Biology subjects

Chatzigeorgiou, A.

Publications and source records attributed to Chatzigeorgiou, A..

5 recordsLinked to original sources

bioRxiv2025

Stabilin levels are related to atherosclerotic plaque burden in type 2 diabetes mellitus individuals

Type 2 diabetes mellitus (T2DM) is a global burgeoning health problem that increases the risk of atherosclerotic cardiovascular disease (ASCVD). Infiltration and oxidative modification of low-density lipoprotein (LDL) cholesterol in the arterial wall and chronic inflammation comprise central pathogenetic mechanisms in ASCVD. Scavenger receptors, particularly Stabilin-1 (Stab1) and Stabilin-2 (Stab2), are pivotal in the clearance of oxidized LDL (oxLDL) cholesterol and pro-atherogenic ligands from circulation. However, their role in atherosclerosis development in the spectrum of T2DM remains poorly characterized. We assessed circulating levels of Stab1, Stab2, and their ligands (TGFbI, Periostin and Reelin) in a cohort of 33 T2DM and 21 non-diabetic individuals, stratified by their atherosclerotic plaque burden as assessed by high-resolution vascular ultrasound. Associations between stabilins, their ligands and conventional cardiovascular risk factors were evaluated. Stab1 levels were significantly elevated in individuals with higher atherosclerotic plaque burden (p<0.05), while Reelin levels were marginally elevated, both in the total study cohort and among T2DM patients. Stab1 levels positively correlated with body mass index and inversely correlated with total cholesterol, LDL, and high-density lipoprotein (HDL) cholesterol levels. Our findings indicate that Stab1 may serve as a marker of dysregulated lipid metabolism and increased atherosclerotic plaque burden in individuals with T2DM. Larger prospective studies are warranted to establish the prognostic and potentially therapeutic value of Stab1 and to clarify its mechanistic role in diabetic atherosclerosis.

physiology↗

bioRxiv2025

Functional Dichotomy of Developmental Foxp3+ Treg Cell Subsets in the Visceral Adipose Tissue of Lean and Obese Mice

Chronic inflammation and loss of Foxp3+ regulatory T (Treg) cells in the visceral adipose tissue (VAT) are hallmarks of the pathogenesis of insulin resistance and obesity. This study explores the roles of VAT Treg cells from thymic (tTreg) and peripheral (pTreg) developmental origin, revealing their opposing roles in metabolic inflammation. Obesity destabilized VAT tTreg cells, causing them to clonally expand into obesogenic Foxp3-IFN-{gamma}+ T effector cells, enhancing pro-inflammatory type 1 responses. Genetic tTreg ablation prevented this shift, promoting anti-inflammatory type 2 response, reduced body weight, and improved insulin resistance. Compared to their tTreg counterpart, pTreg cells were functionally well adapted to maintain VAT homeostasis and protect against obesity. Genetic pTreg ablation promoted spontaneous obesity symptoms even with physiological calorie intake, and worsened VAT inflammation and liver steatosis on a high-calorie diet. These findings highlight tTreg instability as a pathogenic threat and pTreg cells as crucial regulators of metabolic homeostasis. HighlightsO_LIVAT Tregs of lean mice originate from both thymic and peripheral Treg development C_LIO_LIHigh-calorie diet destabilizes tTregs that clonally expand into obesogenic IFN-{gamma}+ Th1 cells C_LIO_LIGenetic tTreg deficiency improves steady-state metabolism and prevents diet-induced obesity C_LIO_LIGenetic pTreg deficiency promotes obesity in both sexes even with normal calorie intake C_LIO_LIVAT pTregs are particularly adapted to regulate VAT homeostasis, including adipogenesis C_LI In BriefObesity and type 2 diabetes are characterized by insulin resistance, regulatory T (Treg) cell loss, and chronic inflammation in visceral adipose tissue (VAT). In this context, Yilmazer et al. dissect the functional roles of tTreg and pTreg cells. They show that VAT pTreg cells are particularly adapted to exert non-redundant homeostatic functions, and that pTreg deficiency predisposes to obesity even with normal calorie intake. In contrast, VAT tTreg cells can contribute to local inflammation by dedifferentiating into Foxp3- Th1-polarized effector cells. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/642664v1_ufig1.gif" ALT="Figure 1"> View larger version (60K): org.highwire.dtl.DTLVardef@19c740corg.highwire.dtl.DTLVardef@86d52borg.highwire.dtl.DTLVardef@152a88org.highwire.dtl.DTLVardef@19b7b13_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2025

Exercise induces anti-inflammatory reprogramming in macrophages via Hsp60

Physical activity exerts systemic anti-inflammatory effects and reduces the risk for multiple non-communicable diseases, with 7.2% of all-cause deaths globally being attributed to physical inactivity. However, the cellular and molecular components of the exercise-induced anti-inflammatory effects remain only partly understood. Herein we show that moderate-intensity exercise promotes anti-inflammatory reprograming of macrophages orchestrated by the skeletal muscle cells secretome. Primary bone marrow-derived macrophages (BMDMs) exposed to the secretome of mechanically-loaded myotubes (exercise-conditioned medium, exCM) acquire an anti-inflammatory transcriptional profile and increased reliance on oxidative phosphorylation, as shown by Seahorse real-time cell metabolic analysis, compatible with an M2-like phenotypic switch. Using an unbiased proteomic analysis of the exCM we identify the chaperonin Hsp60 as a key mediator of the anti-inflammatory effects of exercise. Hsp60 expression increases in mechanically loaded myotubes in vitro, in the quadriceps muscle and serum of mice following an 8-week program of moderate-intensity aerobic exercise, as well as in human muscle after resistance training. Importantly, treatment of BMDMs with Hsp60 in vitro recapitulates the exCM-induced transcriptional reprograming, promoting an M2-like phenotype. Taken together, our data highlight Hsp60 as a novel component of the skeletal muscle cell-macrophage crosstalk, providing mechanistic insights into the anti-inflammatory effects of exercise.

physiology↗

bioRxiv2024

Exercise alleviates liver senescence but does not outmatch the effect of dietary restriction in diet-induced MASLD

BackgroundThe present study aims at deciphering the potential benefits of aerobic exercise and dietary restriction on liver senescence, which is an established hallmark of metabolic dysfunction-associated steatotic liver disease (MASLD), a condition with limited therapeutic options. MethodsC57BL6 mice were subjected to normal diet (ND, 10% of kilocalories from fat) or a high-fat diet (HFD, 60% of kilocalories deriving from fat and water supplemented with 5% High-fructose Corn Syrup, HFCS) for 12 weeks. Then, for additional 8 weeks, the ND group continued with the same diet, while the HFD group was divided into four subgroups: a) mice that continued with the same HFD-5% HFCS in water scheme (HFD), b) mice that continued with the same HFD-5% HFCS in water scheme and underwent supervised aerobic exercise 3-times/week (HFDEX), c) mice that were switched to ND (dietary restriction, DR) and d) mice that were switched to ND while undergoing supervised aerobic exercise 3-times/week (DREX). Phenotypic and histological characterization of obesity and MASLD were performed in all groups. Biomarkers of senescence were analyzed in terms of their mRNA expression levels to assess the impact of all interventions on MASLD-related senescence in the liver. GL13 and p21 immunohistochemical stainings were conducted to examine the protein levels of senescence-associated lipofuscin and p21WAF1/CIP1 respectively, so as to finally investigate their relationship with the grade of steatosis observed in each individual animal. ResultsDR and DREX groups exhibited significantly reduced features of obesity and MASLD-related hepatic steatosis, to a greater extent than the respective amelioration driven by aerobic exercise-only in HFDEX animals. A statistically significant increase of the mRNA expression of cyclin-dependent kinase p21WAF1/CIP1 was detected in HFD livers as compared to ND, which was also reversed upon DR-inclusive interventions. In contrast, the gene expression levels of cyclin-dependent kinase p16INK4a remained similar in all groups even after a combined intervention. Increased hepatic expression of the p27 and p53 components of the p53-p21 CIP/WAF-driven axis of cellular senescence as well as their restoration to ND-like levels upon DR and DREX, suggest an active participation of the p21WAF1/CIP1 mechanism of senescence in the emergence of MASLD, but also in its reversal through DR or/and EX interventions. Immunohistochemical stainings for GL13 and p21 confirmed the aforementioned alterations of p21WAF1/CIP1 at the tissular level. ConclusionLiver senescence is responsive both to exercise and dietary restriction, but its amelioration in the context of MASLD is more robust upon DR-inclusive interventions.

physiology↗

bioRxiv2022

Interferon-induced lysosomal membrane permeabilization causes cDC1-deserts in tumors.

T cell immunity requires antigen capture by conventional dendritic cells (cDCs), digestion and transfer to draining lymph nodes for presentation to antigen-inexperienced T cells. cDCs type I excel as cancer-antigen presenting cells, due to their ability to phagocytose, slowly digest apoptotic cancer cells and translocate cancer antigens to the cytosol for loading to MHCI and cross-presentation to CD8 T cells 1-3. In tumor tissues cDCs1 become particularly scarce and this restricts anti-tumour immunity, immunotherapy responses and patient survival 4-8. Tumor cDC1 paucity is not fully understood and no specific treatment currently exists. Here, we find that type I interferons (IFN) induce lysosomal stress, lysosomal membrane permeabilization (LMP) and lysosomal-dependent cell death (LDCD) in cDCs1. Two parallel pathways downstream of IFNAR1 converged to induce cDC1 LDCD. Up-regulation of expression of lysosomal genes enhanced the proteolytic activity of lysosomes, while IFN-inducible guanylate binding protein-2 (GBP-2) accumulated in the membrane of the stressed lysosomes, leading to LMP, proteolytic enzyme release and death. Protease inhibition or GBP-2 repression rescued cDCs1 from LDCD and boosted their anti-tumor efficacy. GBPs are amongst the most abundant IFN-induced genes and known to form toxic pores in pathogen-containing vacuoles and pathogen membranes 9. GBP-2-driven LMP is likely due to the ability of GBP-2 to form pores on the lysosomes of cDC1s. This might have evolved as a physiological mechanism of antigen translocation to the cytosol for cross-presentation 10. We anticipate our findings to be a starting point for more rational cDC1-directed immunotherapies. For instance, protease inhibition, GBP-2 downregulation or induced expression of LMP repair machinery may boost cDC1 efficacy in adoptive cell therapies or their use as live vaccines11-13.

immunology↗