Fat-Storing Multilocular Cells Expressing CCR5 Increase in the Thymus with Advancing Age: Potential Role for CCR5 Ligands on the Differentiation and Migration of Preadipocytes

Abstract

Age-associated thymic involution is characterized by decreased thymopoiesis, adipocyte deposition and changes in the expression of various thymic microenvironmental factors. In this work, we characterized the distribution of fat-storing cells within the aging thymus. We found an increase of unilocular adipocytes, ERTR7+ and CCR5+ fat-storing multilocular cells in the thymic septa and parenchymal regions, thus suggesting that mesenchymal cells could be immigrating and differentiating in the aging thymus. We verified that the expression of CCR5 and its ligands, CCL3, CCL4 and CCL5, were increased in the thymus with age. Hypothesizing that the increased expression of chemokines and the CCR5 receptor may play a role in adipocyte recruitment and/or differentiation within the aging thymus, we examined the potential role for CCR5 signaling on adipocyte physiology using 3T3-L1 pre-adipocyte cell line. Increased expression of the adipocyte differentiation markers, PPARγ2 and aP2 in 3T3-L1 cells was observed under treatment with CCR5 ligands. Moreover, 3T3-L1 cells demonstrated an ability to migrate in vitro in response to CCR5 ligands. We believe that the increased presence of fat-storing cells expressing CCR5 within the aging thymus strongly suggests that these cells may be an active component of the thymic stromal cell compartment in the physiology of thymic aging. Moreover, we found that adipocyte differentiation appear to be influenced by the proinflammatory chemokines, CCL3, CCL4 and CCL5.

Age-associated alterations in the levels of cytotoxic lipid molecular species and oxidative stress in the murine thymus are reduced by growth hormone treatment

“…We found an increase of TG levels, lipid droplets and adipose cells in the thymus with advancing age. The latter findings are consistent with previous reports that unilocular and multilocular lipid-laden cells progressively infiltrate the thymus during aging (Steinman et al 1985; de Mello-Coelho et al 2010; Langhi et al 2015). Our analysis of lymphocytes isolated from young and middle-age mice showed a trend to decrease their TG levels with age, therefore establishing that the accumulation of TG in the thymus may occur in other cell types, including adipocytes.…”

“…Snap-frozen thymuses were embedded in OCT compound (Sakura Finetek, Torrance, CA) or fixed in 10% buffered neutral formalin solution, dehydrated and embedded in paraffin as described previously (de Mello-Coelho et al 2010). Frozen sections of 5 μm were mounted on polylysine-coated slides and dried overnight at room temperature before hematoxylin and eosin (H&E) staining.…”

“…Oxidative stress is also associated with dyslipidemia during aging (Kirkland et al 2002). In this context, the redistribution and accumulation of various species of lipids and lipid droplets occurs not only in blood vessels but also in lymphohematopoietic organs, including the thymus (Steinmann et al 1985; Flores et al ., 1999; Mello-Coelho et al . 2010; Langhi et al .…”

“…The age-related decline of thymic function is inversely correlated with an increase of intrathymic lipid-laden multilocular and adipose cells, which produce pro-inflammatory molecules, such as leukemia inhibitory factor (LIF), interleukin-6 (IL-6) and other ligands of the gp130 receptor family (Sempowsky et al 2000; de Mello-Coelho et al 2004; Taub et al 2010). Moreover, perithymic and perivascular lipid-laden cells (LLC) express CCR5 and pro-inflammatory chemokine ligands to CCR5 increase in the aging thymus, suggesting that intrathymic LLC could be, originally, preadipocytes migrating from the perithymic adipose tissue into the thymic microenvironment (de Mello-Coelho et al 2010). Conjointly, these factors might contribute to oxidative stress and thymocyte death.…”

Multi-Analyte Profiling Reveals Matrix Metalloproteinase-9 and Monocyte Chemotactic Protein-1 as Plasma Biomarkers of Cardiac Aging

“…30, 31 At the same time, previous studies have shown that MIP-1β and RANTES levels increase in T-cells, in the brain and in the thymus with age. 32-34 The potential of MIP-1β and RANTES as biomarkers and their roles in cardiac aging remain to be investigated.…”