Fasting-activated ventrolateral medulla neurons regulate T cell homing and suppress autoimmune disease in mice.

Dietary fasting markedly influences the distribution and function of immune cells and exerts potent immunosuppressive effects. However, the mechanisms through which fasting regulates immunity remain obscure. Here we report that catecholaminergic (CA) neurons in the ventrolateral medulla (VLM) are activated during fasting in mice, and we demonstrate that the activity of these CA neurons impacts the distribution of T cells and the development of autoimmune disease in an experimental autoimmune encephalomyelitis (EAE) model. Ablation of VLM CA neurons largely reversed fasting-mediated T cell redistribution. Activation of these neurons drove T cell homing to bone marrow in a CXCR4/CXCL12 axis-dependent manner, which may be mediated by a neural circuit that stimulates corticosterone secretion. Similar to fasting, the continuous activation of VLM CA neurons suppressed T cell activation, proliferation, differentiation and cytokine production in autoimmune mouse models and substantially alleviated disease symptoms. Collectively, our study demonstrates neuronal control of inflammation and T cell distribution, suggesting a neural mechanism underlying fasting-mediated immune regulation.

Elevated RHAMM as a biomarker for predicting diabetic kidney disease in patients with type 2 diabetes.

Background: Diabetic kidney disease (DKD) poses a significant challenge globally as a complication of diabetes. Hyaluronan (HA), a critical non-sulfated glycosaminoglycan in the extracellular matrix, plays a pivotal role in the progression of DKD. This study assesses the predictive significance of HA's corresponding receptor, RHAMM (receptor for HA-mediated motility), in DKD pathogenesis in type 2 diabetes (T2DM) patients. Methods: Enzyme-linked immunosorbent assays were utilized to measure plasma and urine levels of HA, CD44 and RHAMM in 99 diabetic patients. Immunohistochemistry staining was employed to examine HA deposition, CD44 and RHAMM expressions from 18 biopsy-proven DKD patients. Spearman correlation analysis, linear regression and receiver operating characteristic (ROC) analysis were conducted to establish associations between plasma HA, CD44 and RHAMM levels, and clinical parameters in DKD patients with T2DM. Results: Elevated plasma and urine HA, CD44 and RHAMM levels were notably observed in the severe renal dysfunction group. Plasma RHAMM exhibited positive correlations with HA (r = 0.616, P < .001) and CD44 (r = 0.220, P < .001), and a negative correlation with estimated glomerular filtration rate (eGFR) (r = -0.618, P < .001). After adjusting for other potential predictors, plasma RHAMM emerged as an independent predictor of declining eGFR (ß = -0.160, P < .05). Increased HA, CD44 and RHAMM levels in kidney biopsies of DKD patients were closely associated with heightened kidney injury. The ROC curve analysis highlighted an area under the curve (AUC) of 0.876 for plasma RHAMM, indicating superior diagnostic efficacy compared to CD44 in predicting DKD pathogenesis. The combined AUC of 0.968 for plasma RHAMM, HA and CD44 also suggested even greater diagnostic potential for DKD pathogenesis. Conclusion: These findings provide initial evidence that elevated RHAMM levels predict DKD pathogenesis in T2DM patients. The formation of a triple complex involving HA, CD44 and RHAMM on the cell surface shows promise as a targetable biomarker for early intervention to mitigate severe renal dysfunctions.