TY - JOUR
T1 - CXCR2 increases in ALS cortical neurons and its inhibition prevents motor neuron degeneration in vitro and improves neuromuscular function in SOD1G93A mice
AU - la Cognata, Valentina
AU - Golini, Elisabetta
AU - Iemmolo, Rosario
AU - Balletta, Sara
AU - Morello, Giovanna
AU - de Rosa, Carla
AU - Villari, Ambra
AU - Marinelli, Sara
AU - Vacca, Valentina
AU - Bonaventura, Gabriele
AU - Dell'Albani, Paola
AU - Aronica, Eleonora
AU - Mammano, Fabio
AU - Mandillo, Silvia
AU - Cavallaro, Sebastiano
N1 - Funding Information: The work at IRIB was supported by grants i) ?Development and application of biosensoristic technologies in genomics? by European Social Fund operational program for the Sicily region (Italy), PO FESR Sicily 2014?2020 (CIP 2014.IT.05.SFOP.014/3/10.4/9.2.10/0008) and ii) ?Flagship Project InterOmics - Cell-based Omics for research applications in precision medicine? by National Research Council ? CNR. The work at IBBC was supported by Infrafrontier-I3 project under EU contract Grant Agreement Number 312325 of the EC FP7; Project of strategic interest ?Aging? from National Research Council ? CNR. Funding Information: The work at IRIB was supported by grants i) “Development and application of biosensoristic technologies in genomics” by European Social Fund operational program for the Sicily region (Italy), PO FESR Sicily 2014–2020 (CIP 2014.IT.05.SFOP.014/3/10.4/9.2.10/0008) and ii) " Flagship Project InterOmics - Cell-based Omics for research applications in precision medicine" by National Research Council – CNR. The work at IBBC was supported by Infrafrontier-I3 project under EU contract Grant Agreement Number 312325 of the EC FP7; Project of strategic interest “Aging” from National Research Council – CNR. Publisher Copyright: © 2021
PY - 2021/12/1
Y1 - 2021/12/1
N2 - Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease characterized by depletion of motor neurons (MNs), for which effective medical treatments are still required. Previous transcriptomic analysis revealed the up-regulation of C-X-C motif chemokine receptor 2 (CXCR2)-mRNA in a subset of sporadic ALS patients and SOD1G93A mice. Here, we confirmed the increase of CXCR2 in human ALS cortex, and showed that CXCR2 is mainly localized in cell bodies and axons of cortical neurons. We also investigated the effects of reparixin, an allosteric inhibitor of CXCR2, in degenerating human iPSC-derived MNs and SOD1G93A mice. In vitro, reparixin rescued MNs from apoptotic cell death, preserving neuronal morphology, mitochondrial membrane potential and cytoplasmic membrane integrity, whereas in vivo it improved neuromuscular function of SOD1G93A mice. Altogether, these data suggest a role for CXCR2 in ALS pathology and support its pharmacological inhibition as a candidate therapeutic strategy against ALS at least in a specific subgroup of patients.
AB - Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease characterized by depletion of motor neurons (MNs), for which effective medical treatments are still required. Previous transcriptomic analysis revealed the up-regulation of C-X-C motif chemokine receptor 2 (CXCR2)-mRNA in a subset of sporadic ALS patients and SOD1G93A mice. Here, we confirmed the increase of CXCR2 in human ALS cortex, and showed that CXCR2 is mainly localized in cell bodies and axons of cortical neurons. We also investigated the effects of reparixin, an allosteric inhibitor of CXCR2, in degenerating human iPSC-derived MNs and SOD1G93A mice. In vitro, reparixin rescued MNs from apoptotic cell death, preserving neuronal morphology, mitochondrial membrane potential and cytoplasmic membrane integrity, whereas in vivo it improved neuromuscular function of SOD1G93A mice. Altogether, these data suggest a role for CXCR2 in ALS pathology and support its pharmacological inhibition as a candidate therapeutic strategy against ALS at least in a specific subgroup of patients.
KW - Amyotrophic lateral sclerosis
KW - CXCR2
KW - IL-8
KW - Motor neurons
KW - Neurodegeneration
KW - Reparixin
KW - SOD1G93A mouse
KW - iPSC
UR - http://www.scopus.com/inward/record.url?scp=85118493557&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.nbd.2021.105538
DO - https://doi.org/10.1016/j.nbd.2021.105538
M3 - Article
C2 - 34743985
SN - 0969-9961
VL - 160
JO - Neurobiology of Disease
JF - Neurobiology of Disease
M1 - 105538
ER -