Role of Tumor Necrosis Factor Superfamily in Neuroinflammation and Autoimmunity

Abstract

Tumor necrosis factor superfamily (TNFSF) molecules play an important role in the activation, proliferation, differentiation, and migration of immune cells into the central nervous system (CNS). Several TNF superfamily molecules are known to control alloimmunity, autoimmunity, and immunity. Development of transgenic and gene knockout animals, and monoclonal antibodies against TNFSF molecules have increased our understanding of individual receptor-ligand interactions, and their intracellular signaling during homeostasis and neuroinflammation. A strong clinical association has been observed between TNFSF members and CNS autoimmunity such as multiple sclerosis and also in its animal model experimental autoimmune encephalomyelitis. Therefore, they are promising targets for alternative therapeutic options to control autoimmunity. Although, TNFSF ligands are widely distributed and have diverse functions, we have restricted the discussions in this review to TNFSF receptor-ligand interactions and their role in the pathogenesis of neuroinflammation and CNS autoimmunity.

Keywords: autoimmunity; blood–brain barrier; multiple sclerosis; neuroinflammation; tumor necrosis factor.

Figure 1

Interaction of TNF superfamily ligand and its receptors. The vertical dotted lines represent the cytoplasmic membrane where receptors or ligands are attached. The horizontal dotted line shows the receptor and its cognate ligand interaction.

Figure 2

TNFSF receptor–ligand interaction at endothelial BBB during neuroinflammation. BBB endothelial cells express TNFSF receptors during inflammatory condition, and interact with the TNFSF ligand in soluble form as well as on infiltrating immune cells. (I) Inflamed BBB endothelial cells express CD40. Interaction of CD40 with CD40L-expressing activated immune cells leads to up-regulation of adhesion molecules and chemokine secretion by BBB endothelial cells. This promotes the migration of pathogenic immune cell subsets into the CNS parenchyma. (II) OX40 expression can be induced in BBB endothelial cells during inflammation, which facilitates the migration of OX40L⁺ immune cells across the BBB. (III) Under inflammatory conditions, BBB endothelial cells up-regulate TNFR-1, which bind to soluble TNF secreted from various immune cells, such as activated Th1 cells, B cells, macrophages, and NK cells. Binding of TNF with TNFR-1 increases the paracellular permeability of BBB endothelial vessels. (IV) Inflamed BBB endothelial cells express Fn14 that binds to soluble TWEAK molecules. This leads to the up-regulation of cytokines, chemokines, cell adhesion molecules, and matrix metalloprotenase-9 (MMP-9). Increased expression of CCL2 and ICAM-1 facilitates the migration of pathogenic immune cells; whereas MMP-9 helps in the degradation of laminin molecules present in the basement membrane, resulting in loosening of the BBB.

Figure 3

TNFSF receptor–ligand interaction in the CNS parenchyma during neuroinflammation. TNFSF receptors and ligands are expressed on both CNS infiltrating effector immune cells and CNS-resident cells. The interaction of this receptor–ligand greatly influences the outcome of neuroinflammatory disease like multiple sclerosis and EAE. (I) Both neurons and oligodendrocytes express functional DR5 in the CNS during EAE. DR5 on the neurons as well as on oligodendrocytes interacts with TRAIL molecules present on either microglial cells or infiltrating immune cells, leading to apoptosis of DR5-expressing cells. (II) Activated astrocytes and microglial cells up-regulate FasL expression on their surface. The interaction of FasL with Fas-expressing cells leads to apoptosis and elimination of pathogenic effector immune cells. (III) Neuronal cells express TNF and that can interact with TNFR-1 present on various CNS-resident cells, such as astrocytes, microglial cells, and oligodendrocytes. Interactions of TNF with TNFR-1-expressing cells lead to apoptosis of TNFR-1⁺ cells. (IV) Mast cells are known to localize close to the astrocytes during EAE in the brain. CD40L present on mast cells interact with CD40-expressing astrocytes, which induces increased production of inflammatory cytokines and chemokines. Local production of inflammatory molecules can augment inflammation and tissue damage in the CNS.