ABSTRACT
Aging is characterized by an increased vulnerability to infection and the development of inflammatory diseases, such as atherosclerosis, frailty, cancer and neurodegeneration. Here, we find that aging is associated with the loss of diurnally rhythmic innate immune responses, including monocyte trafficking from bone marrow to blood, response to lipopolysaccharide and phagocytosis. This decline in homeostatic immune responses was associated with a striking disappearance of circadian gene transcription in aged compared to young tissue macrophages. Chromatin accessibility was significantly greater in young macrophages than in aged macrophages; however, this difference did not explain the loss of rhythmic gene transcription in aged macrophages. Rather, diurnal expression of Kruppel-like factor 4 (Klf4), a transcription factor (TF) well established in regulating cell differentiation and reprogramming, was selectively diminished in aged macrophages. Ablation of Klf4 expression abolished diurnal rhythms in phagocytic activity, recapitulating the effect of aging on macrophage phagocytosis. Examination of individuals harboring genetic variants of KLF4 revealed an association with age-dependent susceptibility to death caused by bacterial infection. Our results indicate that loss of rhythmic Klf4 expression in aged macrophages is associated with disruption of circadian innate immune homeostasis, a mechanism that may underlie age-associated loss of protective immune responses.
Subject(s)
Circadian Clocks/genetics , Macrophages/physiology , Aging , Animals , Atherosclerosis/genetics , Cell Differentiation/genetics , Gene Expression Regulation/genetics , Immunity, Innate/genetics , Inflammation/genetics , Kruppel-Like Factor 4/genetics , Kruppel-Like Transcription Factors/genetics , Male , Mice , Mice, Inbred C57BL , Monocytes/physiology , Phagocytosis/geneticsABSTRACT
Aging is associated with loss of circadian immune responses and circadian gene transcription in peripheral macrophages. Microglia, the resident macrophages of the brain, also show diurnal rhythmicity in regulating local immune responses and synaptic remodeling. To investigate the interaction between aging and microglial circadian rhythmicity, we examined mice deficient in the core clock transcription factor, BMAL1. Aging Cd11bcre;Bmallox/lox mice demonstrated accelerated cognitive decline in association with suppressed hippocampal long-term potentiation and increases in immature dendritic spines. C1q deposition at synapses and synaptic engulfment were significantly decreased in aging Bmal1-deficient microglia, suggesting that BMAL1 plays a role in regulating synaptic pruning in aging. In addition to accelerated age-associated hippocampal deficits, Cd11bcre;Bmallox/lox mice also showed deficits in the sleep-wake cycle with increased wakefulness across light and dark phases. These results highlight an essential role of microglial BMAL1 in maintenance of synapse homeostasis in the aging brain.
Subject(s)
Cognitive Aging , Microglia , Mice , Animals , Microglia/metabolism , CLOCK Proteins/genetics , ARNTL Transcription Factors/genetics , ARNTL Transcription Factors/metabolism , Neuronal PlasticityABSTRACT
Phospholipid Phosphatase-Related Protein Type 1 (PLPPR1) is a six-transmembrane protein that belongs to the family of plasticity-related gene proteins, which is a novel brain-specific subclass of the lipid phosphate phosphatase superfamily. PLPPR1-5 have prominent roles in synapse formation and axonal pathfinding. We found that PLPPR1 overexpression in the mouse neuroblastoma cell line (Neuro2a) results in increase in cell adhesion and reduced cell migration. During migration, these cells leave behind long fibrous looking extensions of the plasma membrane causing a peculiar phenotype. Cells expressing PLPPR1 showed decreased actin turnover and decreased disassembly of focal adhesions. PLPPR1 also reduced active Rac1, and expressing dominant negative Rac1 produced a similar phenotype to overexpression of PLPPR1. The PLPPR1-induced phenotype of long fibers was reversed by introducing constitutively active Rac1. In summary, we show that PLPPR1 decreases active Rac1 levels that leads to cascade of events which increases cell adhesion.
Subject(s)
Cell Adhesion , Focal Adhesions , Gene Expression Regulation, Neoplastic , Membrane Proteins/metabolism , Neuroblastoma/pathology , Neuropeptides/metabolism , Phosphoric Monoester Hydrolases/metabolism , rac1 GTP-Binding Protein/metabolism , Actins/metabolism , Animals , Cell Movement , Membrane Proteins/genetics , Mice , Neuroblastoma/metabolism , Neuropeptides/genetics , Phosphoric Monoester Hydrolases/genetics , Signal Transduction , Tumor Cells, Cultured , rac1 GTP-Binding Protein/geneticsABSTRACT
Stroke is a significant public health concern for elderly individuals. However, the majority of pre-clinical studies utilize young and healthy rodents, which may result in failure of candidate therapies in clinical trials. In this brief review/perspective, the complex link between circadian rhythms, aging, innate immunity, and the gut microbiome to ischemic injury onset, progression, and recovery is discussed. Short-chain fatty acids and nicotinamide adenine dinucleotide+ (NAD+ ) production by the gut microbiome are highlighted as key mechanisms with profound rhythmic behavior, and it is suggested to boost them as prophylactic/therapeutic approaches. Integrating aging, its associated comorbidities, and circadian regulation of physiological processes into stroke research may increase the translational value of pre-clinical studies and help to schedule the optimal time window for existing practices to improve stroke outcome and recovery.