| Leukocyte recruitment into tissues in response to infection or injury is a crucial event for the elimination of pathogens to protect the host. However, when leukocytes invade the central nervous system (CNS) and neuromflammatory disorders result, neurological function may be compromised. Infiltration of the CNS, predominantly by T cells and macrophages, characterizes Multiple Sclerosis and its animal counterpart, Experimental Autoimmune Encephalomyelitis (EAE).; Autoreactive T cells that initiate EAE produce Th1 cytokines (e.g., IFNgamma, TNFalpha). Nevertheless, previous studies also indicated an unnecessary or even protective role for IFNgamma in EAE. I have identified a novel role for IFNgamma in my studies using IFNgamma- or IFNgammaR-knockout mice. IFNgamma promotes the expression of the chemokines RANTES, MIP-1alpha, and MCP-1, which recruit mononuclear cells in the CNS to induce a non-lethal remitting EAE. Without IFNgamma, the chemokines MIP-2 and TCA-3, and polymorphonuclear leukocytes prevail, producing an unusually lethal EAE. MIP-1alpha is, however, dispensable in recruiting mononuclear cells, as EAE could still be induced in mice deficient in MIP-1alpha or its CCRS receptor.; To examine how much T cells depend on the cooperation with macrophages in the CNS to induce EAE, selective depletion of peripheral macrophages in mice was achieved by intravenous administration of clodronate-loaded liposomes. Treated mice showed no clinical signs of EAE following adoptive transfer of myelin-reactive T cells, but an altered distribution of leukocytes. These leukocytes were confined within the perivascular or meningeal space, not invading the CNS parenchyma. Levels of TNFalpha and inducible nitric oxide synthase (iNOS) in the CNS were reduced in these asymptomatic macrophage-depleted mice compared to untreated mice with EAE. In these asymptomatic mice, NOS expression was restricted to parenchymal astrocytes. In mice with EAE, however, both macrophages/microglia and astrocytes in infiltrates expressed NOS. Surprisingly, some astrocytes that were distant from infiltrates also expressed NOS, thus suggesting that astrocytes may modulate leukocyte infiltration via release of NO through their foot processes in the blood-brain barrier. Collectively, my data propose a model of a dynamic network in which the interplay among cytokines, chemokines and nitric oxide, may determine the magnitude, the composition, or the resolution of inflammatory infiltrates, as well as the clinical outcome of EAE. |
