RESUMO
Emerging evidence suggests that immune receptors may participate in many aging-related processes such as energy metabolism, inflammation, and cognitive decline. CD300f, a TREM2-like lipid-sensing immune receptor, is an exceptional receptor as it integrates activating and inhibitory cell-signaling pathways that modulate inflammation, efferocytosis, and microglial metabolic fitness. We hypothesize that CD300f can regulate systemic aging-related processes and ultimately healthy lifespan. We closely followed several cohorts of two strains of CD300f-/- and WT mice of both sexes for 30 months and observed an important reduction in lifespan and healthspan in knockout mice. This was associated with systemic inflammaging, increased cognitive decline, reduced brain glucose uptake observed by 18FDG PET scans, enrichment in microglial aging/neurodegeneration phenotypes, proteostasis alterations, senescence, increased frailty, and sex-dependent systemic metabolic changes. Moreover, the absence of CD300f altered macrophage immunometabolic phenotype. Taken together, we provide strong evidence suggesting that myeloid cell CD300f immune receptor contributes to healthy aging.
Assuntos
Disfunção Cognitiva , Envelhecimento Saudável , Masculino , Feminino , Camundongos , Animais , Macrófagos/metabolismo , Inflamação/metabolismo , Microglia/metabolismo , Camundongos Knockout , Disfunção Cognitiva/metabolismoRESUMO
Activating and inhibitory immune receptors play a critical role in regulating systemic and central nervous system (CNS) immune and inflammatory processes. The CD200R1 immunoreceptor induces a restraining signal modulating inflammation and phagocytosis in the CNS under different inflammatory conditions. However, it remains unknown whether CD200R1 has a role in modulating the inflammatory response after a peripheral nerve injury, an essential component of the successful regeneration. Expression of CD200R1 and its ligand CD200 was analyzed during homeostasis and after a sciatic nerve crush injury in C57Bl/6 mice. The role of CD200R1 in Wallerian Degeneration (WD) and nerve regeneration was studied using a specific antibody against CD200R1 injected into the nerve at the time of injury. We found an upregulation of CD200R1 mRNA after injury whereas CD200 was downregulated acutely after nerve injury. Blockade of CD200R1 significantly reduced the acute entrance of both neutrophils and monocytes from blood after nerve injury. When long term regeneration and functional recovery were evaluated, we found that blockade of CD200R1 had a significant effect impairing the spontaneous functional recovery. Taken together, these results show that CD200R1 has a role in mounting a successful acute inflammatory reaction after injury, and contributes to an effective functional recovery.
Assuntos
Regeneração Nervosa , Receptores de Orexina , Traumatismos dos Nervos Periféricos , Animais , Camundongos , Compressão Nervosa , Receptores de Orexina/metabolismo , Fagocitose/genética , Nervo IsquiáticoRESUMO
A role for microglia in neuropsychiatric diseases, including major depressive disorder (MDD), has been postulated. Regulation of microglial phenotype by immune receptors has become a central topic in many neurological conditions. We explored preclinical and clinical evidence for the role of the CD300f immune receptor in the fine regulation of microglial phenotype and its contribution to MDD. We found that a prevalent nonsynonymous single-nucleotide polymorphism (C/T, rs2034310) of the human CD300f receptor cytoplasmic tail inhibits the protein kinase C phosphorylation of a threonine and is associated with protection against MDD, mainly in women. Interestingly, CD300f-/- mice displayed several characteristic MDD traits such as augmented microglial numbers, increased interleukin 6 and interleukin 1 receptor antagonist messenger RNA, alterations in synaptic strength, and noradrenaline-dependent and persistent depressive-like and anhedonic behaviors in females. This behavioral phenotype could be potentiated inducing the lipopolysaccharide depression model. RNA sequencing and biochemical studies revealed an association with impaired microglial metabolic fitness. In conclusion, we report a clear association that links the function of the CD300f immune receptor with MDD in humans, depressive-like and anhedonic behaviors in female mice, and altered microglial metabolic reprogramming.
Assuntos
Anedonia , Transtorno Depressivo Maior/patologia , Inflamação/etiologia , Microglia/patologia , Polimorfismo de Nucleotídeo Único , Receptores Imunológicos/genética , Receptores Imunológicos/fisiologia , Animais , Comportamento Animal , Estudos de Coortes , Transtorno Depressivo Maior/genética , Transtorno Depressivo Maior/metabolismo , Transtorno Depressivo Maior/psicologia , Feminino , Perfilação da Expressão Gênica , Humanos , Inflamação/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microglia/metabolismo , SinapsesRESUMO
Dim light melatonin onset (DLMO) is the most reliable measure of human central circadian timing. Its modulation by light exposure and chronotype has been scarcely approached. We evaluated the impact of light changes on the interaction between melatonin, sleep, and chronotype in university students (n = 12) between the Antarctic summer (10 days) and the autumn equinox in Montevideo, Uruguay (10 days). Circadian preferences were tested by validated questionnaires. A Morningness-Eveningness Questionnaire average value (47 ± 8.01) was used to separate late and early participants. Daylight exposure (measured by actimetry) was significantly higher in Antarctica versus Montevideo in both sensitive time windows (the morning phase-advancing and the evening phase-delaying). Melatonin was measured in hourly saliva samples (18-24 h) collected in dim light conditions (<30 lx) during the last night of each study period. Early and late participants were exposed to similar amounts of light in both sites and time windows, but only early participants were significantly more exposed during the late evening in Antarctica. Late participants advanced their DLMO with no changes in sleep onset time in Antarctica, while early participants delayed their DLMO and sleep onset time. This different susceptibility to respond to light may be explained by a subtle difference in evening light exposure between chronotypes.
RESUMO
Histone posttranslational modifications play a fundamental role in orchestrating gene expression. In this work, we analyzed the acetylation of H3 and H4 histones (AcH3-AcH4) and its modulation by visual experience in the mouse visual cortex (VC) during normal development and in two experimental conditions that restore juvenile-like plasticity levels in adults (fluoxetine treatment and enriched environment). We found that AcH3-AcH4 declines with age and is upregulated by treatments restoring plasticity in the adult. We also found that visual experience modulates AcH3-AcH4 in young and adult plasticity-restored mice but not in untreated ones. Finally, we showed that the transporter vGAT is downregulated in adult plasticity-restored models. In summary, we identified a dynamic regulation of AcH3-AcH4, which is associated with high plasticity levels and enhanced by visual experience. These data, along with recent ones, indicate H3-H4 acetylation as a central hub in the control of experience-dependent plasticity in the VC.