Preadipocyte secretory factors differentially modulate murine macrophage functions during aging which are reversed by the application of phytochemical EGCG.

ABSTRACT

The present study aimed at evaluating the role of senescent cell microenvironment as an extrinsic causal factor for altered age-associated macrophage functions, and that whether such changes could be ameliorated by the application of tea catechin epigallocatechin gallate (EGCG). To ascertain this, we analyzed the impact of secretory metabolites of proliferating (P) and senescent (S) preadipocyte cells on the induction of phenotypic and functional characteristics associated with aging in macrophages isolated from young (YM) and old (OM) C57BL/6J mice. The role of EGCG as alleviator of preadipocyte media-induced senescence and inflamm-aging was evaluated in OM. Results revealed strong age-related dysregulation in macrophage functions as evident by decreased CD11b expression, enhanced expression of cytokines (IL-6/TNF-α/IL-1ß/IL-10) and cell cycle inhibitors p53/p21WAF1/p16Ink4a, as well as augmentation of M2 phenotype (Arg1/Msr1/Mrc1) and SA-ß-gal activity. Ex vivo exposure of macrophages (YM and OM) to secretory factors of preadipocytes induced differential effects, and treatment with S culture media largely showed an augmentation of senescent phenotype, particularly in the YM. Pretreatment with EGCG (10 µM) to OM caused a dramatic reversal of both age-associated and preadipocyte media-induced changes as evident from upregulation of CD11b and ROS levels, inhibition of inflammatory makers, attenuation of p53/p21WAF1/p16Ink4a expression and SA-ß-gal activity. Our results indicate vital role of adipose tissue-mediated extrinsic factors in shaping macrophage phenotype and functions during aging. It is also apparent that EGCG is a promising candidate in developing preventive therapies aimed at alleviating macrophage inflamm-aging and senescence that may help curb incidences of inflammatory disorders in elderly.