Chemokine MIP-2/CXCL2, Acting on CXCR2, Induces Motor Neuron Death in Primary Cultures

Abstract

Objectives: Chemokines are implicated in many diseases of the central nervous system (CNS). Although their primary role is to induce inflammation through the recruitment of leukocytes by their chemotactic activity, they may also have direct effects on neuronal cells. We evaluated the expression of CXCR1 and CXCR2 and investigated the effect of CXCR2 activation by the agonist MIP-2 (CXCL2) on primary cultured motor neurons. To specifically assess the role of CXCR2 in the neurotoxicity induced by MIP-2, we used the CXCR1/2 inhibitor reparixin and studied the effect of the chemokine on motor neuron cultures from CXCR2-deficient mice. Methods: Primary motor neurons prepared from rat or mouse embryos were treated with MIP-2 and reparixin. Motor neuron viability and receptor expression were assessed by immunocytochemical techniques. Results: Rat primary motor neurons expressed CXCR2 receptors and recombinant rat MIP-2 induced dose-dependent neurotoxicity. This neurotoxicity was counteracted by reparixin, a specific CXCR1/2 inhibitor, and was not observed in motor neurons from CXCR2-deficient mice. Conclusions: CXCR2 activation might directly contribute to motor neuron degeneration. Thus, chemokines acting on CXCR2, including IL-8, may have direct pathogenic effects in CNS diseases, independent of the induction of leukocyte migration.

Selection and Prioritization of Candidate Drug Targets for Amyotrophic Lateral Sclerosis Through a Meta-Analysis Approach

“…3b and 5). These data are corroborated by recent in vitro studies showing that the activation of CXCR2 and its ligand IL-8 induces neurotoxicity and directly contributes to motor neuron degeneration (De Paola et al 2007). The modulation of CXCR2 may thus represent a potential neuroprotective strategy in ALS therapy.…”

The sciatic nerve injury model in pre-clinical research

“…However, although many immortalized and primary neuronal and glial cell lines (Moreno-Flores et al, 2006, Hara et al, 2008Sak and Illes, 2005;Shastry et al, 2001;Trotter, 1993, De Paola et al, 2007, Scanlin et al, 2008 have been proposed for replacing in vivo pre-clinical models, their potential is still limited and, yet, their real capability of predicting nerve regeneration is questionable (Cirillo et al, 2014). The potential of the in vitro investigation of nerve regeneration may be higher if the culturing conditions mimic the 3D organization of the nerve.…”

Increased Il-8 Levels in the Cerebrospinal Fluid of Patients with Amyotrophic Lateral Sclerosis

“…Interestingly, studies from our group documented that activation ofCXCR-2 induces a dose-dependent death on cultured motor neurons (19), thus suggesting that increased IL-8 production by activated glial cells could contribute to motor neuron degeneration in ALS patients. The efficacy or reparixin, an orally active CXCRl/2 inhibitor, to prevent CXCL2-induced death of motor neurons (25), warrants future investigations about the possible neuroprotective role of CXCR2 inhibitors.…”

“…We have recently reported that activation of CXCR2 induces dose-dependent death in cultured motor neurons (19). In this study we tested the hypothesis that CSF levels of IL-8 in ALS patients are higher than those of the general population.…”