Abstract
BackgroundThe 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.MethodsWe 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.ResultsOvariectomy 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.ConclusionsBased 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.
Highlights
The intricate interactions between the immune, endocrine and central nervous systems shape the innate immune response of the brain
Age and ovarian hormone deficiency led to elevation in mRNA expression of Alpha chain of CR3 (Cd11b), Beta chain of CR3 (Cd18), Leukocyte common antigen (Cd45), Cd74 and Cd86 in the frontal cortex of middle-aged female rats We explored the impact of ovarian hormone deficiency on mRNA expression of six genes encoding the alpha and beta chain of complement receptor (CR) type 3 (Cd11b and Cd18), Tumor necrosis factor (TNF) receptor superfamily member 5 (Cd40), leukocyte common antigen (Cd45), MHC class II-associated invariant chain (Cd74) and B72 antigen (Cd86)
As a result of ovariectomy, we found a 1.5- to 2.0-fold increase in mRNA expression of Cd11b (Figure 1A), Cd18 (Figure 1B), Cd45 (Figure 1D) and Cd86 (Figure 1F)
Summary
The intricate interactions between the immune, endocrine and central nervous systems shape the innate immune response of the brain. E2 has no effect on the expression of the same set of genes in the same region of young OVX rats [17] reflecting elevated expression of these immune genes in the frontal cortex of middleaged, ovarian hormone-deficient rats. This notion is supported by the results of human [18,19,20] and rodent [21,22] microarray studies demonstrating up-regulation of immune genes in the cerebral cortex during the course of normal aging. Up-regulation of MHC class I and class II, toll-like receptor, complement and cytokine genes has been shown to be a characteristic feature of aging in both sexes, with proportionally higher expression in women indicating sexually dimorphic changes [20]
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