Biology subjects

Aherne, C. M.

Publications and source records attributed to Aherne, C. M..

3 recordsLinked to original sources

bioRxiv2026

Cannabinoid CB2 receptor activation drives glucose uptake, shifting T cell metabolism.

Cannabinoid receptor 2 (CB2R) is highly expressed on immune cells, but its role in T cell metabolism remains unclear. Here, we show that CB2R activation rapidly increases glucose uptake in human Jurkat T cells and drives a broader metabolic reprogramming away from glycolysis toward oxidative metabolism and the pentose phosphate pathway. Pharmacological CB2R activation increased mitochondrial mass, spare respiratory capacity, proton leak, and NADPH production, while CB2R inverse agonism produced the opposite effects. These metabolic changes were accompanied by upregulation of key pentose phosphate pathway enzymes, including GALT and TALDO1, and were abolished in CNR2-deficient cells, confirming receptor dependence. In primary human lamina propria mononuclear cells, CB2R signalling also influenced memory and gut-homing-associated T cell phenotypes, including integrin 4{beta}7 expression. Together, these findings identify CB2R as a regulator of T cell bioenergetics and suggest that cannabinoid signalling may promote metabolic states linked to memory and tissue-homing functions in chronic intestinal inflammation. Brief SummaryO_LICB2R agonist-mediated increased glucose uptake in human T cells is lost in CNR2-deficient cells, suggesting that the response is receptor-dependent. C_LIO_LICB2R activation rewires T-cell metabolism toward increased oxidative phosphorylation, spare respiratory capacity, mitochondrial mass, and pentose phosphate pathway metabolism, including higher NADPH and PPP-enzyme expression. C_LIO_LIIn primary human intestinal immune cells, CB2R also promotes gut-homing and memory-associated T-cell phenotypes, including 4{beta}7 and CD103 integrin induction ex vivo, suggesting a possible link to exacerbation of chronic intestinal inflammation. C_LI

immunology↗

bioRxiv2026

Amoxicillin induces gut dysbiosis leading to long term suppression of type-17 immune tone in the lungs

T-helper (Th)-17 lymphocytes are central mediators of adaptive type 17 immunity. Decreased type-17 signaling increases severity of infections in humans and mice. However, detrimental effects of excessive type 17 responses in autoimmune and other inflammatory diseases highlight a need for type-17 immune calibration to support beneficial host defense requirements. Mechanisms of type 17 calibration are poorly understood. A gut-lung axis has been proposed to coordinate homeostatic protection and acute host defense. Factors that acutely alter the gut microbiome are heterogeneous and include acute intestinal infections, non-infectious colitis, and medical treatments such as antibiotics. How changes in the gut microbiome affect lung immune tone during homeostasis and acute pulmonary infections are also poorly understood. Prior studies have shown that antibiotics reduce expression of IL-17-mediated host defense in the gut. Since gut microbial homeostasis influences Th17 cell numbers in both the intestine and remote tissues, we postulated that antibiotic treatment would result in gut dysbiosis and weakened type-17 host defense in the lungs. We found that amoxicillin induces significant dysbiosis that is long-lasting and that there is a long-term decrease in type-17 tone in the lungs. We also found that in mice lacking the gut mucin, Muc2, Th17 cells increased in the lungs following inflammatory challenge. These findings suggest that antibiotic-induced dysbiosis can decrease lung immune defenses for long periods of time after cessation of antibiotic treatment.

immunology↗

bioRxiv2025

Cannabinoid CB2R regulates T cell gut-homing in preclinical Crohns model.

Leukocyte trafficking is a critical step in development of chronic intestinal diseases such as Crohns disease. While strategies that block gut-homing have yielded partial success, this disease remains uncurable leaving an unmet clinical need. This is the first paper to describe a role for cannabinoid receptor two (CB2R) signalling in promoting retinoic acid-mediated induction of the gut-homing associated integrin heterodimer 4{beta}7. Using in vitro and in vivo models, we characterised the effects of pharmacological CB2R agonists and inverse agonists on T cell homing receptor expression and transmigration across gut-associated endothelial barriers. This ERK-dependent process coincides with increased T cell adherence in response to CB2R agonism with JWH133. These effects were reversed with an inverse agonist GP-1a in a CB2R dependent manner. Selective deletion of CB2R using CRISPR in vitro or CD4Cre/+ floxed mice in vivo resulted in impaired endothelial cell adherence and decreased diapedesis into the ileal lamina propria. T cell-specific deletion of cnr2, the gene encoding CB2R, attenuated chronic murine ileitis characterised by decreased naive T cell infiltration and loss of tissue architecture in 20wk TNF{Delta}ARE/+mice. This study supports further therapeutic development of CB2R-blocking drugs for the treatment of inflammatory bowel disease.

immunology↗