Chemokine MIP-2/CXCL2, acting on CXCR2, induces motor neuron death in primary cultures.
OBJECTIVE
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.
De Paola
Massimiliano
M
Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italia. depaola@marionegri.it
Buanne
Pasquale
P
Biordi
Leda
L
Bertini
Riccardo
R
Ghezzi
Pietro
P
Mennini
Tiziana
T
D000818:Animals; D016923:Cell Death / Q000502:physiology*; D002478:Cells, Cultured; D054426:Chemokine CXCL2 / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D009046:Motor Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D023063:Receptors, Interleukin-8B / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology
D054426:Chemokine CXCL2; D023063:Receptors, Interleukin-8B; D013449:Sulfonamides; C490707:reparixin