Concentration-dependent effects of the esterase inhibitor BNPP on macrophage migration and myelin phagocytosis

Wallerian degeneration of a peripheral nerve is mainly characterized by axo n and myelin degradation and is paralleled by a massive invasion of periphe ral macrophages into the nerve. These cells enter the nerve attracted by a cascade of chemokines and cytokines but require proteolytic and enzymatic f actors which enables them to cross the blood-nerve barrier. Here we investi gated whether U-naphthyl (alpha -NA) esterases - which have been shown to b e exclusively expressed in human monocytes - play a role during Wallerian d egeneration. These enzymes were blocked by the specific inhibitor bis(4-nit rophenyl)-phosphate (BNPP) in an established in vitro model of Wallerian de generation. Sciatic nerve segments of mice were co-cultured with peritoneal macrophages and BNPP was added to the cultures in various concentrations a nd at different timepoints. The macrophage numbers and myelin density in th e nerve segments and the myelin load of macrophages were evaluated. After B NPP treatment the macrophage number within the nerve was significantly dimi nished and the myelin load within the macrophages was decreased, resulting in elevated levels of preserved myelin within the nerves. These experiments clearly showed a double effect of the UNA esterase inhibitor BNPP on macro phages, First, it suggests a role for UNA esterases on the migratory potent ial of macrophages since their invasion into the nerves was diminished. Sec ond, the reduced myelin uptake is due to the inhibition of phagocytic capac ity of these cells by BNPP. The therapeutical use of this inhibitor for tre atment of autoimmune diseases such as multiple sclerosis or Guillain-Barre syndrome remains to be investigated. (C) 2001 Elsevier Science B.V. All rig hts reserved.