# CARD9 Conveys Pancreatic Islet Sympathetic Nervous β2 Signals to Reshape Macrophage Creatine Metabolism in Type 1 Diabetes

## TL;DR

This study shows how a protein called CARD9 connects nerve signals to immune cell metabolism in type 1 diabetes, offering new insights into disease progression and potential treatments.

## Contribution

The study identifies CARD9 as a novel mediator linking sympathetic nerve signaling to macrophage creatine metabolism and inflammation in type 1 diabetes.

## Key findings

- Loss of CARD9 in macrophages reduces creatine uptake and promotes pro-inflammatory activation.
- Disrupted β2-AR-PKA-CREB1-CARD9 signaling accelerates T1D progression through sympathetic axon ferroptosis.
- Restoring β2-AR signaling preserves macrophage metabolism and anti-inflammatory polarization.

## Abstract

Type 1 diabetes (T1D) is an autoimmune disorder marked by the injury of pancreatic β cells, during which sympathetic neurons in the endocrine region of pancreas are lost, whereas those in the exocrine regions surrounding islets remain intact. This abnormal sympathetic nervous signaling may disrupt the balance of the neuroendocrine‐immune network and contribute to the development of T1D, although its underlying molecular mechanisms are still elusive. Here, single‐cell omics and whole‐tissue immunostaining reveal a decrease in pancreatic sympathetic nerve density in T1D patients and T1D mouse models. Surgical and chemical desensitization of the sympathetic nervous system exacerbates T1D, while macrophage depletion mitigates this effect. Mechanistically, diminished norepinephrine (NE) release impairs β2‐adrenergic receptor (β2‐AR)‐PKA‐CREB1 signaling in islet macrophages, leading to downregulation of the adaptor caspase recruitment domain family member 9 (CARD9). Loss of CARD9 decreases SLC6A8‐mediated creatine uptake, shifts macrophages toward a pro‐inflammatory phenotype, and promotes sympathetic axon ferroptosis driven by decreased neurotrophic factor and anti‐inflammatory factor release. Conversely, β2‐AR agonist formoterol restores PKA‐CREB1‐CARD9 activation, preserves creatine metabolism, and maintains anti‐inflammatory macrophage polarization. These findings define a novel sympathetic‐macrophage‐creatine metabolic axis governed by CARD9 that links neural signals to immune and metabolic regulation in T1D, highlighting neuroimmune interactions as targets for therapies.

This study identifies CARD9 as a key mediator linking sympathetic β2‐adrenergic receptor signaling to macrophage creatine metabolism, inflammatory polarization, and neuronal integrity. Loss of β2‐AR‐PKA‐CREB1‐CARD9 signaling in macrophages reduces creatine uptake, promotes pro‐inflammatory macrophage activation, and drives sympathetic axon ferroptosis. Disruption of this neuro‐immune axis accelerates β‐cell autoimmunity and T1D progression, establishing CARD9 as a central regulator of macrophage metabolism, inflammation, and axon survival.