CXCR2 Is Deregulated in ALS Spinal Cord and Its Activation Triggers Apoptosis in Motor Neuron-Like Cells Overexpressing hSOD1-G93A

Amyotrophic lateral sclerosis (ALS) is a multifactorial neurodegenerative disease characterized by progressive depletion of motor neurons (MNs). Recent evidence suggests 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 cortical sporadic patients. Previous findings also showed that inhibition able to prevent iPSC-derived MNs degeneration vitro improve neuromuscular function SOD1-G93A mice. Here, performing transcriptional analysis immunofluorescence studies, we detailed localization CXCR2 its main ligand CXCL8 human lumbar spinal cord We further investigated functional CXCR2/ligands axis NSC-34 neuron-like cells expressing wild-type (WT) or mutant (G93A) SOD1. A significant doxycycline-induced G93A-SOD1-expressing cells, but not WT cells. In assays activation GROα MIP2α, two murine endogenous ligands homologs CXCL8, reduces cellular viability triggers apoptosis dose dependent manner, while treatment with reparixin, non-competitive allosteric inhibitor, effectively counteracts MIP2α toxicity, significantly inhibiting chemokine-induced cell death. Altogether, data support etiopathogenesis confirm pharmacological modulation as candidate therapeutic strategy.