Fumarates improve psoriasis and multiple sclerosis by inducing type II dendritic cells

Ghoreschi, Kamran; Brück, Jürgen; Kellerer, Christina; Deng, Cheng; Peng, Haiyan; Rothfuss, Oliver C.; Hussain, Rehana Z.; Gocke, Anne R.; Respa, Annedore; Glocova, Ivana; Valtcheva, Nadejda; Alexander, Eva; Feil, Susanne; Feil, Robert; Schulze‐Osthoff, Klaus; Rupec, Rudolf A.; Lovett-Racke, Amy E.; Dringen, Ralf; Racke, Michael K.; Röcken, Martin

doi:10.1084/jem.20100977

Cited by 325 publications

(377 citation statements)

References 59 publications

(134 reference statements)

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“…In this study, we have identified Langerin neg cDCs as the critical pathogenic DC population initiating psoriatic plaque formation in mice via production of IL-23. To this end, our data extend previous findings and provide a functional rational to interfere with IL-23 activity or production using, for example, Ustekinumab, Fumarate, or Apilimod (37)(38)(39). Moreover, our work suggests that future strategies specifically blocking IL-23 secretion by Langerin neg cDCs may provide an effective treatment for psoriasis avoiding the problems associated with the general immunosuppression seen in many therapeutic approaches today.…”

Section: Discussionsupporting

confidence: 83%

Langerin ^neg conventional dendritic cells produce IL-23 to drive psoriatic plaque formation in mice

Wohn

Ober‐Blöbaum

Haak

et al. 2013

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

157

163

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Psoriasis is an autoinflammatory skin disease of unknown etiology. Topical application of Aldara cream containing the Toll-like receptor (TLR)7 agonist Imiquimod (IMQ) onto patients induces flares of psoriasis. Likewise, in mice IMQ triggers pathological changes closely resembling psoriatic plaque formation. Key cytokines like IL-23 and type-I IFN (IFN-I), both being produced mainly by dendritic cells (DCs), have been implicated in psoriasis. Although plasmacytoid DCs (pDCs) are the main source of IFNα and thought to initiate disease, conventional DCs (cDCs) appear to maintain the psoriatic lesions. Any role of cDCs during lesion formation remains elusive. Here, we report that selective activation of TLR7 signaling specifically in CD11c + DCs was sufficient to induce psoriasiform skin disease in mice. Intriguingly, both pDCs and the IFN-I pathway were dispensable for the development of local skin inflammation. Selective TLR7 triggering of Langerin + DCs resulted in attenuated disease, whereas their depletion did not alter the severity of skin lesions. Moreover, after IMQ-painting, IL-23 was exclusively produced by Langerin neg DCs in vivo. In conclusion, TLR7-activated Langerin neg cDCs trigger psoriatic plaque formation via IL-23-mediated activation of innate IL-17/IL-22-producing lymphocytes, independently of pDCs or IFN-I. These results suggest therapeutic targeting of IL-23 production by cDCs to refine current treatment strategies for psoriasis.

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Section: Discussionsupporting

confidence: 83%

Langerin ^neg conventional dendritic cells produce IL-23 to drive psoriatic plaque formation in mice

Wohn

Ober‐Blöbaum

Haak

et al. 2013

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

157

163

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“…14 In addition, DMF switched the immune system towards a Th2 anti-inflammatory type response through the activation of type II DCs and the suppression of type I DCs, which consequently inhibits the generation of inflammatory Th1 or Th17 cells. 17 It has been reported that DMF inhibits the proliferation of melanoma cells 18 and synergizes with dacarbazine to influence the migration of tumor cells. 25 Whether DMF or the DMF derivative MMF exerts any effect on NK cells remains unknown.…”

Section: Discussionmentioning

confidence: 99%

“…15 In addition, DMF inhibits dendritic cell (DC) maturation through a reduction in the release of the inflammatory cytokines IL-6 and IL-12. 16 Ghoreschi et al 17 observed that fumarates switch the immune system towards a Th2 type response. In addition, DMF suppresses STAT1 phosphorylation in DCs, arrests the production of type I DCs and induces the production of type II DCs, which favors the activation of Th2 cells and inhibits the expression of T-bet (Th1 cells) or RORct (Th17 cells).…”

Section: Introductionmentioning

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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“…Reports showed that IL-23 production by DC is inhibited by IL-4 and that downmodulation of DC and IL-23p19 is an early effect during psoriasis treatment (20,26). We did not observe a reduction in IL-23p19 mRNA expression in epidermal and whole PP skin after IL-4 stimulation.…”

Section: Discussionmentioning

confidence: 99%

“…In psoriatic epidermal cells, the expression of the IL-4 receptor is increased (19). Fumarate treatment induces IL-4-producing Th2 cells in vivo and generates type II DC that produce IL-10 instead of IL-12 and IL-23 (20). Clinical improvement of psoriasis is accompanied by activation of IL-4 signaling pathways including upregulated expression of GATA3 (21).…”

mentioning

confidence: 99%

IL-4 Downregulates IL-1β and IL-6 and Induces GATA3 in Psoriatic Epidermal Cells: Route of Action of a Th2 Cytokine

Onderdijk

Baerveldt

Kurek

et al. 2015

The Journal of Immunology

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Clinical improvement of psoriasis induced by IL-4 treatment has been ascribed to changes in dermal inflammatory cells, such as activation of Th2 cells and tolerization of dendritic cells by suppressing IL-23 production. The pathologic epidermal alterations in psoriatic lesional skin include increased epidermal expression of IL-1β, IL-6, S100A7, and human β-defensin 2 (hBD2) and a downregulated expression of the epidermal transcription factor GATA3. Effects of IL-4 on the epidermal compartment of psoriasis lesions were not previously investigated. Therefore, we investigated whether IL-4 directly affects abovementioned psoriatic markers in the epidermal compartment. We cultured freshly isolated psoriatic epidermal cells, whole psoriatic and healthy skin biopsies, human keratinocytes and Langerhans cells with IL-4. The secretion of IL-1β and IL-6 by psoriatic epidermal cells was inhibited by IL-4 via transcriptional and posttranscriptional mechanisms, respectively. In normal skin, IL-4 inhibited IL-1β- and IL-17A–induced hBD2 expression in vitro. In addition, IL-4 reduced the protein expression of hBD2 in psoriatic skin biopsies and induced phospho-STAT6 protein. Epidermal GATA3 mRNA and protein were significantly upregulated by IL-4 in epidermal cells and keratinocytes. Our data argue that IL-4 improves psoriasis not only via modification/induction of Th2 cells and type II dendritic cells, but also via direct inhibition of inflammatory cytokines in resident IL-4R–expressing epidermal cells and thereby alters the psoriatic skin phenotype toward a healthy skin phenotype.

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Fumarates improve psoriasis and multiple sclerosis by inducing type II dendritic cells

Abstract: Fumarates suppress Th1 responses by blocking IL-12 and IL-23 production by dendritic cells via distinct pathways.

Cited by 325 publications

References 59 publications

Langerin ^neg conventional dendritic cells produce IL-23 to drive psoriatic plaque formation in mice

Langerin ^neg conventional dendritic cells produce IL-23 to drive psoriatic plaque formation in mice

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

IL-4 Downregulates IL-1β and IL-6 and Induces GATA3 in Psoriatic Epidermal Cells: Route of Action of a Th2 Cytokine

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Fumarates improve psoriasis and multiple sclerosis by inducing type II dendritic cells

Abstract: Fumarates suppress Th1 responses by blocking IL-12 and IL-23 production by dendritic cells via distinct pathways.

Cited by 325 publications

References 59 publications

Langerin neg conventional dendritic cells produce IL-23 to drive psoriatic plaque formation in mice

Langerin neg conventional dendritic cells produce IL-23 to drive psoriatic plaque formation in mice

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

IL-4 Downregulates IL-1β and IL-6 and Induces GATA3 in Psoriatic Epidermal Cells: Route of Action of a Th2 Cytokine

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Langerin ^neg conventional dendritic cells produce IL-23 to drive psoriatic plaque formation in mice

Langerin ^neg conventional dendritic cells produce IL-23 to drive psoriatic plaque formation in mice