CD74
HLA class II histocompatibility antigen gamma chain (HLA-DR antigens-associated invariant chain) (Ia antigen-associated invariant chain) (Ii) (CD74 antigen) [Contains: Class-II-associated invariant chain peptide (CLIP)] [DHLAG]
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There have been a few descriptive studies in aged rodents about transcriptome changes in the hippocampus, most of them in males. Here, we assessed the age changes in spatial memory performance and hippocampal morphology in female rats and compared those changes with changes in the hippocampal transcriptome. Old rats displayed significant deficits in spatial memory. In both age groups, hole exploration frequency showed a clear peak at hole 0 (escape hole), but the amplitude of the peak was significantly higher in the young than in the old animals. In the hippocampus, there was a dramatic reduction in neurogenesis, whereas reactive microglial infiltrates revealed an inflammatory hippocampal state in the senile rats. Hippocampal RNA-sequencing showed that 210 genes are differentially expressed in the senile rats, most of them being downregulated. Our RNA-Seq data showed that various genes involved in the immune response, including TYROBP, CD11b, C3, CD18, CD4, and CD74, are overexpressed in the hippocampus of aged female rats. Enrichment analysis showed that the pathways overrepresented in the senile rats matched those of an exacerbated inflammatory environment, reinforcing our morphologic findings. After correlating our results with public data of human and mouse hippocampal gene expression, we found an 11-gene signature of overexpressed genes related to inflammatory processes that was conserved across species. We conclude that age-related hippocampal deficits in female rats share commonalities between human and rodents. Interestingly, the 11-gene signature that we identified may represent a cluster of immune and regulatory genes that are deregulated in the hippocampus and possibly other brain regions during aging as well as in some neurodegenerative diseases and low-grade brain tumors. Our study further supports neuroinflammation as a promising target to treat cognitive dysfunction in old individuals and some brain tumors. © 2017 Wiley Periodicals, Inc.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- Animals
- Dementia
- Female
- Gene Expression
- Hippocampus
- Humans
- Male
- Maze Learning
- Microglia
- Middle Aged
- Neurogenesis
- Neurons
- Rats, Sprague-Dawley
- Spatial Memory
- Species Specificity
- Transcriptome
- Young Adult
Keywords
- Barnes maze
- aging
- hippocampal transcriptome
- immune pathways
- spatial memory
Regulated intramembrane proteolysis is of pivotal importance in a diverse set of developmental and physiological processes. Altered intramembrane substrate turnover may be associated with neurodegeneration, cancer and impaired immune function. In this review we will focus on the intramembrane proteases which have been localized in the lysosomal membrane. Members of the γ-secretase complex and γ-secretase activity are found in the lysosomal membrane and are discussed to contribute to intracellular amyloid β production. Mutant or deficient γ-secretase may cause disturbed lysosomal function. The signal peptide peptidase-like (SPPL) protease 2a is a lysosomal membrane component and cleaves CD74, the invariant chain of the MHC II complex, as well as FasL, TNF, ITM2B and TMEM106, type II transmembrane proteins involved in the regulation of immunity and neurodegeneration. Therefore, it can be concluded, that not only proteolysis within the lysosomal lumen but also within lysosomal membranes regulates important cellular functions and contributes essentially to proteostasis of membrane proteins what may become increasingly compromised in the aged individual.
MeSH Terms
- Aging
- Amyloid Precursor Protein Secretases
- Amyloid beta-Peptides
- Antigens, Differentiation, B-Lymphocyte
- Aspartic Acid Endopeptidases
- Cell Membrane
- Histocompatibility Antigens Class II
- Humans
- Lysosomes
- Membrane Proteins
- Nerve Degeneration
- Proteolysis
Keywords
- Alzheimer Disease
- CD74
- Intramembrane proteolysis
- Lysosome
- Signal peptide peptidase-like 2a protease
- γ-Secretase
Age plays a crucial role in the interplay between tumor and host, with additional impact due to irradiation. Proton irradiation of tumors induces biological modulations including inhibition of angiogenic and immune factors critical to 'hallmark' processes impacting tumor development. Proton irradiation has also provided promising results for proton therapy in cancer due to targeting advantages. Additionally, protons may contribute to the carcinogenesis risk from space travel (due to the high proportion of high-energy protons in space radiation). Through a systems biology approach, we investigated how host tissue (i.e. splenic tissue) of tumor-bearing mice was altered with age, with or without whole-body proton exposure. Transcriptome analysis was performed on splenic tissue from adolescent (68-day) versus old (736-day) C57BL/6 male mice injected with Lewis lung carcinoma cells with or without three fractionations of 0.5 Gy (1-GeV) proton irradiation. Global transcriptome analysis indicated that proton irradiation of adolescent hosts caused significant signaling changes within splenic tissues that support carcinogenesis within the mice, as compared with older subjects. Increases in cell cycling and immunosuppression in irradiated adolescent hosts with CDK2, MCM7, CD74 and RUVBL2 indicated these were the key genes involved in the regulatory changes in the host environment response (i.e. the spleen). Collectively, these results suggest that a significant biological component of proton irradiation is modulated by host age through promotion of carcinogenesis in adolescence and resistance to immunosuppression, carcinogenesis and genetic perturbation associated with advancing age.
MeSH Terms
- Age Factors
- Animals
- Carcinoma, Lewis Lung
- Cell Cycle
- Cell Line, Tumor
- Cell Proliferation
- Disease Models, Animal
- Disease Progression
- Humans
- Immune System
- Male
- Mice
- Mice, Inbred C57BL
- Neoplasm Transplantation
- Neoplasms
- Protons
- Radiation, Ionizing
- Spleen
- Transcriptome
Keywords
- aging and cancer
- bioinformatics
- immunosuppression
- protons
- spleen
- transcriptome analysis
- tumor microenvironment
- tumor progression
Mesenchymal stem cells (MSCs)-based therapies have had positive outcomes in animal models of cardiovascular diseases. However, the number and function of MSCs decline with age, reducing their ability to contribute to endogenous injury repair. The potential of stem cells to restore damaged tissue in older individuals can be improved by specific pretreatment aimed at delaying senescence and improving their regenerative properties. Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine that modulates age-related signaling pathways, and hence is a good candidate for rejuvenative function. Bone marrow-derived mesenchymal stem cells (BM-MSCs) were isolated from young (6-month-old) or aged (24-month-old) male donor rats. Cell proliferation was measured using the CCK8 cell proliferation assay; secretion of VEGF, bFGF, HGF, and IGF was assessed by RT-qPCR and ELISA. Apoptosis was induced by hypoxia and serum deprivation (hypoxia/SD) for up to 6 hr, and examined by flow cytometry. Expression levels of AMP-activated protein kinase (AMPK) and forkhead box class O 3a (FOXO3a) were detected by Western blotting. CD74 expression was assayed using RT-qPCR, Western blotting, and immunofluorescence. In this study, we found that MSCs isolated from the bone marrow of aged rats displayed reduced proliferative capacity, impaired ability to mediate paracrine signaling, and lower resistance to hypoxia/serum deprivation-induced apoptosis, when compared to younger MSCs. Interestingly, pretreatment of aged MSCs with MIF enhanced their growth, paracrine function and survival. We detected enhanced secretion of VEGF, bFGF, HGF, and IGF from MIF-treated MSCs using ELISA. Finally, we show that hypoxia/serum deprivation-induced apoptosis is inhibited in aged MSCs following MIF exposure. Next, we found that the mechanism underlying the rejuvenating function of MIF involves increased CD74-dependent phosphorylation of AMPK and FOXO3a. Furthermore, this effect was abolished when CD74, AMPK, or FOXO3a expression was silenced using small-interfering RNAs(siRNA). MIF can rejuvenate MSCs from a state of age-induced senescence by interacting with CD74 and subsequently activating AMPK-FOXO3a signaling pathways. Pretreatment of MSCs with MIF may have important therapeutic implications in restoration or rejuvenation of endogenous bone marrow-MSCs in aged individuals.
MeSH Terms
- AMP-Activated Protein Kinases
- Aging
- Animals
- Antigens, Differentiation, B-Lymphocyte
- Apoptosis
- Bone Marrow Cells
- Cell Hypoxia
- Cell Proliferation
- Cells, Cultured
- Down-Regulation
- Forkhead Box Protein O3
- Forkhead Transcription Factors
- Histocompatibility Antigens Class II
- Intercellular Signaling Peptides and Proteins
- Intramolecular Oxidoreductases
- Macrophage Migration-Inhibitory Factors
- Male
- Mesenchymal Stem Cells
- Myocardium
- Paracrine Communication
- Phosphorylation
- RNA Interference
- Rats
- Rats, Sprague-Dawley
- Signal Transduction
The pathogenesis of chronic obstructive pulmonary disease (COPD) remains poorly understood. Cellular senescence and apoptosis contribute to the development of COPD; however, crucial regulators of these underlying mechanisms remain unknown. Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine that antagonizes both apoptosis and premature senescence and may be important in the pathogenesis of COPD. This study examines the role of MIF in the pathogenesis of COPD. Mice deficient in MIF (Mif(-/-)) or the MIF receptor CD74 (Cd74(-/-)) and wild-type (WT) controls were aged for 6 mo. Both Mif(-/-) and Cd74(-/-) mice developed spontaneous emphysema by 6 mo of age compared with WT mice as measured by lung volume and chord length. This was associated with activation of the senescent pathway markers p53/21 and p16. Following exposure to cigarette smoke, Mif(-/-) mice were more susceptible to the development of COPD and apoptosis compared with WT mice. MIF plasma concentrations were measured in a cohort of 224 human participants. Within a subgroup of older current and former smokers (n = 72), MIF concentrations were significantly lower in those with COPD [8.8, 95%CI (6.7-11.0)] compared with those who did not exhibit COPD [12.7 ng/ml, 95%CI (10.6-14.8)]. Our results suggest that both MIF and the MIF receptor CD74 are required for maintenance of normal alveolar structure in mice and that decreases in MIF are associated with COPD in human subjects.
MeSH Terms
- Adolescent
- Adult
- Age Factors
- Aged
- Aged, 80 and over
- Animals
- Apoptosis
- Cellular Senescence
- Cyclin-Dependent Kinase Inhibitor p16
- Cyclin-Dependent Kinase Inhibitor p21
- Emphysema
- Female
- Humans
- Intramolecular Oxidoreductases
- Lung
- Macrophage Migration-Inhibitory Factors
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Middle Aged
- Pulmonary Disease, Chronic Obstructive
- Receptors, Immunologic
- Smoke
- Smoking
- Tobacco
- Tumor Suppressor Protein p53
- Young Adult
Keywords
- CD74
- COPD
- MIF
- apoptosis
- emphysema
- senescence
Age-related priming of microglia and release of inflammatory cytokines, such as interleukin-1β (IL-1β) and interleuekin-6 (IL-6) have been associated with deficits in cognitive function. The present study assessed whether treatment with minocycline could improve spatial cognition in aged mice, and whether these improvements in behavior were associated with reduced microglia activation and an enhancement in hippocampal neurogenesis. Adult (3 months) and aged (22 months) male BALB/c mice received minocycline in their drinking water or control mice received distilled water for 20 days. Mice received BrdU to label dividing cells on days 8-17. Spatial learning was measured using the water maze. Immunohistochemistry was conducted to measure number of BrdU positive neurons and number and size of microglia by detection of Iba-1 in the dentate gyrus molecular layer. Further, hippocampal samples were collected to measure changes in IL-1β, IL-6, and CD74 expression. The data show that aged mice have increased hippocampal expression of IL-1β, IL-6, and CD74 relative to adults. Minocycline treatment significantly improved acquisition of the water maze in aged mice but not adults. Minocycline reduced the average size of Iba-1 positive cells and total Iba-1 counts, but did not affect hippocampal cytokine gene expression. Minocycline increased neurogenesis in adults but not aged mice. Collectively, the data indicate that treatment with minocycline may recover some aspects of cognitive decline associated with aging, but the effect appears to be unrelated to adult hippocampal neurogenesis.
MeSH Terms
- Aging
- Analysis of Variance
- Animals
- Body Weight
- Bromodeoxyuridine
- Calcium-Binding Proteins
- Cell Differentiation
- Cytokines
- Drinking
- Gene Expression
- Hippocampus
- Male
- Maze Learning
- Mice
- Microfilament Proteins
- Microglia
- Minocycline
- Neurogenesis
- Phosphopyruvate Hydratase
- Time Factors
The intricate interactions between the immune, endocrine and central nervous systems shape the innate immune response of the brain. We have previously shown that estradiol suppresses expression of immune genes in the frontal cortex of middle-aged ovariectomized rats, but not in young ones reflecting elevated expression of these genes in middle-aged, ovarian hormone deficient animals. Here, we explored the impact of menopause on the microglia phenotype capitalizing on the differential expression of macrophage-associated genes in quiescent and activated microglia. We selected twenty-three genes encoding phagocytic and recognition receptors expressed primarily in microglia, and eleven proinflammatory genes and followed their expression in the rat frontal cortex by real-time PCR. We used young, middle-aged and middle-aged ovariectomized rats to reveal age- and ovariectomy-related alterations. We analyzed the expression of the same set of genes in the postcentral and superior frontal gyrus of pre- and postmenopausal women using raw microarray data from our previous study. Ovariectomy caused up-regulation of four classic microglia reactivity marker genes including Cd11b, Cd18, Cd45 and Cd86. The change was reversible since estradiol attenuated transcriptional activation of the four marker genes. Expression of genes encoding phagocytic and toll-like receptors such as Cd11b, Cd18, C3, Cd32, Msr2 and Tlr4 increased, whereas scavenger receptor Cd36 decreased following ovariectomy. Ovarian hormone deprivation altered the expression of major components of estrogen and neuronal inhibitory signaling which are involved in the control of microglia reactivity. Strikingly similar changes took place in the postcentral and superior frontal gyrus of postmenopausal women. Based on the overlapping results of rat and human studies we propose that the microglia phenotype shifts from the resting toward the reactive state which can be characterized by up-regulation of CD11b, CD14, CD18, CD45, CD74, CD86, TLR4, down-regulation of CD36 and unchanged CD40 expression. As a result of this shift, microglial cells have lower threshold for subsequent activation in the forebrain of postmenopausal women.
MeSH Terms
- Adult
- Age Factors
- Aged
- Aging
- Animals
- Antigens, CD
- Cytokines
- Estradiol
- Estrogen Receptor alpha
- Female
- Frontal Lobe
- Gene Expression Regulation
- Histocompatibility Antigens
- Humans
- Menopause
- Middle Aged
- Ovariectomy
- Phagocytosis
- RNA, Messenger
- Rats
- Rats, Wistar
- Toll-Like Receptor 4
- Toll-Like Receptor 9
Age-related cognitive dysfunction, including impairment of hippocampus-dependent spatial learning and memory, affects approximately half of the aged population. Induction of a variety of neuroinflammatory measures has been reported with brain aging but the relationship between neuroinflammation and cognitive decline with non-neurodegenerative, normative aging remains largely unexplored. This study sought to comprehensively investigate expression of the MHC II immune response pathway and glial activation in the hippocampus in the context of both aging and age-related cognitive decline. Three independent cohorts of adult (12-13 months) and aged (26-28 months) F344xBN rats were behaviorally characterized by Morris water maze testing. Expression of MHC II pathway-associated genes identified by transcriptomic analysis as upregulated with advanced aging was quantified by qPCR in synaptosomal fractions derived from whole hippocampus and in hippocampal subregion dissections (CA1, CA3, and DG). Activation of astrocytes and microglia was assessed by GFAP and Iba1 protein expression, and by immunohistochemical visualization of GFAP and both CD74 (Ox6) and Iba1. We report a marked age-related induction of neuroinflammatory signaling transcripts (i.e., MHC II components, toll-like receptors, complement, and downstream signaling factors) throughout the hippocampus in all aged rats regardless of cognitive status. Astrocyte and microglial activation was evident in CA1, CA3 and DG of intact and impaired aged rat groups, in the absence of differences in total numbers of GFAP astrocytes or Iba1 microglia. Both mild and moderate microglial activation was significantly increased in all three hippocampal subregions in aged cognitively intact and cognitively impaired rats compared to adults. Neither induction of MHCII pathway gene expression nor glial activation correlated to cognitive performance. These data demonstrate a novel, coordinated age-related induction of the MHC II immune response pathway and glial activation in the hippocampus, indicating an allostatic shift toward a para-inflammatory phenotype with advancing age. Our findings demonstrate that age-related induction of these aspects of hippocampal neuroinflammation, while a potential contributing factor, is not sufficient by itself to elicit impairment of spatial learning and memory in models of normative aging. Future efforts are needed to understand how neuroinflammation may act synergistically with cognitive-decline specific alterations to cause cognitive impairment.
MeSH Terms
- Aging
- Animals
- Behavior, Animal
- Biomarkers
- Cognition Disorders
- Gene Expression Profiling
- Genes, MHC Class II
- Hippocampus
- Histocompatibility Antigens Class II
- Humans
- Major Histocompatibility Complex
- Male
- Maze Learning
- Microarray Analysis
- Neuroglia
- Rats
- Rats, Inbred F344
- Transcriptome