“Venerunt, activaverunt, nervos vulnaverunt”: they came, they activated, they hurt the nerves – mast cells as drivers of nerve injury in diabetic neuropathy

Aims: To investigate the role of mast cells (MC) in the pathogenesis of diabetic peripheral neuropathy (DPN) and delineate the molecular mechanisms by which a hyperglycaemic (HG) environment modulates MC activity and contributes to neuropathic injury.

Methods: Single-cell RNA sequencing of tibial nerve samples from DPN (n=7) patients and traumatic limb amputation (TLA) controls (n=10) was performed to determine differences in cell population and examine transcriptional changes. Streptozotocin-induced (STZ) diabetic, MC-deficient (KitW-sh/W-sh) and saline-treated WT mice (n=18 each, 6/group) were used to assess in vivo relevance. Nerve conduction velocity (NCV) testing was conducted, and tissue was harvested at 24 weeks post-STZ administration. In vitro cocultures of bone marrow-derived MCs with dorsal root ganglion (DRG) neurons or Schwann cells under HG conditions were used to assess paracrine neurotoxicity. Analyses included qPCR, immunohistochemistry, ELISA, and proximity ligation assay.

Results: Single-cell transcriptomics found increased MC infiltration and distinct MC subclusters in DPN nerves (DPN: n=4), relative to TLA nerves (n=3). MC marker gene expression was significantly higher in tibial nerves from people with DPN compared to TLA for KIT (p=0.0015), CMA1 (p=0.0282), TPBAB1 (p=0.0018), MS4A2 (p=0.0002), and CPA3 (p=0.0009). Increased infiltration of CD45⁺ve and tryptase⁺ve cells was also observed in DPN (p=0.0016 and p<0.0001, respectively) compared to TLA tibial nerves. DPN nerves showed axonal loss, demyelination, and reduced NF200 and S100β expression (all p<0.0002). TNF-α and IL-1β were elevated at mRNA (p=0.0011 and p<0.0001) and protein levels (both p<0.0001). NCV was improved in KitW-sh/W-sh mice compared to STZ-treated controls (p<0.0001). KitW-sh/W-sh mice showed increased NF200 (p<0.0001) and S100β (p=0.002) expression, greater intact myelin (p<0.0001), and fewer demyelinated axons (p=0.0007) compared to STZ-treated mice. In vitro, HG upregulated MC GLUT3 (p=0.03) but not GLUT1 (p=0.9), and increased ERK1/2 and mTOR phosphorylation (both p<0.0001), endoplasmic reticulum (ER)–mitochondrial contact (p=0.0346), and IP3R1–VDAC1 interaction (p=0.0086). ER stress markers CHOP and HSPA5 were also significantly upregulated under HG conditions (both p<0.0001). GLUT3 knockdown reduced GLUT3 expression (p<0.0001) and attenuated ERK1/2 phosphorylation (p=0.0025). HG-exposed MCs significantly suppressed DRG neurite outgrowth; reduced axon length was observed in cocultures compared to monocultures (p<0.0001 and p=0.0034, respectively).

Conclusions: MCs are increased and transcriptionally active in DPN tibial nerves. Their degranulation drives neuroinflammation, demyelination, and axonal injury. In STZ mice, mast cell deficiency abrogated nerve damage. In vitro, HG induced mast cell activation via GLUT3–ERK1/2–mTOR signalling, triggering ER stress, mitochondrial dysfunction, and neurotoxic effects. This pathway is a potential therapeutic target.

Comments: MCs contribute to DPN, though mediators likely extend beyond TNF-α and IL-1β. Activation under hyperglycaemia was inferred, not directly shown. Site and stage specific metabolic reprogramming of nerves may potentially converge with the hyperglycaemic-MC signalling axis (Eid SA et al Transl Res 2024;270:24-41) in DPN. Microstructural abnormalities in peripheral nerves correspond to disease progression (Mooshage CM et al Diabetologia 2024;67:275-289) and may possibly intersect with the present structural evidence of MC-mediated axonal/myelin damage. Indeed, the GLUT3–ERK1/2–mTOR axis and downstream mediators, especially in subclinical disease, remain incompletely understood warranting further investigation.

Jamie Burgess

Reference: Yao X, Wang X, Zhang R, Kong L, Fan C, Qian Y. Dysregulated MC activation induced by diabetic milieu exacerbates the progression of diabetic peripheral neuropathy in mice. Nat Commun. 2025 May 5;16(1):4170. doi: 10.1038/s41467-025-59562-z. PMID: 40325050; PMCID: PMC12052842.

🔗 https://www.nature.com/articles/s41467-025-59562-z