochondria functions. The circadian clock regulates the expression and activity of mitochondrial metabolic and antioxidant enzymes. The regulation involves a direct transcriptional control by CLOCK/BMAL1, NRF2 transcriptional network and sirtuin dependent posttranslational protein modifications. Future Perspectives. We hypothesize that the circadian clock orchestrates mitochondria physiology to synchronize it with the feeding/fasting cycle. Circadian coordination of mitochondrial function couples energy metabolism with diets and contributes to antioxidant defense to prevent metabolic diseases and delay aging.

DOI: https://doi.org/10.1089/ars.2021.0274