Jeremie Lemarié

Bio: Jeremie Lemarié is an academic researcher from University of Paris. The author has contributed to research in topics: Cytotoxic T cell & Granzyme. The author has an hindex of 1, co-authored 1 publications receiving 7 citations.

Cytotoxic CD8+ T cells promote granzyme B-dependent adverse post-ischemic cardiac remodeling.

Abstract: Acute myocardial infarction is a common condition responsible for heart failure and sudden death. Here, we show that following acute myocardial infarction in mice, CD8+ T lymphocytes are recruited and activated in the ischemic heart tissue and release Granzyme B, leading to cardiomyocyte apoptosis, adverse ventricular remodeling and deterioration of myocardial function. Depletion of CD8+ T lymphocytes decreases apoptosis within the ischemic myocardium, hampers inflammatory response, limits myocardial injury and improves heart function. These effects are recapitulated in mice with Granzyme B-deficient CD8+ T cells. The protective effect of CD8 depletion on heart function is confirmed by using a model of ischemia/reperfusion in pigs. Finally, we reveal that elevated circulating levels of GRANZYME B in patients with acute myocardial infarction predict increased risk of death at 1-year follow-up. Our work unravels a deleterious role of CD8+ T lymphocytes following acute ischemia, and suggests potential therapeutic strategies targeting pathogenic CD8+ T lymphocytes in the setting of acute myocardial infarction.

CD4+ T-lymphocytes exhibit biphasic kinetics post-myocardial infarction

Abstract: CD4+ T-cells facilitate wound healing post-myocardial infarction (MI) but promote left-ventricular (LV) remodeling during ischemic heart failure (HF; 8 weeks post-MI). Therefore, it is critical to understand if sustained CD4+ T-cell activation leads to this pathological response, or if phenotypically different T-cells are activated during MI vs. HF. Using flow cytometry, we found that cardiac CD4+ T-cells exhibit two distinct patterns of transmigration. First pattern consisted of a rapid CD4+ T-cell response with maximal levels seen at 3 days post-MI which return to baseline by 14 days. However, during HF we observed a 2nd phase of activation and CD4+ T-cells were ∼20-fold higher in HF as compared to sham-operated mice. Importantly, these biphasic kinetics were observed with all major T-cell subsets such as Th1, Th2, Th17, and regulatory T-cells suggesting a global change. To determine the role of this 2nd peak of T-cell activation, CD4-iDTR mice were generated and treated with DT every 10 from 28 days post-MI to deplete CD4+ T-cells during chronic HF. While littermate control mice showed increased end-systolic and end-diastolic volumes (ESV and EDV) and decreased ejection fraction (EF) from 4 to 8 weeks post-MI, depletion of CD4+ T-cells in Cre + mice significantly blunted LV remodeling and inhibited progressive increases in the EDV and ESV, and reduction in EF. This suggests that CD4+ T-cell responses occurring during HF are different than those occurring during MI and promote LV remodeling and progressive cardiac dysfunction. Temporal immunomodulation of CD4+ T-cells could be a translatable modality for ischemic HF.

Inflammatory Cells in Atherosclerosis

Abstract: Atherosclerosis is a chronic progressive disease that involves damage to the intima, inflammatory cell recruitment and the accumulation of lipids followed by calcification and plaque rupture. Inflammation is considered a key mediator of many events during the development and progression of the disease. Various types of inflammatory cells are reported to be involved in atherosclerosis. In the present paper, we discuss the involved inflammatory cells, their characteristic and functional significance in the development and progression of atherosclerosis. The detailed understanding of the role of all these cells in disease progression at different stages sheds more light on the subject and provides valuable insights as to where and when therapy should be targeted.

Hypoxia-inducible factors individually facilitate inflammatory myeloid metabolism and inefficient cardiac repair.

Abstract: Hypoxia-inducible factors (HIFs) are activated in parenchymal cells in response to low oxygen and as such have been proposed as therapeutic targets during hypoxic insult, including myocardial infarction (MI). HIFs are also activated within macrophages, which orchestrate the tissue repair response. Although isoform-specific therapeutics are in development for cardiac ischemic injury, surprisingly, the unique role of myeloid HIFs, and particularly HIF-2α, is unknown. Using a murine model of myocardial infarction and mice with conditional genetic loss and gain of function, we uncovered unique proinflammatory roles for myeloid cell expression of HIF-1α and HIF-2α during MI. We found that HIF-2α suppressed anti-inflammatory macrophage mitochondrial metabolism, while HIF-1α promoted cleavage of cardioprotective MerTK through glycolytic reprogramming of macrophages. Unexpectedly, combinatorial loss of both myeloid HIF-1α and HIF-2α was catastrophic and led to macrophage necroptosis, impaired fibrogenesis, and cardiac rupture. These findings support a strategy for selective inhibition of macrophage HIF isoforms and promotion of anti-inflammatory mitochondrial metabolism during ischemic tissue repair.

Single-cell profiling reveals distinct immune phenotypes that contribute to ischaemia-reperfusion injury after steatotic liver transplantation

Abstract: OBJECTIVES The discrepancy between supply and demand of organ has led to an increased utilization of steatotic liver for liver transplantation (LT). Hepatic steatosis, however, is a major risk factor for graft failure due to increased susceptibility to ischaemia-reperfusion (I/R) injury during transplantation. MATERIALS AND METHODS To assess the plasticity and phenotype of immune cells within the microenvironment of steatotic liver graft at single-cell level, single-cell RNA-sequencing (scRNA-Seq) was carried out on 23 675 cells from transplanted rat livers. Bioinformatic analyses and multiplex immunohistochemistry were performed to assess the functional properties, transcriptional regulation, phenotypic switching and cell-cell interactions of different cell subtypes. RESULTS We have identified 11 different cell types in transplanted livers and found that the highly complex ecosystem was shaped by myeloid-derived cell subsets that transit between different states and interact mutually. Notably, a pro-inflammatory phenotype of Kupffer cells (KCs) with high expression of colony-stimulating factor 3 (CSF3) that was enriched in transplanted steatotic livers was potentially participated in fatty graft injury. We have also detected a subset of dendritic cells (DCs) with highly expressing XCR1 that was correlated with CD8+ T cells, mediating the severer steatotic liver damage by I/R injury. CONCLUSIONS The findings of our study provide new insight into the mechanisms by which steatosis exacerbates liver damage from I/R injury. Interventions based on these observations create opportunities in attenuating fatty liver graft injury and expanding the donor pool.

Dual Roles of Granzyme B

Abstract: Granzyme B (GZMB) was first identified as a factor that could eliminate cells such as tumour cells and bacteria/virus‐infected cells. However, comprehensive studies conducted on GZMB have gradually revealed the negative extracellular functions of GZMB; for example, it is an aetiology and a factor responsible for the aggravation of several diseases. This review focuses on the positive role of GZMB (in the elimination of tumour cells, bacteria, parasites and viruses, and in the identification, diagnosis and treatment of diseases) and the negative effects of GZMB (with regard to extracellular function and other characteristics). The current research on GZMB inhibitors has been briefly introduced, and few studies on GZMB fusion proteins and several GZMB material delivery systems have been discussed.