TNFR1/2 are expressed in all cell types and activate both cellular responses [155–157] and mediate anti-apoptotic and inflammatory responses through the recruitment of TNF receptor-associated factor (TRAF) 2 and receptor-associated protein (RIP)-1, which are critical in the activation of NF-kB, c-Jun NH2 terminal kinase (JNK) and mitogen-activated protein kinase (MAPK) [158]. Although the two receptors have similar extracellular sequences that are rich in cysteine, the hallmark

of the TNF superfamily, TNFR1 alone possesses a cytoplasmic death domain, an 80 amino acid sequence that rapidly engages the apoptotic signalling pathway of the cells [159]. Because dysregulated TNF-α secretion has been implicated in several autoimmune diseases, blocking TNF-α production has therefore been shown to have beneficial effects against various autoimmune diseases [160]. However, the timing IBET762 of TNF-α therapy is critical for its therapeutic outcome. For example,

administration of dimerized TNFR1 (TNFR1-IgG) to block TNF-α-TNFR interaction after the onset of experimental autoimmune neuritis (EAN) failed to alter the course of disease [161]. However, TNFR1-IgG therapy when administered at the onset of disease delayed EAN and was accompanied by inhibition of blood–nerve barrier permeability and Pirfenidone inflammation [161]. Interestingly, blockade of TNF-α–TNFR interaction by specific fusion proteins during CIA in DBA/1 strain versus endogenous TNFR1 gene deletion yielded mixed results. Treatment of CIA mice with TNFR1–IgG1 fusion protein to neutralize systemic TNF-α before the onset

of clinical disease showed inhibition of clinical disease in these mice [162]. In contrast, induction of CIA in TNFR1−/− mice on a DBA/1 background showed an initial milder form of disease but, with time, the severity of joint disease was comparable among wild-type and TNFR1−/− mice [162]. The importance of TNFR1 gene deletion and increased severity of CIA was suggested further by the observation that mainly TNFR1 gene deletion caused development and exacerbation of inflammation [162,163]. Nitroxoline In contrast to the effect of TNFR1 gene deletion, which showed severe arthritis [162,163], suppression of MOG-induced EAE is less severe in TNFR1−/− mice [164]. Also, TNFR1−/− mice who have defective IFN-γ-dependent nitric oxide (NO) production from macrophages and significantly reduced CD113+ and CD4+ cells within the target organ are resistant to the induction of EAU [165,166]. In accordance, blockade of TNF-TNFR by soluble TNFR1–Ig fusion protein was shown to inhibit clinical symptoms associated with EAE [167,168]. To understand further the relative roles of TNFRI and TNFRII in MOG-induced EAE, Suvannavejh et al. observed that disease was reduced significantly in TNFR1−/−/2−/− double knock-out and TNFR1−/− but not in TNFR2−/− mice.