No description available.

Macrophages belong to the mononuclear phagocyte system and they perform fundamental roles to maintain homeostasis in the organism. Macrophage development, survival, proliferation and functionality depend upon the colony stimulating factor 1 (CSF1) and interleukin-34 (IL-34), which signal through the CSF1 receptor (CSF1R). CSF1R is a type III tyrosine kinase receptor that is present in the plasma membrane of monocytes and macrophages. Mutations in Csf1r in mice produce the loss of many tissue macrophage populations and multiple developmental abnormalities. In humans, abnormal enhancement of CSF1R expression has been correlated to adverse prognosis in a subset of carcinomas; and mutations in the human CSF1R are associated with an autosomal-dominant neurodegenerative disease. CSF1R is encoded by the c-fms proto-oncogene and its expression is partially controlled by the fms-intronic regulatory element (FIRE). The FIRE sequence is highly conserved across species and contains binding motifs for multiple transcription factors, which are relevant for haematopoiesis. Previous results from murine Csf1r transgenes showed that FIRE is essential for driving Csf1r expression, and that interactions between FIRE and multiple myeloid transcription factors contribute to maximal regulatory activity. This project aimed to study the role of FIRE in its normal chromatin context, in vivo. A FIRE knockout (FIRE-/-) mouse model was generated using the CRISPR/Cas9 technology in mouse embryonic stem cells (ESCs) and in mice. In ESCs, the deletion severely compromised the differentiation of macrophages from embryoid bodies generated in vitro. In mice, the frequency of the FIRE- /- genotype in the progeny does not follow a Mendelian distribution and about 5% of the offspring developed hydrocephalus. Unlike Csf1r -/-mice, which die before weaning, most surviving FIRE-/- mice grew normally and were fertile. The impact of the mutation on macrophage populations is selective. FIRE-/- mice are not monocyte deficient (identified as F4/80+ Csf1r+ cells in peripheral blood), although these cells have reduced levels of Csf1r mRNA and do not bind porcine CSF1 Fc fusion protein. The development of peritoneal macrophages and Iba-1+ microglia was abolished, but Adgre1+ (F4/80+) macrophage populations in liver and spleen were unaffected. Csf1r was greatly reduced in bone marrow progenitors, but about 30% of these cells were able to differentiate into macrophages in vitro, upon exposure to recombinant human CSF1 (rhCSF1). This study shows that FIRE is essential for the development of a subset of tissue-resident macrophage populations. In FIRE-/- mice, potential compensation from additional regulatory elements within Csf1r might underlie the development of unaffected tissue-resident macrophages.

No description available.

GPR120 est un récepteur couplé à une protéine G pour les acides gras à longue chaîne (AGCL), connu pour ses effets anti-inflammatoires et pour la médiation des effets de sensibilisation à l'insuline des acides gras oméga-3. Les études révèlent une forte expression de GPR120 dans les microglies, suggérant son rôle potentiel dans les réponses immunitaires du cerveau. Cependant, l'impact spécifique de GPR120 microgliale sur les changements de comportement reste incertain. Les études suggèrent qu'un système Cre-Lox inducible élimine GPR120 dans les microglies, entraînant une augmentation des comportements semblables à l'anxiété et favorisant une augmentation de la prise alimentaire, du gain de poids et une réduction de la dépense énergétique chez les souris. Cette recherche vise à étudier l'impact de GPR120 microgliale sur l'équilibre énergétique et le comportement semblable à l'anxiété dans des conditions basales. À cet effet, nous avons créé un modèle de souris knockout pour GPR120 (génétiquement modifié ; GPR120lox/CXCR1Cre-ER). Ensuite, une cohorte de ces souris a été soumise à des analyses comportementales et métaboliques. Les évaluations métaboliques comprenaient la surveillance de l'apport alimentaire et de la dépense énergétique dans des chambres métaboliques. Des tests comportementaux tels que le labyrinthe en croix surélevé (EPM), la boîte claire-sombre (LDB) et le test des trois chambres (3CT) pour l'interaction sociale ont été réalisés. Nous avons observé que les souris femelles GPR120 KO présentaient une interaction significativement accrue dans le 3CT, suggérant une sociabilité améliorée. De plus, les souris avec GPR120 KO microgliale ont montré une augmentation du poids corporel et une réduction de l'apport alimentaire dans les cages métaboliques par rapport aux témoins. Les niveaux de corticostérone étaient augmentés chez les mâles et une tendance à l’augmentation a aussi observée chez les femelles. En conclusion, nos résultats soulignent l'influence potentielle de GPR120 sur les processus comportementaux et métaboliques. Une investigation plus poussée est essentielle pour comprendre pleinement le rôle de GPR120 dans la neuroinflammation et l'activité microgliale. Cette exploration de GPR120 offre des perspectives prometteuses pour le développement de nouvelles options thérapeutiques pour divers troubles. / GPR120 is a G protein-coupled receptor for long-chain fatty acids (LCFAs), known for its anti-inflammatory and insulin-sensitizing effects of omega-3 fatty acids. Studies reveal high expression of GPR120 in microglia, suggesting its potential role in brain immune responses. However, the specific impact of microglial GPR120 on behavioral changes remains unclear.The studies suggest that an inducible Cre-Lox system will knock out GPR120 in microglia, leading to increased anxiety-like behavior and promoting increased feeding, body weight gain, and reduced energy expenditure in mice. This research aims to investigate the impact of microglial GPR120 on energy balance and anxiety-like behavior under basal conditions For this purpose we created a knockout GPR120 mouse mode (genetically modified; GPR120lox/CXCR1Cre-ER). Subsequently, a cohort of these mice underwent behavioral and metabolic analyses. Metabolic assessments included monitoring food intake, and energy expenditure in metabolic chambers. Behavioral tests such as the elevated plus maze (EPM), light-dark box (LDB), and three-chamber test (3CT) for social interaction were conducted. We observed that Female GPR120 KO mice exhibited significantly increased interaction in the 3CT, suggesting enhanced sociability. Moreover, mice with microglial GPR120 KO showed increased body weight and reduced food intake in metabolic cages compared to controls. Corticosterone levels exhibited increased in males and a trend in females. In conclusion, our findings underscore the potential influence of GPR120 on both behavioral and metabolic processes. Further investigation is essential to fully understand the role of GPR120 in neuroinflammation and microglial activity. This exploration of GPR120 holds promise for developing novel treatment options for various disorders.