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2024

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09

Huazhong University of Science and Technology Wang Cong Yi/Sun Fei found in obese environment really pathogenic adipose tissue macrophage subsets

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Adipose tissue macrophages (ATMs) play an important role in maintaining adipose tissue homeostasis and coordinating metabolic inflammation.Given the extensive functional heterogeneity and phenotypic plasticity of ATMs, there is a need to identify truly pathogenic subpopulations of ATMs in the context of obesity.

On September 17, 2024, Wang cong-yi and sun Fei of Huazhong university of science and technology jointly communicated inCell MetabolismPublished online entitled"PDIA3 defines a novel subset of adipose macrophages to exaggation the development of obesity and metabolic disordersThe study performed single-core RNA sequencing (snRNA-seq) and revealed a distinct subpopulation of ATMs, definedATF4hiPDIA3hiACSL4hiCCL2hiInflammation and Metabolically Activated Macrophages (iMAMs) in which PDIA3 is required to maintain their migratory and pro-inflammatory properties.

Mechanically, ATF4 acts as a metabolic stress sensor to transcribe PDIA3, which then exerts redox control on RhoA activity through RhoA-Yap signaling and enhances the pro-inflammatory and migratory properties of iMAMs. Pdia3 small interfering RNA (siRNA)-loaded liposomes effectively inhibit fat inflammation and high-fat diet (HFD)-induced obesity.Taken together, the data from this study support that strategies to target iMAMs by inhibiting the expression or activity of PDIA3 may be a viable approach for the clinical treatment of obesity and metabolic disorders.

 

Obesity is characterized by a chronic low-grade inflammatory state characterized by infiltration and dysregulation of immune cells in adipose tissue and other metabolic organs.Over the past few decades, studies have identified metabolic inflammation in adipose tissue caused by overnutrition as a key driver of insulin resistance and type 2 diabetes (T2D). In general, current therapeutic approaches aim to alleviate the symptoms of obesity-related metabolic disorders, but do not correct the underlying immunopathology. Therefore, elucidation of the immune mechanisms involved in the development of obesity may be the basis for establishing effective complementary therapies.
Immune cells interact with adipocytes and other matrix components to maintain adipose tissue homeostasis.Adipose tissue macrophages (ATMs) play an important role in regulating metabolic inflammation. In a typical case, physiological ATMs are uniformly distributed and predominantly exhibit an anti-inflammatory alternative activation (M2) phenotype. ATMs, however, are organized into a "coronal" structure (CLS) that surrounds dead fat cells and exhibits a pro-inflammatory M1 phenotype in an obese setting. There is good evidence that M1-predisposed ATMs are responsible for the development and progression of insulin resistance and T2D.

Activated M1 macrophages secrete multiple chemokines and cytokines in the obese stateSuch as CC motif ligand -2 (CCL2, also known as monocyte chemoattractant protein -1 [MCP-1]), interleukin (IL)-6, tumor necrosis factor (TNF)-α, etc., spread inflammation and damage adipocyte function. However, because macrophages are extremely dynamic and plastic in different tissues, and the so-called M1 macrophage fraction is beneficial in combating infection of adipose tissue and other organs, the overly simplified classification of M1/M2 macrophage phenotype has been severely challenged.Therefore, in order to develop an effective macrophage-targeted immunotherapy for metabolic diseases, it is necessary to identify the truly pathogenic ATM subsets that contribute to the pathogenesis of human obesity.

Mononuclear RNA sequencing (snRNA-seq) has greatly improved our understanding of the functional heterogeneity of specific cell types and led to the identification of new ATM subpopulations in rodent modelsincluding vascular-associated macrophages (VAMs), sympathetic neuron-associated macrophages (SAMs), and lipid-associated macrophages (LAMs). Interestingly, through snRNA-seq analysis of adipose tissue samples from lean versus obese people, the researchers observed an accumulation of a unique subset of ATM, called ATF4, in obese subjects. hiPDIA3 hiACSL4 hiCCL2 hiInflammation and metabolism activate macrophages (iMAMs). ATF4, ACSL4 and CCL2 regulate macrophage function, while the role of PDIA3 in macrophages is unclear. Protein disulfide isomerase 3 (PDIA3) belongs to the PDI family, with isomerase and redox activity, and participates in the unfolded protein reaction (UPR).
Previous studies have shown that PDIA3 is an SUMOylation target for inducing proinsulin misfolding and endoplasmic reticulum stress in pancreatic β-cells., predisposing to type 1 diabetes (T1D), but its role in the pathogenesis of T2D-related obesity is largely unknown. The study explores the feasibility of PDIA3 as a biomarker for human obesity and provides experimental evidence supporting that PDIA3 is an effector molecule that modulates iMAM function, thereby exacerbating dietary obesity. Mechanically, PDIA3 exerts redox control over RhoA activity via RhoA- YAP signaling, enhancing the proinflammatory and migratory capacity of macrophages.

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