Abstract
The Mrp8 and Mrp14 proteins (calprotectin) accumulate within tissues during aging and may contribute to chronic inflammation. To address this possibility, we evaluated female calprotectin-deficient Mrp14-KO and wild-type (WT) mice at 5 and 24 months of age. However, there was no evidence that age-related inflammation is blunted in KO mice. Inflammation markers were in fact elevated in livers from old KO mice, and microarray analysis revealed more consistent elevation of genes specifically expressed by B-cells and T-cells. Adipose-specific genes, however, were less consistently elevated in aged KO mice, suggesting an anti-steatosis effect of Mrp8/14 deficiency. Consistent with this, genes decreased by the anti-steatosis agent SRT1720 were decreased in old KO compared to old WT mice. Expression of lipid metabolism genes was altered in KO mice at 5 months of age, along with genes associated with development, biosynthesis and immunity. These early-age effects of Mrp8/14 deficiency, in the absence of any external stressor, were unexpected. Taken together, our findings demonstrate a pro-steatosis rather than pro-inflammatory role of calprotectin within the aging liver. This appears to reflect a developmental-metabolic phenotype of Mrp14-KO mice that is manifest at a young age in the absence of pro-inflammatory stimuli.
Highlights
Aging is associated with chronic low-grade inflammation and the accumulation of immune cell deposits within tissues
Mrp8 and Mrp14 have been identified as biomarkers of the aging process [3], but while their pro-inflammatory activity has been documented in young mice under acute stress [16,17,18,19,20,21,22,23], their contributions to chronic inflammation at older ages remains unclear
This study compared Mrp14-KO and WT mice at young and old ages but obtained no evidence that age-related inflammation is blunted by Mrp8/
Summary
Aging is associated with chronic low-grade inflammation and the accumulation of immune cell deposits within tissues. This process, termed “inflammaging”, may contribute to functional and cognitive decline with increased age, and is proposed to be an important target for development of drugs to promote healthy aging and increased healthspan [1]. In humans, aging leads to increased Mrp and Mrp mRNA abundance in airway epithelia and throughout the central nervous system (temporal lobe, hippocampus, parietal lobe and frontal lobe) [3]. Increased Mrp and Mrp expression with age is likely due to immune cell infiltration into aging tissues, but may reflect local responses of cells to age-related stress, damage or senescence [4, 5]. Mrp8/Mrp accumulation may contribute to chronic inflammation [6,7,8,9], enhance atherosclerosis and vascular disease [10], promote tumorigenesis [11], and facilitate plaque formation in the brain leading to memory impairment [12,13,14,15]
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