TY - JOUR
T1 - CXCR2 Is Deregulated in ALS Spinal Cord and Its Activation Triggers Apoptosis in Motor Neuron-Like Cells Overexpressing hSOD1-G93A
AU - la Cognata, Valentina
AU - D'Amico, Agata Grazia
AU - Maugeri, Grazia
AU - Morello, Giovanna
AU - Guarnaccia, Maria
AU - Magrì, Benedetta
AU - Aronica, Eleonora
AU - D'Agata, Velia
AU - Cavallaro, Sebastiano
N1 - Funding Information: This research was funded by the IRIB-CNR project “A multi-omics approach for the study of neurodegeneration” (grant number: DSB.AD007.304 to S.C). E.A. was supported by ALS Stichting (grant “ALS Tissue Bank—NL”). Publisher Copyright: © 2023 by the authors.
PY - 2023/7/9
Y1 - 2023/7/9
N2 - Amyotrophic lateral sclerosis (ALS) is a multifactorial neurodegenerative disease characterized by progressive depletion of motor neurons (MNs). Recent evidence suggests a role in ALS pathology for the C-X-C motif chemokine receptor 2 (CXCR2), whose expression was found increased at both mRNA and protein level in cortical neurons of sporadic ALS patients. Previous findings also showed that the receptor inhibition is able to prevent iPSC-derived MNs degeneration in vitro and improve neuromuscular function in SOD1-G93A mice. Here, by performing transcriptional analysis and immunofluorescence studies, we detailed the increased expression and localization of CXCR2 and its main ligand CXCL8 in the human lumbar spinal cord of sporadic ALS patients. We further investigated the functional role of CXCR2/ligands axis in NSC-34 motor neuron-like cells expressing human wild-type (WT) or mutant (G93A) SOD1. A significant expression of CXCR2 was found in doxycycline-induced G93A-SOD1-expressing cells, but not in WT cells. In vitro assays showed CXCR2 activation by GROα and MIP2α, two murine endogenous ligands and functional homologs of CXCL8, reduces cellular viability and triggers apoptosis in a dose dependent manner, while treatment with reparixin, a non-competitive allosteric CXCR2 inhibitor, effectively counteracts GROα and MIP2α toxicity, significantly inhibiting the chemokine-induced cell death. Altogether, data further support a role of CXCR2 axis in ALS etiopathogenesis and confirm its pharmacological modulation as a candidate therapeutic strategy.
AB - Amyotrophic lateral sclerosis (ALS) is a multifactorial neurodegenerative disease characterized by progressive depletion of motor neurons (MNs). Recent evidence suggests a role in ALS pathology for the C-X-C motif chemokine receptor 2 (CXCR2), whose expression was found increased at both mRNA and protein level in cortical neurons of sporadic ALS patients. Previous findings also showed that the receptor inhibition is able to prevent iPSC-derived MNs degeneration in vitro and improve neuromuscular function in SOD1-G93A mice. Here, by performing transcriptional analysis and immunofluorescence studies, we detailed the increased expression and localization of CXCR2 and its main ligand CXCL8 in the human lumbar spinal cord of sporadic ALS patients. We further investigated the functional role of CXCR2/ligands axis in NSC-34 motor neuron-like cells expressing human wild-type (WT) or mutant (G93A) SOD1. A significant expression of CXCR2 was found in doxycycline-induced G93A-SOD1-expressing cells, but not in WT cells. In vitro assays showed CXCR2 activation by GROα and MIP2α, two murine endogenous ligands and functional homologs of CXCL8, reduces cellular viability and triggers apoptosis in a dose dependent manner, while treatment with reparixin, a non-competitive allosteric CXCR2 inhibitor, effectively counteracts GROα and MIP2α toxicity, significantly inhibiting the chemokine-induced cell death. Altogether, data further support a role of CXCR2 axis in ALS etiopathogenesis and confirm its pharmacological modulation as a candidate therapeutic strategy.
KW - CXCL1
KW - CXCL2
KW - CXCL8
KW - CXCR2
KW - GROα
KW - IL-8
KW - MIP2α
KW - amyotrophic lateral sclerosis
KW - inflammation
KW - neurodegeneration
KW - reparixin
UR - http://www.scopus.com/inward/record.url?scp=85165969335&partnerID=8YFLogxK
U2 - https://doi.org/10.3390/cells12141813
DO - https://doi.org/10.3390/cells12141813
M3 - Article
C2 - 37508478
SN - 2073-4409
VL - 12
JO - Cells
JF - Cells
IS - 14
M1 - 1813
ER -