AMPK-driven immunometabolic reprogramming enhances CD19⁺CD21^hiCD24^hi regulatory B-cell-mediated suppression of atopic dermatitis.

Abstract

Atopic dermatitis (AD) is characterized by dysregulated immune responses and persistent inflammation. Regulatory B (Breg) cells suppress inflammation, but the metabolic mechanisms constraining their function in AD remain unclear. We sought to define whether immunometabolic regulation governs Breg cell differentiation and function in AD. Mouse and human B cells were stimulated with the adenosine monophosphate-activated protein kinase (AMPK) activator 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) under inflammatory conditions, with genetic and pharmacologic perturbations. Functional and mechanistic analyses were performed with coculture systems, a 2,4-dinitrochlorobenzene and Dermatophagoides farinae extract-induced murine model of AD, adoptive transfer approaches, adoptive transfer, and human peripheral blood mononuclear cells from patients with AD. AICAR treatment or adoptive transfer of AICAR-induced Breg cells significantly attenuated AD-like inflammation, whereas AMPK inhibition or IL-10 blockade abrogated these effects. Mechanistically, AICAR induced IL-10-producing Breg cells through AMPK-dependent suppression of mTOR signaling and mitochondrial reactive oxygen species while preserving oxidative phosphorylation. This reprogramming selectively enhanced regulatory B-cell function and suppressed STAT1 signaling without affecting STAT3. Functionally, these Breg cells suppressed T_H1, T_H2, and T_H17 responses in an IL-10-dependent manner without expanding Foxp3⁺ regulatory T cells. In human peripheral blood mononuclear cells from patients with AD, AICAR restored immunometabolic coupling by increasing IL-10-producing B cells and reducing proinflammatory cytokine production. These findings identify an AMPK-mTOR-redox metabolic checkpoint that governs regulatory B-cell function and restrains AD inflammation, linking metabolic control to immune regulation.