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Cited by 20Multiple Sclerosis Research StudiesReceptor Mechanisms and SignalingPsoriasis: Treatment and Pathogenesis

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

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Parodi, Benedetta, Sanna, Alessia, Cedola, Alessia, Uccelli, Antonio, Kerlero de Rosbo, Nicole·2021·Frontiers in Immunology
DOI 10.3389/fimmu.2021.655212PMC PMC8167049
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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.

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Metadata

Authors
Parodi, B., Sanna, A., Cedola, A., Uccelli, A., & Kerlero de Rosbo, N.
Affiliations
  • University of Genoa (IT)
  • Ospedale Policlinico San Martino (IT)
Corresponding author
Parodi, Benedetta
ORCID
Venue
Frontiers in Immunology
Publisher
Frontiers Media SA
Published
2021-05-18
Volume
12
Pages
655212-655212
ISSN
1664-3224 (ISSN-L)
DOI
10.3389/fimmu.2021.655212
PMC
PMC8167049
OpenAlex
W3163740214
Cited by
20
References
1
Citations by year
2026: 2 · 2025: 6 · 2024: 2 · 2023: 4 · 2022: 5 · 2021: 1
FWCI
2.00
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Immunology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • CINECA IRIS Institutial Research Information System (University of Genoa) (submittedVersion)
Funders
Biogen
Topics
  • Health Sciences › Medicine › Clinical Neurology › Multiple Sclerosis Research Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
  • Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
Keywords
monomethyl fumarate, dimethyl fumarate, multiple sclerosis, dendritic cells, T cell differentiation, intestinal epithelial cells, cyclooxygenase-2, skin flushing, gastrointestinal adverse effects, experimental autoimmune encephalomyelitis, intestinal inflammation, aldehyde dehydrogenase, TGF-beta, lamina propria, mesenteric lymph nodes, pleiotropic signaling, immunosuppressants
MeSH terms
Animals, Dendritic Cells, Disease Models, Animal, Encephalomyelitis, Autoimmune, Experimental, Fumarates, Immunohistochemistry, Immunosuppressive Agents, Intestinal Mucosa, Lymph Nodes, Multiple Sclerosis, Signal Transduction, Biomarkers, Mice, Knockout, Mitogen-Activated Protein Kinase 1, Receptors, G-Protein-Coupled, Mitogen-Activated Protein Kinase 3, Mice

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