Uveitis is comprised of a variety of a heterogeneous group of disorders with uncertain etiology and pathogenesis. Because of the limit in obtaining samples at ocular level, various EAU animal models have been developed for studying and understanding this pathology. Numerous therapeutic agents have been discovered, which have been put into successful clinical use (Bansal et al. 2015).
Dimethylfumarate is commonly prescribed as a first-line agent with favourable safety and efficacy profiles. The potential benefits of DMF against other diseases appears pathogenically different (Kourakis et al. 2020). In the study outlined here, we examined the potential anti-inflammatory and immunomodulatory effect of DMF on the experimental model of autoimmune uveitis with regards to systemic levels of NO and TNF-α production, retina histological changes, and local expression of iNOS, CD68, CD20, CD25, CD4 and CD8.
Dimethylfumarate is a methyl ester of fumaric acid registered for the treatment of relapsing forms of Multiple Sclerosis (Kappos et al. 2008; Gold 2012; Michell-Robinson et al. 2015) and psoriasis (Litjens et al. 2004; Reszke and Szepietowski 2020). DMF influences a variety of cell types and molecules pathways involved in inflammatory mechanisms. Indeed, Wilms et al. (2010) demonstrated that DMF exerts an inhibitory effect on the proinflammatory response characterised by increased microglial and astrocytic synthesis of NO, IL-1, IL-6 and TNF-α in an in vitro model of brain inflammation. In our conditions, we reported with interest a significant decrease of systemic NO and TNF-α level after DMF treatment. In the same line, we showed a positive correlation between the NO and the TNF-α systemic production (Fig. 2C).
As previously reported by our team, during EAU activity, a significant proportion of damages in ocular structures was observed and attributed mainly to nitric oxide (Djeraba et al. 2010; Arroul-Lammali et al. 2012; Touri et al. 2019). In addition, TNF-α, has been shown to be an important cytokine involved in alteration of ocular tissue (Dick et al. 2004). The histological structure of retina showed an alteration and disorganization of different layers (Fig. 3C). Interestingly, the damage observed in retina architecture with significant expression of iNOS, CD68 and CD20, was related to establishment of inflammatory reaction (P < 0.005, Table 1, Fig. 5C, H and M). Heiligenhaus et al. (2011) have used an anti-CD20 monoclonal antibody (rituximab) for the treatment of severe uveitis associated with juvenile idiopathic arthritis.
Intragastric administration of DMF in Wistar rats caused an amelioration of tissue architecture and an important decrease of inflammatory cells infiltration (CD68, CD20). These observations correlate with down-regulation of iNOS expression and up regulation of the Treg markers (CD4 and CD25) in DMF/Uveoretinitis group. Pitarokoili et al. (2019) demonstrated that DMF exhibited an immunomodulatory effect by an increase of regulatory T cells (CD4+ CD25+), exerting a protective role in experimental neuritis.
We noted a little expression of CD8 in Uveoretinitis and DMF/Uveoretinitis groups. In fact, Calder et al. (1993) suggest that depleting CD8 + cells had no effect on the course of disease and that CD8 + cells do not play a crucial role in the immunoregulation of EAU.
Fumarates are potent therapeutic compounds that exert pleiotropic immunomodulatory effects. Multiple pathways have been implicated in mediating these effects, the cytoprotective and anti-oxidant responses through the strong potentiation of the Nrf2 pathway, and the anti-inflammatory effect by inhibition of NF-κβ pathway (Gillard et al. 2015). DMF attenuate colon injury, pro-inflammatory cytokine and adhesion molecule production, and NF-κβ signalling, in experimental rodent models of colitis (Casili et al. 2015). In mouse models of Parkinson’s disease, DMF reduced damage and degeneration to preserve neuronal populations by upregulating Nrf2-dependent antioxidant genes and suppressing NF-κβ-mediated inflammation (Lastres-Becker et al. 2016; Campolo et al. 2017). In the same context of inflammatory conditions, it was reported that COX-2 plays an important role in inflammation during experimental autoimmune uveitis (Shiratori et al. 2004). Lal et al (2021) have reported that DMF treatment reduced the COX-2 levels. The anti-arthritic activity of DMF may be mediated by the activation of the Nrf2/HO-1 pathway, which reduced oxidative damage and inflammation.
NF-κβ is recognized as a central mediator in the pathophysiology of many chronic inflammatory diseases, which lead to an increased risk of ocular inflammation. Moreover, the expression of TNF-α and iNOS are transcriptionally regulated by the transcription factor NF-κβ. DMF showed inhibition of NF-κβ activity in an Nrf2-independent manner (Gillard et al. 2015).
In conclusion, our analysis of local retinal inflammatory responses using an experimental autoimmune uveitis could be in part related to the increased expression of inflammatory markers such as iNOS, CD68, CD20 and CD4. Dimethylfumarate represents a promising approach for the treatment of EAU. Our results suggest that DMF appears to be more effective in reducing inflammatory effects in the retina and could constitute a good candidate for monitoring an acute ocular inflammatory diseases.