A Tumor Necrosis Factor Receptor 1-Dependent Conversation between Central Nervous System-Specific T Cells and the Central Nervous System Is Required for Inflammatory Infiltration of the Spinal Cord

Abstract

Experimental autoimmune encephalomyelitis (EAE) is an autoimmune demyelinating disease of the central nervous system (CNS). Because of similarities in clinical symptoms and CNS histology, 1-5 EAE serves as a model for multiple sclerosis and can be induced in mice by either immunization with myelin protein or peptides 6 or by adoptive transfer of myelin-specific Th1 CD4 ϩ T cells. 7,8As a result, inflammatory cells consisting mostly of CD4 ϩ T lymphocytes and macrophages infiltrate the CNS leading to demyelination and neuronal damage. 9Tumor necrosis factor receptor 1 (TNFR1), also known as the p55 kd TNF receptor, binds to two ligands, TNF and lymphotoxin-␣. 10 The dominant signaling pathway for TNFR1 promotes inflammation by up-regulating inflammatory cytokines, chemokines, and adhesion molecules 11-17 and also suppresses apoptosis by the induction of IAPs (inhibitors of apoptosis) through nuclear factor (NF)-B-dependent pathways.18 TNFR1 also has the ability to induce apoptosis through a death domain in its cytoplasmic region that initiates the FADD-dependent extrinsic apoptotic pathway. 19Our previous experiments have demonstrated that TNFR1 contributes to the pathogenesis of EAE mainly by promoting CNS inflammation, 20 and thereby, in the absence of TNFR1 expression, clinical disease is limited. Through our adoptive transfer experiments we have found a dramatic difference in the location of encephalitogenic T cells within the CNS of wild-type (WT) versus TNFR1-null mice. Although we observed equivalent numbers of T cells in the CNS of TNFR1-deficient mice compared to WT mice, we found that the T cells in the TNFR1-null animals were confined to the leptomeninges and perivascular spaces of the spinal cord, whereas in the

Cerebral Microglia Recruit Monocytes into the Brain in Response to Tumor Necrosis Factorα Signaling during Peripheral Organ Inflammation

“…TNF␣ signaling via TNFR1 plays a dominant role in mediat- ing inflammation in numerous diseases (Probert et al, 2000;Gimenez et al, 2006). To determine whether differential TNF␣ signaling via TNFR1 or TNFR2 affects cerebral monocyte recruitment in BDR mice, we conducted recruitment studies in day 10 BDR mice deficient in TNFR1 or TNFR2.…”

The cellular response in neuroinflammation: The role of leukocytes, microglia and astrocytes in neuronal death and survival

“…In vitro data suggest that astrocyte interactions with the cerebrovasculature endothelium play a key role in the induction and maintenance of the tight junctions characteristic of the intact BBB. Furthermore, astrocyte production of pro-inflammatory cytokines such as TNFα play key roles in facilitating leukocyte extravasation from the bloodstream across the BBB into the CNS parenchyma [29][30][31][32]. Lastly, it is largely unexplored to what extent the many homeostatic functions of astrocytes such as the buffering of pH and glutamate are significantly altered by their cellular transition into "reactive" astrocytes.…”

Targeting of Tumor Necrosis Factor Alpha Receptors as a Therapeutic Strategy for Neurodegenerative Disorders

“…Akassoglou et al (1998) demonstrated a dominant role for TNFR1 signaling in TNF-mediated oligodendrocyte apoptosis and primary demyelination [147]. In addition, TNFR1 was suggested to contribute to inflammatory infiltration of the EAE spinal cord [148]. Interestingly, it was recently shown in different studies that administration of an antagonistic antibody that selectively targets TNFR1 ameliorated disease symptoms in the EAE mouse model [18,149].…”