Les chimiokines (CKs) jouent un role important dans l’orchestration de la reponse immunitaireen controlant notamment la mobilisation des cellules immunitaires. Les cellules myeloides et, enparticulier, les monocytes sont impliquees dans le processus inflammatoire et notamment dansle developpement des cancers. En effet, les cellules derivees des monocytes ou macrophagesassocies aux tumeurs sont fortement representes dans le micro environnement tumoral et sontsouvent associes a un mauvais pronostic. La caracterisation des mecanismes aboutissant aurecrutement des monocytes dans la tumeur representent donc un enjeu majeur pourl’optimisation des protocoles therapeutiques anti-cancereux. Chez la souris, deux populationsmonocytaires sont caracterisees sur la base de l’expression differentielle des recepteurs auxchimiokines CCR2 et CX3CR1 et interviennent dans leur recrutement et leur differenciation enmacrophages dans les tissus, les monocytes inflammatoires (CCR2+, CX3CR1low) et les monocytesdits residents (CCR2-, CX3CR1high). L’objectif principal de mon projet de recherche a ete de mieuxcomprendre les mecanismes controlant la mobilisation des monocytes suite a un traitementchimiotherapeutique. J’ai entrepris d’etudier le role des recepteurs aux chimiokines, enparticulier CX3CR1, dans la reconstitution monocytaire apres traitement chimiotherapeutiquepar le cyclophosphamide (CP), un agent alkylant reconnu pour son activite myelosuppressive. LeCP provoque un renouvellement des monocytes et une forte infiltration de la tumeur par les LTspecifiques de la tumeur (issus d’un transfert adoptif) associes a la reactivation de la reponseimmune anti-tumorale. Cependant, les LTs specifiques de l’antigene de la tumeur se localisentpreferentiellement dans des zones riches en cellules dendritiques associees a la tumeur (TuDCs)et sont pieges par ces dernieres. Ces interactions diminuent potentiellement le nombre decontacts entre les LT et les cellules tumorales suggerant un role pro tumoral des TuDCs. Letraitement au CP provoque une depletion des cellules myeloides suivie d’une reconstitutionmassive des reservoirs de monocytes (moelle osseuse et rate). Au cours de la reconstitutionmonocytaire, l’expression de CX3CR1 diminue et est correlee a une diminution de l’adherence exvivo des cellules medullaires. Nous avons mis en evidence une mobilisation accrue desmonocytes inflammatoires au sein des souris CX3CR1- /- comparee aux souris WT et CCR2-/-.L’imagerie in vivo de la moelle osseuse au sein de souris CX3CR1-/- ou a l’aide d’un antagonistede CX3CR1 nous a permis de montrer un role specifique de CX3CR1 dans le « crawling » sur lescellules endotheliales et le confinement des cellules monocytaires au niveau des sinus et duparenchyme medullaire. Nous suggerons qu’au cours de la mobilisation cellulaire induite par leCP le recepteur CX3CR1 controle la retention medullaire des monocytes. Nous pensons que lamodulation du taux de mobilisation cellulaire au cours de la reconstitution induite par CP et/oule ciblage de CX3CR1 pourrait, par augmentation du pool de cellules myeloides leucocytairesd’un hote, contribuer a l’amelioration des reponses cellulaires a la suite d’une lesion tissulaireou d’un dysfonctionnement des defenses immunitaires. De plus, le ciblage de CX3CR1 pourraittrouver des applications dans le domaine de la greffe de HSCs.
Abstract Treg are immune cells that play a critical role in the regulation of the immune response. Although the transcription factor Foxp3 is widely accepted as the standard marker of Treg, specific surface markers are needed to better characterize these cells and decipher their mechanisms of action. Neuropilin‐1 (Nrp‐1), a membrane protein primarily involved in the nervous system, was identified as a specific marker of murine Treg, but its expression has not been rigorously investigated in human Treg. Here we show that in contrast to murine Treg and regardless of their origins (blood, thymus, spleen, lymph node or tonsil), human Foxp3 + Treg do not specifically express Nrp‐1. However, a population of Foxp3 − Nrp‐1 + T cells can be detected in human secondary lymphoid organs, and Nrp‐1 expression is induced on peripheral blood T lymphocytes upon in vitro activation. We conclude that Nrp‐1 cannot be used as a specific marker of human Treg, but might represent a novel activation marker of human T cells both in vitro and in vivo .
Abstract Regenerative capabilities of the endothelium rely on vessel-resident progenitors termed endothelial colony forming cells (ECFCs). This study aimed to investigate if these progenitors are impacted by conditions (i.e., obesity or atherosclerosis) characterized by increased serum levels of oxidized low-density lipoprotein (oxLDL), a known inducer of Endothelial-to-Mesenchymal Transition (EndMT). Our investigation focused on understanding the effects of EndMT on the self-renewal capabilities of progenitors and the associated molecular alterations. In the presence of oxLDL, ECFCs displayed classical features of EndMT, through reduced endothelial gene and protein expression, function as well as increased mesenchymal genes, contractility, and motility. Additionally, ECFCs displayed a dramatic loss in self-renewal capacity in the presence of oxLDL. RNA-sequencing analysis of ECFCs exposed to oxLDL validated gene expression changes suggesting EndMT and identified SOX9 as one of the highly differentially expressed genes. ATAC sequencing analysis identified SOX9 binding sites associated with regions of dynamic chromosome accessibility resulting from oxLDL exposure, further pointing to its importance. EndMT phenotype and gene expression changes induced by oxLDL in vitro or high fat diet (HFD) in vivo were reversed by the silencing of SOX9 in ECFCs or the endothelial-specific conditional knockout of Sox9 in murine models. Overall, our findings support that EndMT affects vessel-resident endothelial progenitor’s self-renewal. SOX9 activation is an early transcriptional event that drives the mesenchymal transition of endothelial progenitor cells. The identification of the molecular network driving EndMT in vessel-resident endothelial progenitors presents a new avenue in understanding and preventing a range of condition where this process is involved.
Myeloproliferative neoplasms (MPN) are a phenotypically defined, heterogeneous group of blood cancers characterised by the proliferation of progenitor cells and the accumulation of mature myeloid cells, linked by a propensity to transform into myelofibrosis or acute myeloid leukaemia. The Jak2V617F
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