Background and Objectives It is not fully understood how large-scale events affect well-being. Older adults showed the highest levels of resilience following the September 11th (9/11) terrorist attacks, but during the severe acute respiratory syndrome (SARS) outbreak there were no age-related differences in well-being. The current study examined the Coronavirus Disease 2019 (COVID-19) disruption on well-being throughout adulthood. Research Design and Methods Perceived stress and affect were examined in 166 community-dwelling adults (Mage=35.65; SD=15.53; range=18-79) in relation to the perceived disruption of the COVID-19 pandemic to their lives. Results A significant moderation was found for age and COVID-19 disruption on perceived stress [F(5, 153) = 8.88, p & .05, R2= .22] and negative affect [F(5, 154) = 4.91, p & .05, R2= .14], but not for positive affect. For participants over 50, those who rated COVID-19 as a low or high disruption had similar scores on stress and negative affect, but with younger aged participants, perceiving high disruption corresponded with higher levels of stress and negative affect. Discussion and Implications Findings are consistent with the strength and vulnerability integration (SAVI) model, wherein older adults try to maintain positive emotional well-being; with middle-aged and older adults in the current study having experienced less negative impact on well-being. Middle-aged and older adults may be better able to regulate negative emotions, from COVID-19, than younger adults. SAVI proposes a greater negative impact on older adults when they experience sustained stressors; as the challenges with COVID-19 continue, further data will need to be examined.

Background and Purpose The pathogenesis of the inflammatory bowel diseases (IBD), comprising Crohn's disease (CD) and ulcerative colitis (UC), involves aberrant interactions between a genetically susceptible individual, their microbiota and environmental factors. Alterations in xenobiotic receptor expression and function are associated with increased risk for IBD. Here, we have assessed the role of the constitutive androstane receptor (CAR), a xenobiotic receptor closely related to the pregnane X receptor, in the regulation of intestinal mucosal homeostasis. Experimental Approach CAR expression was assessed in intestinal mucosal biopsies obtained from CD and UC patients, and in C57/Bl6 mice exposed to dextran sulphate sodium (DSS; 3.5% w/v in drinking water) to evoke intestinal inflammation and tissue damage. CAR‐deficient mice were exposed to DSS and mucosal healing assessed. Modulation of wound healing by CAR was assessed in vitro. The therapeutic potential of CAR activation was evaluated, using 3,3′,5,5′‐tetrachloro‐1,4‐bis(pyridyloxy)benzene (TCPOBOP), a selective rodent CAR agonist. Key Results CAR expression was reduced in CD and UC samples, compared with expression in healthy controls. This was reproduced in our DSS studies, where CAR expression was reduced in colitic mice. CAR‐deficient mice exhibited reduced healing following DSS exposure. In vitro, CAR activation accelerated intestinal epithelial wound healing by enhancing cell migration. Lastly, treating mice with TCPOBOP, following induction of colitis, enhanced mucosal healing. Conclusion and Implications Our results support the notion that xenobiotic sensing is altered during intestinal inflammation, and suggest that CAR activation may prove effective in enhancing mucosal healing in patients with IBD.

The pregnane X receptor (PXR) is a ligand-activated nuclear receptor that acts as a xenobiotic sensor, responding to compounds of foreign origin, including pharmaceutical compounds, environmental contaminants, and natural products, to induce transcriptional events that regulate drug detoxification and efflux pathways. As such, the PXR is thought to play a key role in protecting the host from xenobiotic exposure. More recently, the PXR has been reported to regulate the expression of innate immune receptors in the intestine and modulate inflammasome activation in the vasculature. In the current study, we report that activation of the PXR in primed macrophages triggers caspase-1 activation and interleukin-1 β release. Mechanistically, we show that this response is nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain-containing 3-dependent and is driven by the rapid efflux of ATP and P2X purinoceptor 7 activation following PXR stimulation, an event that involves pannexin-1 gating, and is sensitive to inhibition of Src-family kinases. Our findings identify a mechanism whereby the PXR drives innate immune signaling, providing a potential link between xenobiotic exposure and the induction of innate inflammatory responses.

Background: Intestinal fibrosis is a common complication of the inflammatory bowel diseases(IBD), contributing to tissue stiffening and luminal narrowing. NR4A1 was previously reported to regulate mesenchymal cell function and dampen fibrogenic signaling. NR4A1 gene variants are associated with IBD risk, and it has been shown to regulate intestinal inflammation. Here, we tested the hypothesis that NR4A1 acts as a negative regulator of intestinal fibrosis through regulating myofibroblast function. Methods: Using the SAMP1/YitFc mouse, we tested whether two pharmacological agents known to enhance NR4A1 signaling: cytosporone B(Csn-B) or 6-mercaptopurine(6-MP); could reduce fibrosis. We also employed the dextran sulphate sodium(DSS) model of colitis and assessed the magnitude of colonic fibrosis in Nr4a1-/- and their wild-type littermates(Nr4a1+/+). Lastly, intestinal myofibroblasts isolated from Nr4a1-/- and Nr4a1+/+ mice or primary human intestinal myofibroblasts were stimulated with transforming growth factor-beta-1(TGF-β1), in the presence or absence of Csn-B or 6-MP, and proliferation and ECM gene expression assessed. Results: Csn-B or 6-MP treatment significantly reduced ileal thickness, collagen and overall ECM content in SAMP1/YitFc mice. This was associated with a reduction in proliferative markers within the mesenchymal compartment. Nr4a1-/- mice exposed to DSS exhibited increased colonic thickening and ECM content. Nr4a1-/- myofibroblasts displayed enhanced TGF-β1-induced proliferation. Furthermore, Csn-B or 6-MP treatment was anti-proliferative in Nr4a1+/+, but not Nr4a1-/- cells. Lastly, activating NR4A1 in human myofibroblasts reduced TGF-β1-induced collagen deposition and fibrosis-related gene expression. Conclusions: Our data suggest that NR4A1 can attenuate fibrotic processes in intestinal myofibroblasts and could provide a valuable clinical target to treat inflammation-associated intestinal fibrosis.

BackgroundThe pregnane X receptor (PXR) is a xenobiotic sensing nuclear receptor that is activated by a diverse array of substances, including environmental toxins, pharmaceutical compounds and metabolites released from the intestinal microbiota. While the PXR's prototypical role is to regulate the expression of the drug metabolizing/detoxifying genes in the liver and intestinal epithelium, we and others have reported that it plays a role in regulating inflammatory signaling. More specifically, the PXR can inhibit NFκB‐dependent inflammatory signaling and regulates the function/expression of innate immune receptors, including TLR4 and NLRP3. In the current study, we sought to characterize the function of the PXR in macrophages. Given the interactions between the PXR and innate immune receptors described in other non‐immune cell types, we hypothesized that its activation would modulate NLRP3 inflammasome activation and the resulting processing/release of IL‐1β.AimsTo evaluate the effect of PXR activation of NLRP3 inflammasome activation and to determine the mechanism(s) whereby the PXR modulates inflammasome activity.MethodsMouse peritoneal macrophages and PMA‐differentiated THP‐1 cells were used to assess NLRP3 inflammasome activation. Due to species‐specific ligand interactions with the PXR, in mouse studies we used pregnenolone 16α‐carbonitrile (PCN), whereas in THP‐1 experiments, we used the human PXR agonists, rifaximin and SR12813. To test if PXR activation modulated NLRP3 inflammasome activation, LPS‐primed macrophages or PMA‐differentiated THP‐1 were pretreated for one hour with PXR agonists and then challenged with ATP (5mM), a known NLRP3 inflammasome activator. Caspase‐1 cleavage and IL‐1β secretion were measured to assess inflammasome activation. In some experiments, extracellular ATP was measured following PXR agonist treatment.ResultsWhile PXR activation had no effect on ATP‐induced NLRP3 inflammasome activation, each PXR agonist alone stimulated the cleavage of caspase‐1 and the secretion of IL‐1ββ, reminiscent of inflammasome activation. In PXR−/− macrophages, these responses were absent, supporting a direct role of the PXR in these responses. Deletion of NLRP3 in mouse macrophages and THP‐1 cells attenuated PXR agonist‐induced caspase‐1 cleavage and IL‐1β secretion, suggesting that PXR activation triggers NLRP3 inflammasome activation. Furthermore, PXR driven responses were attenuated following caspase‐1 inhibition. Mechanistically, NLRP3 activation by the PXR did not involve ROS production, nor was it sensitive to chelation of intracellular calcium. However, treating cells with apyrase, to catabolize extracellular ATP, or selective inhibition of the P2X7 receptor attenuated PXR agonist‐induced caspase‐1 activation and IL‐1β secretion. Interestingly, we subsequently found that PXR activation led to a rapid (within 15 seconds) increase in extracellular ATP, reaching levels previous described in NLRP3 inflammasome activation models. This response was absent in PXR−/− cells, supporting a direct role of the PXR in ATP release.ConclusionsTaken together, our data suggest that activation of the xenobiotic sensing PXR triggers the release of ATP, which in turn causes NLRP3 inflammasome activation in macrophages. These findings suggest a novel mechanism whereby non‐microbial/non‐viral agents of environmental origin can stimulate innate immune responses and contribute to inflammatory disease.Support or Funding InformationCrohn's and Colitis CanadaNSERCLloyd Sutherland Investigatorship in IBD/GI researchThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.