Biology subjects

Piollet, M.

Publications and source records attributed to Piollet, M..

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

Mucosal-Associated Invariant T Cells Promote Atherosclerosis Through Monocyte-Driven Inflammation

Mucosal-associated invariant T (MAIT) cells are unconventional T lymphocytes that may contribute to inflammatory responses, although their specific role in atherosclerosis remains poorly understood. In this study, we identified MAIT cells within human atherosclerotic plaques and found that they were significantly enriched among CD3 T cells in plaques compared to matched peripheral blood samples. MAIT cells within plaques exhibited an activated phenotype and showed upregulation of genes associated with inflammation and cellular activation, compared to circulating MAIT cells from the same patients. Using murine models, we found that low-density lipoprotein receptor (Ldlr)-/- mice carrying the CAST locus, which confers naturally higher frequencies of MAIT cells, displayed increased MAIT cell accumulation in both the liver and atherosclerotic plaques when fed a high-cholesterol diet. In contrast, MAIT cell-deficient Ldlr-/-CAST MR1-/- mice exhibited a reduced atherosclerotic burden, diminished liver fibrosis, smaller myocardial infarcts following coronary artery ligation, without significant changes in plasma cholesterol levels. These atheroprotective effects were accompanied by lower monocyte counts in the bone marrow and blood, as well as reduced plaque macrophage accumulation in the plaques. Furthermore, deletion of CCR2, which impairs monocyte mobilization, abrogated the pro-atherogenic effects of MAIT cells, indicating that MAIT-driven atherogenesis occurs through a monocyte-dependent mechanism. Taken together, these findings identify MAIT cells as active contributors to vascular inflammation and position them as potential therapeutic targets for atherosclerosis and its complications.

immunology↗

bioRxiv2026

Neutrophil terminal programming in the ischemic heart drives fibrosis after myocardial infarction

Following myocardial infarction (MI), the heart undergoes massive neutrophil infiltration characterized by the emergence of distinct subsets, notably a SiglecF+ population that accumulates according to specific temporal dynamics. The mechanisms governing cardiac neutrophil heterogeneity and the subsequent functional impact of this diversity on tissue repair following myocardial infarction remain to be elucidated. Using single-cell RNA-sequencing of neutrophils in the heart and peripheral organs of infarcted mice, we here show that while acquisition of the SiglecF+ state only fully occurs in the ischemic heart tissue, MI primes neutrophils in the periphery to acquire Siglecf and to upregulate receptors for TGF{beta} and GM-CSF that drive acquisition of the SiglecF+ state. Ly6G targeting in vivo shifted cardiac neutrophils towards the SiglecF+ state at day 3 post-MI, induced the emergence of reprogrammed SiglecF+Ly6Glo and Retnlghi neutrophil states at day 5, and was associated with increased fibrosis of the infarct border zone. Mechanistically, Ly6G targeting reshaped the cardiac immune landscape with increased recruitment of pro-fibrotic {gamma}{delta} T cells and monocytes, and SiglecF+ neutrophils exerted direct pro-fibrotic effects on fibroblasts in a co-culture system. Altogether, our results indicate that peripheral neutrophil priming combined with their terminal programming towards a SiglecF+ state in the ischemic heart drives cardiac fibrosis after MI.

physiology↗

bioRxiv2025

Targeting platelet GPVI or GPIIb/IIIa only minimally affect acute inflammation and cardiac repair in experimental permanent myocardial infarction

BackgroundBeyond their role in hemostasis, platelets are recognized as key regulators of inflammatory responses in ischemic diseases, including cardiac ischemia/reperfusion (I/R) injury with key roles of platelet membrane glycoproteins (GP)VI and IIb/IIIa. However, whether platelet-driven thrombo-inflammatory pathways affect acute inflammation and cardiac repair processes in permanent, non-reperfused myocardial infarction (MI) is unknown. MethodsWe targeted GPVI and GPIIb/IIIa in experimental permanent MI in mice. Cardiac, bone marrow, and blood innate immune responses were evaluated by flow cytometry and single-cell RNA-sequencing. Survival and cardiac repair were assessed over the inflammatory and scar formation phase, until day 10 after permanent MI. ResultsPlatelet GPVI immunodepletion by injection of the anti-GPVI antibody JAQ1 did not affect levels of neutrophil or monocyte subsets (Ly6Chi and Ly6Clow) in the bone marrow and blood, and did not alter accumulation of monocytes, macrophage subsets (defined by expression of MHCII and TIM4), or neutrophil subsets (SiglecFhi/low) in the infarcted heart on day 4. GPVI depletion only had a minimal effect on cardiac repair, slightly decreasing interstitial fibrosis in the infarct border zone on day 10. Four days after MI, GPIIb/IIIa inhibition by JON/A-F(ab')2 had no effect on cardiac or systemic innate immune cell levels as measured by flow cytometry and did not affect composition and transcriptomic profile of the cardiac immune infiltrate as revealed by single-cell RNA-sequencing. GPIIb/IIIa inhibition did not improve cardiac remodeling, and was even associated with an increased mortality rate over 10 days post-MI. ConclusionTargeting the GPVI-GPIIb/IIIa axis only had minor effects on post-MI inflammatory responses and cardiac wound healing in permanent myocardial ischemia. Our findings demonstrate that the therapeutic benefits of inhibiting platelet-driven thrombo-inflammation are particularly relevant in the subacute reperfusion phase.

physiology↗

bioRxiv2023

TREM2 limits necrotic core formation during atherogenesis by controlling macrophage survival and efferocytosis

Atherosclerosis is a chronic disease of the vascular wall driven by lipid accumulation and inflammation in the intimal layer of arteries [1], [2], and its main complications, myocardial infarction and stroke, are the leading cause of mortality worldwide [3]. Recent studies have identified Triggering receptor expressed on myeloid cells 2 (TREM2), a lipid-sensing receptor regulating several key myeloid cell functions [4], as a highly expressed marker of macrophage foam cells in experimental and human atherosclerosis [5]. However, the function of TREM2 in the development of atherosclerosis is unknown. Here, we show that hematopoietic or global TREM2 deficiency increases necrotic core formation in early experimental atherosclerosis. We further demonstrate that TREM2 is essential for the efferocytosis capacities of macrophages, and to the survival of lipid-laden macrophages, altogether indicating a crucial role of TREM2 in maintaining the balance between foam cell death and their clearance in atherosclerotic lesions, thereby controlling plaque necrosis.

immunology↗