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Store-operated calcium entry drives alcohol-exacerbated neuroinflammation in retinal degeneration
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  • Published: 31 March 2026

Store-operated calcium entry drives alcohol-exacerbated neuroinflammation in retinal degeneration

  • Théo Henrique de Lima-Vasconcellos1,
  • Bruna de Albuquerque Menezes1,
  • Marília Inês Móvio1,
  • Gabrieli Bovi do Santos1,
  • Gabriela Maria Badin1,
  • William Silva1 &
  • …
  • Alexandre Hiroaki Kihara  ORCID: orcid.org/0000-0002-4027-72611,2 

Cell Death Discovery , Article number:  (2026) Cite this article

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We are providing an unedited version of this manuscript to give early access to its findings. Before final publication, the manuscript will undergo further editing. Please note there may be errors present which affect the content, and all legal disclaimers apply.

Subjects

  • Inflammation
  • Mechanisms of disease
  • Microglia
  • Neuroimmunology
  • Retinal diseases

Abstract

Patients with neurodegenerative diseases such as retinitis pigmentosa (RP) may engage in maladaptive coping behaviors, including alcohol misuse, which can aggravate disease progression. Neuroinflammation, a hallmark of RP, is largely driven by microglial activation and amplified when cells are primed by oxidative stress. Store-operated calcium entry (SOCE), primarily mediated by Orai1 channels, regulates microglial metabolism and inflammatory signaling. Here, we tested whether ethanol (EtOH) exacerbates RP-related neuroinflammation through SOCE-dependent mechanisms and whether 2-aminoethoxydiphenyl borate (2-APB) mitigates these effects. In mixed retinal cultures, a “double-hit” (oxidative stress + EtOH) triggered pronounced microglial activation, neuronal loss, and altered cytokine expression and correlation patterns, assessed by multiplex bead assays and hierarchical clustering analysis. Indeed, 2-APB restored ramified morphology and improved neuronal survival. Conditioned medium experiments revealed that both microglia and Müller cells responded to the double-hit, but only microglia were sensitive to SOCE inhibition. In vivo, subretinal delivery of EtOH and 2-APB in rd1 mice, a genetic model of RP, altered microglial morphology and reduced pro-inflammatory cytokine levels without affecting photoreceptor density. Notably, in situ assessment of CD86/CD206 showed no change in expression, indicating that microglial activation in vivo is better captured by morphological and cytokine-network alterations than by classical surface markers. These findings show that alcohol misuse amplifies retinal neuroinflammation in RP via calcium-dependent mechanisms and identify SOCE as a therapeutic target for limiting damage from systemic comorbidities in retinal degeneration.

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Data availability

The datasets generated and/or analyzed during the current study are available from the corresponding author upon reasonable request.

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Acknowledgements

The authors acknowledge the Multiuser Center Facility (CEM) at UFABC.

Funding

AHK is grateful for grants from Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP, Brazil, #2020/11667-0), Universidade Federal do ABC (UFABC, Brazil), and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, Brazil, 315372/2021-4). The following authors were recipients of fellowships from FAPESP: THLV (#2021/11969-9 and #2024/00828-3), GBS (#2021/14227-3), and GMB (#2024/10858-7). The following authors were recipients of fellowships from Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES, Brazil): MIM (Finance Code 001, #88887.597402/2021-00). The funders had no role in study design, data collection and analysis, decision to publish, or manuscript preparation.

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Authors and Affiliations

  1. Laboratório de Neurogenética, Universidade Federal do ABC, São Bernardo do Campo, SP, Brasil

    Théo Henrique de Lima-Vasconcellos, Bruna de Albuquerque Menezes, Marília Inês Móvio, Gabrieli Bovi do Santos, Gabriela Maria Badin, William Silva & Alexandre Hiroaki Kihara

  2. Centro de Matemática, Computação e Cognição, Universidade Federal do ABC, São Bernardo do Campo, SP, Brasil

    Alexandre Hiroaki Kihara

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  1. Théo Henrique de Lima-Vasconcellos
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Contributions

Conceived and designed the research: THLV and AHK. Performed experiments: THLV, BAM, GBS, GMB, and WS. Acquired, analyzed, or interpreted data: THLV, MIM, BAM, GBS, GMB, WS, and AHK. Wrote the manuscript: THLV and AHK. Revised the manuscript: THLV, MIM, and AHK.

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Correspondence to Alexandre Hiroaki Kihara.

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Lima-Vasconcellos, T.H.d., Menezes, B.d.A., Móvio, M.I. et al. Store-operated calcium entry drives alcohol-exacerbated neuroinflammation in retinal degeneration. Cell Death Discov. (2026). https://doi.org/10.1038/s41420-026-03074-2

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  • Received: 19 August 2025

  • Revised: 02 March 2026

  • Accepted: 11 March 2026

  • Published: 31 March 2026

  • DOI: https://doi.org/10.1038/s41420-026-03074-2

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Cell Death Discovery (Cell Death Discov.)

ISSN 2058-7716 (online)

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