Hydroxycarboxylic Acid Receptor 2, a Pleiotropically Linked Receptor for the Multiple Sclerosis Drug, Monomethyl Fumarate. Possible Implications for the Inflammatory Response

Abstract

Monomethyl fumarate (MMF), metabolite of dimethyl fumarate (DMF), an immunosuppressive drug approved for the treatment of multiple sclerosis (MS), is a potent agonist for hydroxycarboxylic acid receptor 2 (HCAR2), eliciting signals that dampen cell activation or lead to inflammation such as the skin flushing reaction that is one of the main side effects of the treatment, together with gastrointestinal inflammation. Our aim is to further understand the molecular basis underlying these differential effects of the drug. We have used wild-type and HCAR2 knock-out mice to investigate, in vitro and ex vivo under steady-state and pathological conditions, the HCAR2-mediated signaling pathways activated by MMF in dendritic cells (DC), which promote differentiation of T cells, and in intestinal epithelial cells (IEC) where activation of a pro-inflammatory pathway, such as the cyclooxygenase-2 pathway involved in skin flushing, could underlie gastrointestinal side effects of the drug. To understand how DMF treatment might impact on gut inflammation induced by experimental autoimmune encephalomyelitis (EAE), the animal model for MS, we have used 3D X-ray phase contrast tomography and flow cytometry to monitor possible intestinal alterations at morphological and immunological levels, respectively. We show that HCAR2 is a pleiotropically linked receptor for MMF, mediating activation of different pathways leading to different outcomes in different cell types, depending on experimental in-vitro and in-vivo conditions. In the small intestine of EAE-affected mice, DMF treatment affected migration of tolerogenic DC from lamina propria to mesenteric lymph nodes, and/or reverted their profile to pro-inflammatory, probably as a result of reduced expression of aldehyde dehydrogenase and transforming growth factor beta as well as the inflammatory environment. Nevertheless, DMF treatment did not amplify the morphological alterations induced by EAE. On the basis of our further understanding of MMF signaling through HCAR2, we suggest that the pleiotropic signaling of fumarate via HCAR2 should be addressed for its pharmaceutical relevance in devising new lead compounds with reduced inflammatory side effects.

GANAB and N-Glycans Substrates Are Relevant in Human Physiology, Polycystic Pathology and Multiple Sclerosis: A Review

“…This small molecule is thought to affect disease progression and neuroinflammation by acting on the Hydroxycarboxylic Acid Receptor 2 (HCAR2) as well [454]. However, the PERK involvement suggests an additional MOA concerning ER stress in MS.…”

Innovative hierarchical X-ray imaging approach to assess the sequential evolution of multi-organ damage in multiple sclerosis

“…Although we had observed cellular in ltration of the villi by immuno uorescence in ongoing disease 39 , XPCT enabled us to obtain a more pertinent quantitative evaluation based on the 3D volume of the villi, and therefore a longitudinal monitoring of cellular in ltration, which showed a peak at clinical disease onset and had decreased four days after. Such data are possibly commensurate with the observation that, in EAE induced by adoptive transfer of encephalitogenic T cells, these cells in ltrate the gut lamina propria at an early stage of EAE when they are not detected in the CNS, but can be traced to the CNS at a later stage, when they have decreased in the gut 4 .…”

“…Although it is now recognized that gastrointestinal manifestations are frequent in MS, and gut in ammation has been described in EAE, little is known as yet about the structural and/or cellular alterations in the gut of EAE animals. Nevertheless, a decrease in intestinal barrier integrity, together with morphological alterations, was observed in mice induced for EAE prior to clinical disease onset 3 and our recent publication 39 , which combined XPCT and immuno uorescence analysis, reported morphological alterations accompanied by in ltration of in ammatory cells in mice with ongoing disease 39 . In the present study, 3D XPCT permitted the clear visualization of the massive cellular in ltration in the villi.…”

The Effects of Nuclear Factor Erythroid 2 (NFE2)-Related Factor 2 (Nrf2) Activation in Preclinical Models of Peripheral Neuropathic Pain

“…Furthermore, the dimethyl fumarate-induced antinociceptive activity was retained in wildtype mice, but lost in both male and female Nfe2l2 −/− mice with SNI as well as when treated with the Nrf2 inhibitor trigonelline [ 144 ]. It is important to note that besides targeting Nrf2, dimethyl fumarate and its metabolite monomethyl fumarate are potent agonists for the hydroxycarboxylic acid receptor 2 (HCAR2) and are approved for the treatment of multiple sclerosis [ 156 , 157 , 158 ]. HCAR2 also regulated neuropathic pain plasticity in CCI and SNI models of neuropathic pain and dimethyl fumarate alleviated the neuropathic pain-induced hypersensitivities [ 159 ].…”