Abstract
Prior studies of aging and neuropathic injury have focused on senescent animals compared to young adults, while changes in middle age, particularly in the dorsal root ganglia (DRG), have remained largely unexplored. 14 neuroimmune mRNA markers, previously associated with peripheral nerve injury, were measured in multiplex assays of lumbar spinal cord (LSC), and DRG from young and middle-aged (3, 17 month) naïve rats, or from rats subjected to chronic constriction injury (CCI) of the sciatic nerve (after 7 days), or from aged-matched sham controls. Results showed that CD2, CD3e, CD68, CD45, TNF-α, IL6, CCL2, ATF3 and TGFβ1 mRNA levels were substantially elevated in LSC from naïve middle-aged animals compared to young adults. Similarly, LSC samples from older sham animals showed increased levels of T-cell and microglial/macrophage markers. CCI induced further increases in CCL2, and IL6, and elevated ATF3 mRNA levels in LSC of young and middle-aged adults. Immunofluorescence images of dorsal horn microglia from middle-aged naïve or sham rats were typically hypertrophic with mostly thickened, de-ramified processes, similar to microglia following CCI. Unlike the spinal cord, marker expression profiles in naïve DRG were unchanged across age (except increased ATF3); whereas, levels of GFAP protein, localized to satellite glia, were highly elevated in middle age, but independent of nerve injury. Most neuroimmune markers were elevated in DRG following CCI in young adults, yet middle-aged animals showed little response to injury. No age-related changes in nociception (heat, cold, mechanical) were observed in naïve adults, or at days 3 or 7 post-CCI. The patterns of marker expression and microglial morphologies in healthy middle age are consistent with development of a para-inflammatory state involving microglial activation and T-cell marker elevation in the dorsal horn, and neuronal stress and satellite cell activation in the DRG. These changes, however, did not affect the establishment of neuropathic pain.
Highlights
Normal healthy aging is associated with neuroimmune changes that have been referred to as “inflammaging”, an elevation of inflammatory tone with age that may contribute to the agingPLOS ONE | DOI:10.1371/journal.pone.0134394 August 4, 2015Aging and Neuropathic Pain Response process itself, as well as enhance susceptibility to neurodegeneration [1,2,3,4,5]
Multiple inflammatory markers increase with age in various brain regions of healthy rats, mice, and primates [5,6,7], the pro-inflammatory cytokines interleukin 1β (IL1β), tumor necrosis factor α (TNFα) and interleukin 6 (IL6), as well as microglial activation markers, Cd11b (Ox42, C3A receptor) and MHCII, and the astrogliosis marker, glial fibrillary acidic protein (GFAP); challenging the senescent CNS with lipopolysaccharide (LPS) or with mechanical injury induces exaggerated neuroinflammatory responses, exacerbates decline, and delays functional recovery [6,7,8,9]
lumbar spinal cord (LSC) GFAP mRNA levels were beyond the upper bounds of the linear range of our assay, whereas IL2 and IL4 levels were too low (
Summary
Normal healthy aging is associated with neuroimmune changes that have been referred to as “inflammaging”, an elevation of inflammatory tone with age that may contribute to the agingPLOS ONE | DOI:10.1371/journal.pone.0134394 August 4, 2015Aging and Neuropathic Pain Response process itself, as well as enhance susceptibility to neurodegeneration [1,2,3,4,5]. Multiple inflammatory markers increase with age in various brain regions of healthy rats, mice, and primates [5,6,7], the pro-inflammatory cytokines interleukin 1β (IL1β), tumor necrosis factor α (TNFα) and interleukin 6 (IL6), as well as microglial activation markers, Cd11b (Ox42, C3A receptor) and MHCII (major histocompatibility complex II), and the astrogliosis marker, glial fibrillary acidic protein (GFAP); challenging the senescent CNS with lipopolysaccharide (LPS) or with mechanical injury induces exaggerated neuroinflammatory responses, exacerbates decline, and delays functional recovery [6,7,8,9]. Neuroimmune profiles of healthy aged and diseased brains suggest that early para-inflammatory changes, activation of microglia [10], may contribute to neurodegenerative disorders, such as Alzheimer’s dementia [11, 12] and Parkinson’s disease [13]
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