Hydroxycarboxylic acid receptor 2 mediates dimethyl fumarate’s protective effect in EAE

Chen, Hui; Assmann, Julian C.; Krenz, Antje; Rahman, Mahbubur; Grimm, Myriam; Karsten, Christian M.; Köhl, Jörg; Offermanns, Stefan; Wettschureck, Nina; Schwaninger, Markus

doi:10.1172/jci72151

Cited by 254 publications

(227 citation statements)

References 26 publications

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“…In this regard, MMF is a potent agonist of the hydroxycarboxylic acid receptor 2 (HCAR2) (GPR109A) (34). It was also observed that HCAR2 deficiency prevented the beneficial effects of DMF treatment in acute EAE in mice, suggesting that HCAR2 may, indeed, be a principal target in DMF therapy of EAE (35). Our results in this report, highlighting the importance of the Nrf2-independent immunologic and clinical effects of DMF, are complementary with studies that identified HCAR2 as a potential target for DMF (34)(35)(36).…”

Section: Discussionmentioning

confidence: 99%

Dimethyl fumarate treatment induces adaptive and innate immune modulation independent of Nrf2

Schulze-Topphoff

Varrin‐Doyer

Pekarek

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

247

213

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Dimethyl fumarate (DMF) (BG-12, Tecfidera) is a fumaric acid ester (FAE) that was advanced as a multiple sclerosis (MS) therapy largely for potential neuroprotection as it was recognized that FAEs are capable of activating the antioxidative transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway. However, DMF treatment in randomized controlled MS trials was associated with marked reductions in relapse rate and development of active brain MRI lesions, measures considered to reflect CNS inflammation. Here, we investigated the antiinflammatory contribution of Nrf2 in DMF treatment of the MS model, experimental autoimmune encephalomyelitis (EAE). C57BL/6 wild-type (WT) and Nrf2-deficient (Nrf2 −/− ) mice were immunized with myelin oligodendrocyte glycoprotein (MOG) peptide 35-55 (p35-55) for EAE induction and treated with oral DMF or vehicle daily. DMF protected WT and Nrf2 −/− mice equally well from development of clinical and histologic EAE. The beneficial effect of DMF treatment in Nrf2 −/− and WT mice was accompanied by reduced frequencies of IFN-γ and IL-17-producing CD4 + cells and induction of antiinflammatory M2 (type II) monocytes. DMF also modulated B-cell MHC II expression and reduced the incidence of clinical disease in a B-cell-dependent model of spontaneous CNS autoimmunity. Our observations that oral DMF treatment promoted immune modulation and provided equal clinical benefit in acute EAE in Nrf2 −/− and WT mice, suggest that the antiinflammatory activity of DMF in treatment of MS patients may occur through alternative pathways, independent of Nrf2.multiple sclerosis | dimethyl fumarate | Nrf2 | EAE | M2 monocytes

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Section: Discussionmentioning

confidence: 99%

Dimethyl fumarate treatment induces adaptive and innate immune modulation independent of Nrf2

Schulze-Topphoff

Varrin‐Doyer

Pekarek

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

247

213

View full text Add to dashboard Cite

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“…14). The activation of HCA 2 inhibits adhesion and migration of neutrophils and induces the death of these cells in vitro 38,39 . Whether modulation of neutrophils contributes to the neuroprotective effects of HCA 2 in cerebral ischemia is still unclear.…”

Section: Discussionmentioning

confidence: 99%

“…Our data now demonstrate that the neuroprotective activity of nicotinic acid depends on HCA 2 , very much as that of BHB and ketogenic diet. HCA 2 may also mediate the protective effect of dimethyl fumarate and its metabolite monomethyl fumarate in multiple sclersosis 38,61 . Novel HCA 2 agonists showed evidence of a superior potency or of fewer side effects than nicotinic acid during clinical trials testing anti-dyslipidemic effects 16,62,63 .…”

Section: Discussionmentioning

confidence: 99%

The β-hydroxybutyrate receptor HCA2 activates a neuroprotective subset of macrophages

et al. 2014

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The ketone body b-hydroxybutyrate (BHB) is an endogenous factor protecting against stroke and neurodegenerative diseases, but its mode of action is unclear. Here we show in a stroke model that the hydroxy-carboxylic acid receptor 2 (HCA 2 , GPR109A) is required for the neuroprotective effect of BHB and a ketogenic diet, as this effect is lost in Hca2 À / À mice. We further demonstrate that nicotinic acid, a clinically used HCA 2 agonist, reduces infarct size via a HCA 2 -mediated mechanism, and that noninflammatory Ly-6C Lo monocytes and/or macrophages infiltrating the ischemic brain also express HCA 2 . Using cell ablation and chimeric mice, we demonstrate that HCA 2 on monocytes and/or macrophages is required for the protective effect of nicotinic acid. The activation of HCA 2 induces a neuroprotective phenotype of monocytes and/or macrophages that depends on PGD 2 production by COX1 and the haematopoietic PGD 2 synthase. Our data suggest that HCA 2 activation by dietary or pharmacological means instructs Ly-6C Lo monocytes and/or macrophages to deliver a neuroprotective signal to the brain.

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“…35 Moreover, it was recently observed that HCA 2 mediates the therapeutic effects of DMF/MMF in mouse models of experimental autoimmune encephalomyelitis. 36 These authors showed that MMF exerts HCA 2 -dependent and HCA 2 -independent effects on various neutrophil functions. Similar mechanisms might also apply to NK cells, particularly the release of Granzyme B from these cells, explaining the differential effects of anti-NKp46, which is currently being investigated in our laboratory.…”

Section: Discussionmentioning

confidence: 99%

Monomethyl fumarate augments NK cell lysis of tumor cells through degranulation and the upregulation of NKp46 and CD107a

et al. 2014

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Dimethyl fumarate (DMF) is a new drug used to treat multiple sclerosis (MS) patients. Here, we examined the effects of DMF and the DMF metabolite monomethyl fumarate (MMF) on various activities of natural killer (NK) cells. We demonstrated that MMF augments the primary CD56 1 , but not CD56 2 , NK cell lysis of K562 and RAJI tumor cells. MMF induced NKp46 expression on the surface of CD56 1 , but not CD56 2 , NK cells after incubation for 24 h. This effect was closely correlated with the upregulation of CD107a expression on the surface of CD56 1 NK cells and the induction of Granzyme B release from these cells through this metabolite. An anti-NKp46 antibody inhibited the MMF-induced upregulation of CD107a and the lysis of tumor cells through CD56 1 NK cells. Thus, these results are the first to show that MMF augments CD56 1 NK cell lysis of tumor target cells, an effect mediated through NKp46. This novel effect suggests the use of MMF for therapeutic and/or preventive protocols in cancer.

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Hydroxycarboxylic acid receptor 2 mediates dimethyl fumarate’s protective effect in EAE

Cited by 254 publications

References 26 publications

Dimethyl fumarate treatment induces adaptive and innate immune modulation independent of Nrf2

Dimethyl fumarate treatment induces adaptive and innate immune modulation independent of Nrf2

The β-hydroxybutyrate receptor HCA2 activates a neuroprotective subset of macrophages

Monomethyl fumarate augments NK cell lysis of tumor cells through degranulation and the upregulation of NKp46 and CD107a

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