Type 2 Diabetes-Associated Phenylacetylglutamine Induces Deleterious Inflammation Cycle in Myeloid Cells through β2 Adrenergic Receptors and Impedes Wound Healing.

Publisher: WILEY-VCH Country of Publication: Germany NLM ID: 101664569 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2198-3844 (Electronic) Linking ISSN: 21983844 NLM ISO Abbreviation: Adv Sci (Weinh) Subsets: MEDLINE

Original Publication: Weinheim : WILEY-VCH, [2014]-

Wound Healing*/physiology ; Wound Healing*/drug effects ; Diabetes Mellitus, Type 2*/metabolism ; Diabetes Mellitus, Type 2*/complications ; Receptors, Adrenergic, beta-2*/metabolism ; Myeloid Cells*/metabolism ; Inflammation*/metabolism ; Glutamine*/analogs & derivatives ; Glutamine*/metabolism; Animals ; Mice ; Humans ; Male ; Mice, Inbred C57BL ; Female

Despite advances in glucose-lowering therapies, many diabetic patients still suffer inflammation-related complications such as chronic non-healing wounds. The microbiota-derived metabolite phenylacetylglutamine (PAGln) is identified as a causal driver of these wounds via a transmissible, β2-adrenergic receptor-mediated trained-immunity loop. Metabolomics reveals PAGln is elevated in type 2 diabetes and tightly associated with poor healing in both diabetic and non-diabetic human patients. Pharmacokinetic comparison shows that mouse PAGln exposure closely matches the concentrations and kinetics seen in humans. It is validated that PAGln delays wound closure, impairs collagen restoration, and reduces neovascularization in wild-type, T1DM, and T2DM mice-defects rescued by β-blocker treatment. Mechanistically, PAGln epigenetically trains myeloid cells via β2-adrenergic receptors, promoting their hyperresponsiveness, heightening systemic inflammation. This epigenetic reprogramming extends to HSCs, expanding hyper-responsive myeloid cells and sustaining a myeloid-biased inflammatory loop. This PAGln-induced hyper-inflammatory, wound-healing deficit is transmissible via bone marrow transplantation to irradiated naïve recipients, confirming that PAGln-trained hematopoietic cells propagate these deleterious phenotypes. β-blockers co-treatment reverses PAGln-induced cytokine elevation and wound-healing deficits. These findings link a diet-derived microbial metabolite, PAGln, to chronic wound and inflammation in T2DM and PAA-related clinical conditions and highlight β-blockade as a readily translatable therapy to disrupt the PAGln-driven deleterious inflammation cycle.
(© 2025 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

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22MC1940300 Natural Science Foundation of Shanghai Municipality

Keywords: adrenergic receptors; innate immunity training; phenylacetylglutamine; type 2 diabetes; wound healing

0 (Receptors, Adrenergic, beta-2)
0RH81L854J (Glutamine)

Date Created: 20250814 Date Completed: 20251114 Latest Revision: 20251119

20260130

PMC12622421

10.1002/advs.202508205

40810653