Age-related adiposity has been linked to chronic inflammatory diseases in late-life. To date, the studies on adipose tissue leukocytes and aging have not taken into account the heterogeneity of adipose tissue macrophages (ATMs), nor have they examined how age impacts other leukocytes such as T cell in fat. Therefore, we have performed a detailed examination of ATM subtypes in young and old mice using state of the art techniques. Our results demonstrate qualitative changes in ATMs with aging that generate a decrease in resident Type 2 (M2) ATMs. The profile of ATMs in old fat shifts towards a pro-inflammatory environment with increased numbers of CD206-CD11c- (double negative) ATMs. The mechanism of this aging-induced shift in the phenotypic profile of ATMs was found to be related to a decrease in PPARγ expression in ATMs and alterations in chemokine/chemokine receptor expression profiles. Furthermore, we have revealed a profound and unexpected expansion of adipose tissue T (ATT) cells in visceral fat with aging that includes a significant induction of regulatory T cells (Tregs) in fat. Our findings demonstrate a unique inflammatory cell signature in the physiologic context of aging adipose tissue that differs from those induced in setting of diet-induced obesity.

We demonstrate that the mechanism of redox remodeling during mouse T cell activation involves secretion of glutathione by dendritic cells and its subsequent cleavage to cysteine. Extracellular cysteine accumulation results in a lower redox potential, which is conducive to proliferation, and changes the net redox status of exofacial protein domains. Regulatory T cells inhibit this redox metabolite-signaling pathway, which represents a previously unrecognized mechanism for immunosuppression of effector T cells.

Our findings highlight the potential of an Ad-vector-based delivery system, which is both egg-independent and adjuvant-independent and offers stockpiling options for the development of a pandemic influenza vaccine.

In patients with NASH, pentoxifylline therapy effectively achieved significant clinical and biochemical improvement with reduction in HOMA(IR). These benefits are possibly mediated through suppression of TNF-alpha.

Regulatory T-cell (Treg, CD4+CD25+) dysfunction is suspected to play a key role in immune senescence and contributes to increased susceptibility to diseases with age by suppressing T-cell responses. FoxP3 is a master regulator of Treg function, and its expression is under control of several epigenetically labile promoters and enhancers. Demethylation of CpG sites within these regions is associated with increased FoxP3 expression and development of a suppressive phenotype. We examined differences in FoxP3 expression between young (3–4 months) and aged (18–20 months) C57BL/6 mice. DNA from CD4+ T cells is hypomethylated in aged mice, which also exhibit increased Treg numbers and FoxP3 expression. Additionally, Treg from aged mice also have greater ability to suppress effector T-cell (Teff) proliferation in vitro than Tregs from young mice. Tregs from aged mice exhibit greater redox remodeling–mediated suppression of Teff proliferation during coculture with DCs by decreasing extracellular cysteine availability to a greater extent than Tregs from young mice, creating an adverse environment for Teff proliferation. Tregs from aged mice produce higher IL-10 levels and suppress CD86 expression on DCs more strongly than Tregs from young mice, suggesting decreased T-cell activity. Taken together, these results reveal a potential mechanism of higher Treg-mediated activity that may contribute to increased immune suppression with age.

The influence of dechlorinating microorganisms on PCE and its reduced end products in the presence of a PCEcontaining nonaqueous phase liquid (NAPL) was investigated. Experiments were conducted in continuous-flow stirredtank reactors (CFSTRs) containing a mixed PCE dechlorinating culture and a model NAPL consisting of PCE and tridecane. Comparisons between biotic and abiotic CFSTRs demonstrated that dechlorination resulted in a factor of 14 increase in PCE removal rates from the NAPL. The formation of dechlorination daughter products trichloroethene and cisdichloroethene were observed, and cis-dichloroethene was not dechlorinated further. Partitioning of daughter products between phases caused temporal changes in the chlorinated ethenes distribution within the NAPL. The combined effects of dissolution and dechlorination on the removal of chlorinated ethenes from the NAPL were described using a mathematical model that approximated dechlorination as a pseudo-first-order process. Pseudofirst-order dechlorination rate coefficients for PCE and TCE were determined and were 0.18 and 0.27 h -1 , respectively. It was determined that total chlorinated ethenes removal from the NAPL would be achieved in 13 days in biotic CFSTRs, as compared to 77 days in the abiotic CFSTRss corresponding to an 83% reduction in longevity of the chlorinated ethenes component of the NAPL.

Microglial neuroinflammatory responses affect the onset and progression of Parkinson's disease (PD). We posit that such neuroinflammatory responses are, in part, mediated by microglial interactions with nitrated and aggregated alpha-synuclein (alpha-syn) released from Lewy bodies as a consequence of dopaminergic neuronal degeneration. As disease progresses, secretions from alpha-syn-activated microglia can engage neighboring glial cells in a cycle of autocrine and paracrine amplification of neurotoxic immune products. Such pathogenic processes affect the balance between a microglial neurotrophic and neurotoxic signature. We now report that microglia secrete both neurotoxic and neuroprotective factors after exposure to nitrated alpha-syn (N-alpha-syn). Proteomic (surface enhanced laser desorption-time of flight, 1D sodium dodecyl sulfate electrophoresis, and liquid chromatography-tandem mass spectrometry) and limited metabolomic profiling demonstrated that N-alpha-syn-activated microglia secrete inflammatory, regulatory, redox-active, enzymatic, and cytoskeletal proteins. Increased extracellular glutamate and cysteine and diminished intracellular glutathione and secreted exosomal proteins were also demonstrated. Increased redox-active proteins suggest regulatory microglial responses to N-alpha-syn. These were linked to discontinuous cystatin expression, cathepsin activity, and nuclear factor-kappa B activation. Inhibition of cathepsin B attenuated, in part, N-alpha-syn microglial neurotoxicity. These data support multifaceted microglia functions in PD-associated neurodegeneration.

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