Hydrogen peroxide coordinates axon-Schwann cell signaling to regulate CXCR4 dynamics during nerve regeneration

Name: Hydrogen peroxide coordinates axon-Schwann cell signaling to regulate CXCR4 dynamics during nerve regeneration
Published: 2026
Keywords: CXCR4, EVs, local translation, ERK1/2, STAT3, schwann cells, hydrogen peroxide, Molecular mechanisms of signalling pathways, Protein synthesis, modification, turnover, Neural cell function, communication and signalling, neurotransmission in neuronal and/or glial cells, Neuronal development, plasticity and regeneration

Tonellato, Marika and Cosci, Chiara and Baggio, Chiara and Amoretti, Stefano and Montecucco, Cesare and Negro, Samuele and Rigoni, Michela (2026) Hydrogen peroxide coordinates axon-Schwann cell signaling to regulate CXCR4 dynamics during nerve regeneration. [Data Collection]

Collection description

Peripheral nerve regeneration requires rapid and coordinated signaling among different cell types, yet the mechanisms controlling spatial and temporal gene expression after injury remain incompletely understood. Here, we investigated the regulation of the chemokine receptor CXCR4, a developmental receptor re-expressed after a peripheral nerve injury, and a promoter of axonal regeneration. Using in vivo nerve injury models combined with high-resolution imaging and transcript detection, we show that CXCR4 is rapidly upregulated in motor axons upon nerve damage, including in distal segments disconnected from the motor neuron soma, indicating a major contribution of local protein synthesis. Consistently, inhibition of local translation significantly reduces receptor accumulation. In parallel, nerve injury leads to a rapid and translation-dependent upregulation of CXCR4 at the neuromuscular synapse, identifying this site as a distal sensor and effector of injury signals. We further show that Cxcr4 mRNA is dynamically regulated, with transcripts increasing at the injury site early after damage and predominantly localized in myelinating SCs (mSCs). Functional experiments reveal that mSCs contribute to axonal CXCR4 expression through exosome-mediated transfer of Cxcr4 transcripts that are axonally translated. Mechanistically, we identify hydrogen peroxide (H2O2) as a key upstream regulator of CXCR4 expression. Pharmacological scavenging of H2O2 suppresses the induction of both Cxcr4 mRNA and protein. Downstream of H2O2, we reveal a functional divergence between signaling pathways: the MEK/ERK axis regulates Cxcr4 transcription in mSCs, whereas STAT3 phosphorylation is required for CXCR4 availability in the axon without altering transcript levels, suggesting a post-transcriptional role. Together, our findings reveal a multilayered mechanism in which redox signaling coordinates transcriptional activation in mSCs with local translation in axons via intercellular mRNA transfer. This integrated response enables rapid and spatially resolved CXCR4 expression, highlighting a general strategy for efficient peripheral nerve regeneration.

DOI:

10.25430/researchdata.cab.unipd.it.00001901

Keywords:

CXCR4, EVs, local translation, ERK1/2, STAT3, schwann cells, hydrogen peroxide

Subjects:

Life Sciences > Molecular Biology, Biochemistry, Structural Biology and Molecular Biophysics: Molecular synthesis, modification, mechanisms and interactions; biochemistry; structural biology, molecular biophysics; metabolism; signalling pathways > Molecular mechanisms of signalling pathways
Life Sciences > Molecular Biology, Biochemistry, Structural Biology and Molecular Biophysics: Molecular synthesis, modification, mechanisms and interactions; biochemistry; structural biology, molecular biophysics; metabolism; signalling pathways > Protein synthesis, modification, turnover
Life Sciences > Neuroscience and Neural Disorders: Neural cell function and signalling, systems neuroscience, neural bases of cognitive and behavioural processes, neurological and psychiatric disorders > Neural cell function, communication and signalling, neurotransmission in neuronal and/or glial cells
Life Sciences > Neuroscience and Neural Disorders: Neural cell function and signalling, systems neuroscience, neural bases of cognitive and behavioural processes, neurological and psychiatric disorders > Neuronal development, plasticity and regeneration

Department:

Departments > Dipartimento di Scienze biomediche (DSB)

Depositing User:

Marika Tonellato

Date Deposited:

15 Aug 2026 10:02

Last Modified:

15 Aug 2026 10:02

Creators/Authors:

Creators	Email	ORCID
Tonellato, Marika	marika.tonellato@unipd.it	UNSPECIFIED
Cosci, Chiara	chiara.cosci@studenti.unipd.it	UNSPECIFIED
Baggio, Chiara	chiara.baggio.7@studenti.unipd.it	UNSPECIFIED
Amoretti, Stefano	stefano.amoretti@gmail.com	UNSPECIFIED
Montecucco, Cesare	cesare.montecucco@gmail.com	UNSPECIFIED
Negro, Samuele	samuele.negro@unipd.it	orcid.org/0000-0002-8038-1696
Rigoni, Michela	michela.rigoni@unipd.it	UNSPECIFIED