Biology subjects

Ninni, A.

Publications and source records attributed to Ninni, A..

5 recordsLinked to original sources

bioRxiv2026

TREM2 drives accumulation of pro-scarring monocyte-derived macrophages in the infarcted myocardium

Myocardial infarction is a leading cause of death and disability worldwide. Ischemic injury leads to irreversible loss of cardiomyocytes, the contractile cells of the heart, and formation of a fibrotic scar. After infarction, macrophages massively infiltrate the heart and orchestrate the tissue repair process by removing dead cells and modulating fibroblast activation for scar formation. We previously demonstrated that diverse monocyte-derived macrophage populations dynamically accumulate in the heart following myocardial infarction, notably a pro-repair Trem2hi subset. In this study, we leveraged spatial transcriptomics, single-cell RNA-seq, and functional assays to elucidate the role of TREM2 in driving macrophage-mediated cardiac tissue repair post-infarction. We show that Trem2hi macrophages localize in scarring areas of the infarcted myocardium in the vicinity of collagen-producing myofibroblasts. In Trem2-/- mice, cardiac accumulation of monocyte-derived macrophages with a pro-scarring matrisome-associated macrophage signature was reduced. TREM2 deficiency was functionally associated with reduced fibroblast proliferation, accumulation of myofibroblasts, decreased collagen deposition in the infarcted heart, and increased infarct size. In vitro, we show that TREM2 mediates efferocytosis-induced pro-fibrotic gene expression and promotes macrophage ability to induce fibroblast migration. IL-4 priming of bone marrow-derived macrophages further increased the pro-fibrotic response in macrophages, suggesting that IL-4 and efferocytosis act synergistically to drive this phenotype. Altogether, our results show that TREM2 is essential for the accumulation and function of pro-scarring monocyte-derived macrophages in the infarcted myocardium.

immunology↗

bioRxiv2026

Primary Hyperparathyroidism Reveals Limited Adipose Remodeling in Human

BackgroundPreclinical models implicate the parathyroid hormone/parathyroid-hormone-related protein (PTH/PTHrP)-PTH1 receptor (PTH1R) axis in adipocyte lipolysis, adipose browning, and energy wasting. Whether this catabolic program is reproduced in vivo in humans remains unresolved. Primary hyperparathyroidism (PHPT), a condition of chronic endogenous PTH excess, provides a clinically relevant model to test the translational relevance of this pathway. MethodsWe combined population-scale analyses with a prospective human intervention study. PTH/PTH1R associations with body composition were evaluated in the UK Biobank and compared with PTH dynamics in cancer-associated cachexia using TRACERx proteomic data. In parallel, patients with PHPT were assessed before and after parathyroidectomy and compared with matched surgical controls. Biochemical parameters, circulating adipocytokines, DXA- and BIA-derived body composition, histology, UCP1 immunohistochemistry, and supraclavicular adipose tissue transcriptomic and proteomic profiles were integrated, with external validation in an independent supraclavicular adipose dataset. ResultsIn the UK Biobank, apparent positive associations between circulating PTH/PTH1R signals and fat or lean mass were markedly attenuated after matching for age, sex, and BMI, arguing against a disease-specific adiposity effect of PHPT. In TRACERx, circulating PTH did not increase across BMI-adjusted weight-loss grades. In the prospective cohort, parathyroidectomy normalized PTH, calcium, and phosphate but did not induce coherent changes in glucose metabolism, lipid profile, inflammatory markers, body weight, fat mass, lean mass, or thermogenic adipose signatures. Supraclavicular adipose histology, UCP1 staining, RNA-seq, proteomics, pathway analysis, and external dataset reanalysis converged on the absence of browning or thermogenic activation. By contrast, PHPT was associated with a selective adipose-related secretory phenotype: adiponectin, adipsin, and retinol-binding protein 4 were reversible after surgery, whereas lipocalin- 2 and thrombospondin-1 remained elevated. ConclusionsChronic endogenous PTH excess is not sufficient to induce a detectable thermogenic or energy- dissipating adipose program in humans under basal clinical conditions. These findings challenge direct extrapolation from rodent PTH/PTHrP models and reposition the human PTH-adipose axis as a selective secretory and remodeling pathway rather than a dominant driver of adipose browning or wasting. HighlightsO_LIPHPT provides an in vivo human model of chronic endogenous PTH excess. C_LIO_LIPTH/PTH1R associations with body composition are lost after stringent confounder control. C_LIO_LIParathyroidectomy normalizes mineral metabolism without inducing adipose browning or wasting. C_LIO_LISupraclavicular adipose histology, UCP1 staining, transcriptomics, and proteomics show no thermogenic activation. C_LIO_LIPHPT unmasks a selective adipose-related secretory signature with reversible and persistent components. C_LI

physiology↗

bioRxiv2025

Non-canonical TERT function mitigates adipose tissue inflammation in obesity by modulating stem cell-macrophage communication and macrophage states

Background and aimsObesity drives adipose tissue (AT) expansion and chronic inflammation, leading to metabolic dysfunction through adipocyte hypertrophy, impaired ASPC differentiation, immune infiltration, and fibrosis. Stromal vascular remodeling prominently features expansion of Gdf15- and Trem2-expressing lipid-associated macrophages (LAMs), which respond to adipocyte stress and act as lipid scavengers to buffer excess lipids released by adipocytes. Here, we examined macrophage reprogramming in p21+/Tert and p21+/TertCi mice, which express active TERT or its catalytically inactive TERTCi mutant from the endogenous Cdkn1a promoter. ResultsFollowing HFD exposure, conditional expression of TERT or TERTCi resulted in a pronounced downregulation of p21 in macrophage subsets, accompanied by a reduction in AT inflammation. Notably, TERT and TERTCi expression reshaped the adipose-tissue macrophage (ATM) landscape depleting Trem2+ and Gdf15+ LAMs while preserving resident macrophages. This shift was accompanied by marked suppression of the Trem2 transcriptional program and down-regulation of PPAR-{gamma} and NR1H3 in LAMs and by impaired ASPC-LAM signaling pathways that normally drive LAM recruitment and activation. Proteomic profiling further showed that p21+/Tert ASPCs secreted markedly higher levels of proteins associated with non-conventional secretion, while extracellular matrix-associated factors and cytokines/chemokines including key mediators of ASPC-LAM communication such as Ccl2, C3, and Csf1 were substantially reduced. However, only p21+/Tert mice, and not p21+/TertCi mice, exhibited significant metabolic improvements, indicating that macrophage remodeling alone is insufficient to restore systemic metabolic function. Consistent with this, enhanced ASPC expansion and differentiation, supporting improved adipose-tissue remodeling, was observed exclusively in p21+/Tert obese mice. ConclusionsTERT remodels adipose tissue immunity independently of its enzymatic activity, and TERT-driven reprogramming of the ASPC secretome may emerge as a promising strategy to combat obesity-related metabolic dysfunction. HighlightsO_LIConditional expression of TERT or catalytically inactive TERTCi results in the depletion Trem2+ and Gdf15+ LAMs while preserving resident macrophages C_LIO_LITERT and TERTCi expression impairs ASPC-adipocyte/LAM communication pathways that normally drive LAM recruitment and activation. C_LIO_LIIn vitro, TERT conditional expression in ASPCs promotes non-conventional protein secretion and reduces the secretion of key mediators of ASPC-LAM communication C_LIO_LIOnly p21+/Tert mice, and not p21+/TertCi mice, exhibited enhanced ASPC expansion, improved adipose-tissue remodeling, and systemic metabolic benefits, demonstrating that macrophage remodeling alone is insufficient to restore metabolic function. C_LI

physiology↗

bioRxiv2024

MACanalyzeR: scRNA-seq Analysis Tool Reveals PPARγHI Lipid-Associated Macrophages Facilitate Thermogenic Expansion in BAT

Macrophages in brown adipose tissue (BAT) play a complex role in regulating its activity. However, the role of macrophages in regulating BAT activation/deactivation has not yet been comprehensively characterized. To elucidate this, we developed MACanalyzeR, a scRNAseq-based tool specifically designed to explore the macrophage features at molecular and metabolic level. MACanalyzeR was applied in scRNA-seq datasets obtained from BAT with thermogenic loss (db/db mice) and activation (High Fat Diet, HFD). Our computational approach revealed that macrophages accumulating in BAT upon these conditions resemble lipid-associated macrophages (LAMs) with foaming-like features. BAT LAMs also show a significant enrichment of genes associated with mitochondria and lysosomes. Interestingly, LAMs identified in BAT from HFD mice positively correlate with thermogenic genes and exhibit an enrichment in PPAR{gamma} signaling pathway, with an activated mitochondrial metabolism. Cell dynamic strategy, revealed that LAM with high Pparg expression levels (PpargHIGH) progressively accumulate during skeletal muscle regeneration, suggesting a potential role for this LAM subcluster in maintaining tissue homeostasis. Our findings suggest PpargHIGH LAMs as a subclass of macrophages potentially contributing in preserving tissue homeostasis associated with high energy demand conditions such as thermogenic and regenerative stimuli.

physiology↗

bioRxiv2023

Frataxin Deficiency Drives a Shift from Mitochondrial Metabolism to Glucose Catabolism, Triggering an Inflammatory Phenotype in Microglia

Immunometabolism investigates the complex interplay between the immune system and cellular metabolism. This study highlights the effects of mitochondrial frataxin (FXN) depletion, which causes Friedreichs ataxia (FRDA), a neurodegenerative condition characterized by coordination and muscle control deficiencies. Using single-cell RNA sequencing, we identified specific cell groups in the cerebellum of a FRDA mouse model, emphasizing a notable inflammatory microglial response. These FXN-deficient microglia cells exhibited enhanced inflammatory reactions. Furthermore, our metabolomic analyses revealed increased glycolysis and itaconate production in these cells, possibly driving the inflammation. Remarkably, butyrate treatment counteracted these immunometabolic changes, triggered an antioxidant response via the itaconate-Nrf2-GSH pathways, and dampened inflammation. The study also pinpointed Hcar2 (GPR109A) as a potential agent for butyrate anti-inflammatory impact on microglia. Tests on FRDA mice highlighted the neuroprotective attributes of butyrate intake, bolstering neuromotor performance. In essence, our findings shed light on how cerebellar microglia activation contributes to FRDA and highlight butyrate potential to alleviate neuroinflammation, rectify metabolic imbalances, and boost neuromotor capabilities in FRDA and similar conditions.

physiology↗