bims-ecmrat 2023-10-08 papers

Matrix Biol. 2023 Oct 02. pii: S0945-053X(23)00104-X. [Epub ahead of print]

Molecular cues for immune cells from small leucine-rich repeat proteoglycans in their extracellular matrix-associated and free forms.

George Maiti, Sean Ashworth, Tansol Choi, Shukti Chakravarti.

In this review we highlight emerging immune regulatory functions of lumican, keratocan, fibromodulin, biglycan and decorin, which are members of the small leucine-rich proteoglycans (SLRP) of the extracellular matrix (ECM). These SLRPs have been studied extensively as collagen-fibril regulatory structural components of the skin, cornea, bone and cartilage in homeostasis. However, SLRPs released from a remodeling ECM, or synthesized by activated fibroblasts and immune cells contribute to an ECM-free pool in tissues and circulation, that may have a significant, but poorly understood foot print in inflammation and disease. Their molecular interactions and the signaling networks they influence also require investigations. Here we present studies on the leucine-rich repeat (LRR) motifs of SLRP core proteins, their evolutionary and functional relationships with other LRR pathogen recognition receptors, such as the toll-like receptors (TLRs) to bring some molecular clarity in the immune regulatory functions of SLRPs. We discuss molecular interactions of fragments and intact SLRPs, and how some of these interactions are likely modulated by glycosaminoglycan side chains. We integrate findings on molecular interactions of these SLRPs together with what is known about their presence in circulation and lymph nodes (LN), which are important sites of immune cell regulation. Recent bulk and single cell RNA sequencing studies have identified subsets of stromal reticular cells that express these SLRPs within LNs. An understanding of the cellular source, molecular interactions and signaling consequences will lead to a fundamental understanding of how SLRPs modulate immune responses, and to therapeutic tools based on these SLRPs in the future.

Keywords: ECM; biglycan; fibroblast stromal cells; inflammation; lumican; lymph node

DOI: https://doi.org/10.1016/j.matbio.2023.10.001

Genes Dev. 2023 Oct 05.

Mesenchymal stromal cells as conductors of adipose tissue remodeling.

Jessica Cannavino, Rana K Gupta.

Adipose tissue exhibits a remarkable capacity to expand, contract, and remodel in response to changes in physiological and environmental conditions. Here, we describe recent advances in our understanding of how functionally distinct tissue-resident mesenchymal stromal cell subpopulations orchestrate several aspects of physiological and pathophysiological adipose tissue remodeling, with a particular focus on the adaptations that occur in response to changes in energy surplus and environmental temperature. The study of adipose tissue remodeling provides a vehicle to understand the functional diversity of stromal cells and offers a lens through which several generalizable aspects of tissue reorganization can be readily observed.

Keywords: adipogenesis; adipose tissue; fibrosis; inflammation; mesenchymal stromal cells; obesity; white adipocyte

DOI: https://doi.org/10.1101/gad.351069.123

J Clin Invest. 2023 Oct 02. pii: e169173. [Epub ahead of print]133(19):

Reduction of SPARC protects mice against NLRP3 inflammasome activation and obesity.

Seungjin Ryu, Olga Spadaro, Sviatoslav Sidorov, Aileen H Lee, Sonia Caprio, Christopher Morrison, Steven R Smith, Eric Ravussin, Irina Shchukina, Maxim N Artyomov, Yun-Hee Youm, Vishwa Deep Dixit.

The comprehensive assessment of long-term effects of reducing intake of energy (CALERIE-II; NCT00427193) clinical trial established that caloric restriction (CR) in humans lowers inflammation. The identity and mechanism of endogenous CR-mimetics that can be deployed to control obesity-associated inflammation and diseases are not well understood. Our studies have found that 2 years of 14% sustained CR in humans inhibits the expression of the matricellular protein, secreted protein acidic and rich in cysteine (SPARC), in adipose tissue. In mice, adipose tissue remodeling caused by weight loss through CR and low-protein diet feeding decreased, while high-fat diet-induced (HFD-induced) obesity increased SPARC expression in adipose tissue. Inducible SPARC downregulation in adult mice mimicked CR's effects on lowering adiposity by regulating energy expenditure. Deletion of SPARC in adipocytes was sufficient to protect mice against HFD-induced adiposity, chronic inflammation, and metabolic dysfunction. Mechanistically, SPARC activates the NLRP3 inflammasome at the priming step and downregulation of SPARC lowers macrophage inflammation in adipose tissue, while excess SPARC activated macrophages via JNK signaling. Collectively, reduction of adipocyte-derived SPARC confers CR-like metabolic and antiinflammatory benefits in obesity by serving as an immunometabolic checkpoint of inflammation.

Keywords: Adipose tissue; Inflammation; Innate immunity; Metabolism; Obesity

DOI: https://doi.org/10.1172/JCI169173

Am J Physiol Endocrinol Metab. 2023 Oct 04.

Unravelling Adipose Tissue Proteomic Landscapes in Severe Obesity: Insights into Metabolic Complications and Potential Biomarkers.

Pavel Hruska, Jan Kucera, Daniela Kuruczova, Marek Buzga, Matej Pekar, Pavol Holeczy, David Potesil, Zbynek Zdrahal, Julie Bienertova-Vasku.

In this study, we aimed to comprehensively characterise the proteomic landscapes of subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) in severely obese patients, to establish their associations with clinical characteristics, and to identify potential serum protein biomarkers indicative of tissue-specific alterations or metabolic states. We conducted a cross-sectional analysis of 32 severely obese patients (16 males and 16 females) of Central European descent who underwent bariatric surgery. Clinical parameters and body composition were assessed using dual-energy X-ray absorptiometry (DXA) and bioelectrical impedance, with 15 patients diagnosed with type 2 diabetes (T2D) and 17 with hypertension. Paired SAT and VAT samples, along with serum samples, were subjected to state-of-the-art proteomics liquid chromatography-mass spectrometry (LC-MS). Our analysis identified 7,284 proteins across SAT and VAT, with 1,249 differentially expressed proteins between the tissues and 1,206 proteins identified in serum. Correlation analyses between differential protein expression and clinical traits suggest a significant role of SAT in the pathogenesis of obesity and related metabolic complications. Specifically, the SAT proteomic profile revealed marked alterations in metabolic pathways and processes contributing to tissue fibrosis and inflammation. Although we do not establish a definitive causal relationship, it appears that VAT might respond to SAT metabolic dysfunction by potentially enhancing mitochondrial activity and expanding its capacity. However, when this adaptive response is exceeded, it could possibly contribute to insulin resistance and in some cases, it may be associated with the progression to T2D. Our findings provide critical insights into the molecular foundations of SAT and VAT in obesity and may inform the development of targeted therapeutic strategies.

Keywords: Obesity; Proteomics; Subcutaneous adipose tissue; Type 2 diabetes; Visceral adipose tissue

DOI: https://doi.org/10.1152/ajpendo.00153.2023