Inhibition of p38mapk Reduces Adipose Tissue Inflammation in Aging Mediated by Arginase-II

Abstract

<b><i>Background:</i></b> Adipose tissue inflammation occurs not only in obesity but also in aging and is mechanistically linked with age-associated diseases. Studies show that ablation of the l-arginine-metabolizing enzyme arginase-II (Arg-II) reduces adipose tissue inflammation and improves glucose tolerance in obesity. However, the role of Arg-II in aging adipose tissue inflammation is not clear. <b><i>Objective:</i></b> This study investigated the role of Arg-II in age-associated adipose tissue inflammation. <b><i>Methods:</i></b> Visceral adipose tissues of young (3–6 months) and old (20–24 months) wild-type (WT) and Arg-II<sup>−/−</sup> mice were investigated. Immunofluorescence confocal microscopy was performed for analysis of macrophage accumulation and cellular localization of arginase and cytokines; expression of arginase and cytokines was analyzed by qRT-PCR or immunoblotting or ELISA; activation of mitogen-activated protein kinases in adipose tissues was analyzed by immunoblotting; and arginase activity was measured by colorimetric determination of urea production. <b><i>Results:</i></b> In the old WT mice, there is more macrophage accumulation in the visceral adipose tissues than in Arg-II knockout animals. An age-associated increase in arginase activity and Arg-II expression in adipose tissues of WT mice is observed. Arg-II knockout enhances Arg-I expression and activity, but inhibits interleukin (IL)-6 expression and secretion and reduces active p38mapk in aging adipose tissue macrophages and stromal cells. Treatment of aging adipose tissues of WT mice with a specific p38mapk inhibitor SB203580 reduces IL-6 secretion. <b><i>Conclusions:</i></b> Arg-II promotes IL-6 production in aging adipose tissues through p38mapk. The results suggest that targeting Arg-II or inhibiting p38mapk could be beneficial in reducing age-associated adipose tissue inflammation.

Arginine and Endothelial Function

“…This mechanism has emerged as an essential factor underlying impaired endothelial functions [ 68 , 69 ]. Specifically, an increased arginase activity has been associated with endothelial dysfunction in a number of experimental models of hypertension, atherosclerosis, diabetes, and aging [ 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 ].…”

p38MAPK Signaling Pathway in Osteoarthritis: Pathological and Therapeutic Aspects

“…26 Recent studies have provided ample evidence, supporting that the p38MAPK signaling pathway is associated with a variety of age-related diseases. [27][28][29][30][31][32] For example, according to Moreno-Cugnon et al, the elevated p38MAPK activity was associated with neural stem cell aging. 29 Chen et al suggested that RAB7 was a protective factor for intervertebral discs, which retarded the intervertebral disc degeneration by inhibiting the p38MAPK pathway.…”

Inflamm-Aging: Arginase-II as Stage Setter in Age-Related Adipose Tissue Inflammation

“…In this issue of Pharmacology , Huang et al [6] report a role of Arg-II in age-associated adipose tissue inflammation by promoting IL-6 production. IL-6 is a key cytokine associated with inflamm-aging, and systemic IL-6 neutralization by a blocking antibody improves physical fitness in mice [7].…”

“…IL-6 is a key cytokine associated with inflamm-aging, and systemic IL-6 neutralization by a blocking antibody improves physical fitness in mice [7]. Huang et al [6] showed that IL-6 mRNA and protein levels were increased in adipose tissue or in conditioned medium from peri-uterus fat tissue from old but not young mice. In contrast, both IL-6 mRNA and protein levels were significantly decreased in old Arg-II knockout (Arg-II −/− ) mice compared to age-matched wild-type mice, and less macrophage accumulation was observed.…”

“…The study by Huang et al [6] suggests that Arg-II is critically involved in age-related adipose tissue inflammation as it influences the production of a key cytokine (IL-6) in the process of inflamm-aging. Therapeutic strategies targeting immune cells and immune networks in aging adipose tissue may have great future potential.…”