P2X4 Drives Sex-Specific neuroprotection in autoimmune neuroinflammation
Brain, Behavior, and Immunity. 2026-08-01; 136: 106771
DOI: 10.1016/j.bbi.2026.106771
Mata P(1), Bosch-Juan M(1), Luengo-Arias S(2), Montilla A(1), Astiz M(3),
Battefeld A(4), Carracedo S(4), Sanchez-Gomez MV(1), Matute C(5), Pérez-Samartín
A(1), Boué-Grabot E(4), Domercq M(6).
Author information:
(1)Achucarro Basque Center for Neuroscience, E-48940 Leioa, Spain; Department of
Neuroscience, University of the Basque Country (EHU), E-48940 Leioa, Spain.
(2)Department of Neuroscience, University of the Basque Country (EHU), E-48940
Leioa, Spain.
(3)Achucarro Basque Center for Neuroscience, E-48940 Leioa, Spain; Ikerbasque
Foundation, E-48009 Bilbao, Spain.
(4)University of Bordeaux, CNRS, IMN, UMR 5293, F-33000 Bordeaux, France.
(5)Department of Neuroscience, University of the Basque Country (EHU), E-48940
Leioa, Spain; Centro de Investigación Biomédica en Red de Enfermedades
Neurodegenerativas (CIBERNED), Spain.
(6)Achucarro Basque Center for Neuroscience, E-48940 Leioa, Spain; Department of
Neuroscience, University of the Basque Country (EHU), E-48940 Leioa, Spain.
Electronic address: .
Microglia critically influence multiple sclerosis (MS) pathophysiology through
debris clearance, myelin repair, and modulation of neuroinflammation. These
processes are partly regulated by ATP-gated ion channel P2X4, predominantly
expressed in microglia. We previously reported that ivermectin (IVM), a positive
allosteric modulator of P2X4, modulates microglia activation and function in
myelin phagocytosis and promotes following lysolecithin-induced demyelination,
and ameliorates neurological symptoms in experimental autoimmune
encephalomyelitis (EAE). Here, we dissected the molecular and cellular basis of
this protective effect using P2X4mCherryIN knock-in (P2X4KI) mice, in which P2X4
is replaced by a non-internalized variant (P2X4KI), leading to increased surface
localization at the plasma membrane. Indeed, ATP-evoked currents were increased
in P2X4KI microglia. Transcriptomic analyses revealed that P2X4KI microglia
exhibit suppressed inflammatory and immune signaling pathways, suggesting that
P2X4 orchestrates microglial responses to injury. Both constitutive and
myeloid-specific P2X4KI mice showed a significant amelioration of EAE motor
deficits, although exclusively in females. Notably, ovariectomy abolished
P2X4-mediated protection in females whereas administration of progesterone gave
protection to P2X4KI males, confirming the requirement of female hormones for
P2X4-mediated protection. Indeed, progesterone potentiated P2X4 currents and
prolonged channel deactivation, revealing direct hormonal modulation of P2X4
gating. These findings identify P2X4 as a key regulator of neuroinflammatory
outcomes and reveal a previously unrecognized interaction between female
hormones and P2X4 that underlies sex-specific disease modulation. Targeting this
pathway may enable the development of precision therapies for MS.
Copyright © 2026. Published by Elsevier Inc.
DOI: 10.1016/j.bbi.2026.106771
PMID: 42013921
Conflict of interest statement: Declaration of Competing Interest The authors
declare that they have no known competing financial interests or personal
relationships that could have appeared to influence the work reported in this
paper.