Increased expression of IL-12p70 and IL-23 by multiple dendritic cell and macrophage subsets in plaque psoriasis

Yawalkar, Nikhil; Tscharner, Gion G.; Hunger, Robert E.; Hassan, Akmal S.

doi:10.1016/j.jdermsci.2009.01.003

Cited by 95 publications

(83 citation statements)

References 22 publications

(26 reference statements)

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“…In accordance with this finding, immunohistological analysis of psoriasis skin demonstrated expression of IL-23 by CD11c + cDCs, but not CD1a + LCs (34). Moreover, in patients an increase of dermal CD11c + DCs marks the critical step in early stages of psoriatic lesion formation and disease development (28,35).…”

Section: Discussionsupporting

confidence: 69%

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.

161

169

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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: 69%

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.

161

169

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“…Our results show that, besides neutrophils, skin lesions in GPP are highly infiltrated with different cell populations of the innate immune system like myeloid DC, M1 and M2 macrophages. Myeloid DC and M1 macrophages represent the main source of pivotal cytokines like TNFα, CXCL8/IL-8, IL-12 and IL-23 [8,9,10]. In correlation with the increased infiltrate, an enhanced expression of these cytokines was readily found in GPP before therapy.…”

Section: Discussionmentioning

confidence: 99%

Rapid Downregulation of Innate Immune Cells, Interleukin-12 and Interleukin-23 in Generalized Pustular Psoriasis with Infliximab in Combination with Acitretin

Tang¹,

Spanou²,

Tang³

et al. 2012

Dermatology

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Background: Generalized pustular psoriasis (GPP) is a severe inflammatory disease characterized by recurrent eruptions of sterile pustules on erythematous skin. Although tumor necrosis factor (TNF) antagonists may lead to a rapid resolution of GPP, the mechanism of action of these agents remains to be investigated. Here, we sought to evaluate markers of immune response in the skin of a patient who experienced a rapid amelioration of GPP after treatment with infliximab and acitretin. Methods: A skin biopsy was obtained before and 72 h after initiation of treatment. Immunohistochemical stainings were performed to characterize alterations of the infiltrates, the apoptosis marker caspase 3 and key cytokines like TNFα, interleukin (IL)-12, IL-23 and the chemokine CXCL8/IL-8. Results: Parallel with clinical improvement, a striking decline of neutrophils, myeloid and plasmacytoid dendritic cells, M1 macrophages and partly of CD4+ T cells was observed. There was no evidence of increased apoptosis mediated through the caspase-3 pathway. A marked reduction particularly of IL-12 and IL-23 and, to a lesser degree, of TNFα and CXCL8/IL-8 was observed. Conclusion: A swift clinical improvement of GPP by infliximab and acitretin is associated with a marked reduction particularly of innate and partially of the acquired immune cells as well as IL-12 and IL-23.

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“…[18][19][20][21][22] Psoriatic lesions contain primarily T H 1 and T H 17 cells, 19 and possess CD11c ϩ myeloid DCs that strongly resemble the functional characteristics attributed to DC Th1 and DC Th17. [24][25][26][27] Most notably, CD11c ϩ DCs in psoriatic lesions express elevated levels of TNF-␣, IL-12p40, and IL-23 25,27 and drive the formation of T H 1 and T H 17 cells ex vivo. 24 Conversely, atopic dermatitis lesions contain large numbers of T H 2 cells 20,22,23 and CD11c ϩ DCs that share several characteristics with DC Th2 .…”

Section: Discussionmentioning

confidence: 99%

“…20,23 Not surprisingly, DCs that accumulate in each of these diseases exhibit markedly different phenotypes. 21,24,25 DCs present in psoriatic lesions express IL-12p40, IL-23, and TNF-␣ [25][26][27] while DCs present in atopic dermatitis lesions express low or undetectable levels of these cytokines. 25 DCs from each of these diseases also differentially express cell surface molecules such as DC-SIGN.…”

Section: Introductionmentioning

confidence: 99%

TH1, TH2, and TH17 cells instruct monocytes to differentiate into specialized dendritic cell subsets

Alonso¹,

Wong

Zhang³

et al. 2011

Blood

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Monocytes and T helper (T H ) cells rapidly infiltrate inflamed tissues where monocytes differentiate into inflammatory dendritic cells (DCs IntroductionDCs are phenotypically and functionally divergent antigen presenting cells that originate from bone marrow precursors such as monocytes. [1][2][3][4][5][6] Encompassing a broad anatomical distribution, DCs continuously sample the microenvironment in search of danger signals recognized by a wide spectrum of pattern recognition receptors (PRRs). 1,2,6 Depending on the cytokine milieu and the pathogen encountered, DCs differentially up-regulate costimulatory molecules and secrete a variety of cytokines that dictate the nature of the T cell response. 7-10 DC exposure to particular intracellular pathogens or their products, including lipopolysaccharide (LPS) and double-stranded RNA, leads to DC-driven T H 1 differentiation primarily through IL-12 secretion. 11 Conversely, DCs mediate T H 2 differentiation in response to extracellular parasites, such as S mansoni, which likely results from diminished IL-12 secretion and increased OX40L expression. 7,8 Several reports have implicated DC-derived IL-1␤, IL-6, IL-23, and TGF-␤ in the polarization of T H 17 cells, 9,12-17 which mediate defense against extracellular bacteria and various fungal infections. 15 Psoriasis and atopic dermatitis are common inflammatory skin diseases characterized by the rapid accumulation of T H cells and DCs. [18][19][20][21][22] While both diseases share several pathologic features, 18,22 the T H cells implicated in the pathogenesis of each disease are distinct. 19,20,23 Infiltration of T H 1 and T H 17 cells is commonly observed in psoriatic lesions, 19 which is accompanied by elevated levels of the T H 1 cytokine, IFN-␥, and the T H 17 cytokines, Conversely, acute atopic dermatitis lesions contain elevated levels of T H 2 cells and their associated effector cytokines, 23 Not surprisingly, DCs that accumulate in each of these diseases exhibit markedly different phenotypes. 21,24,25 DCs present in psoriatic lesions express IL-12p40, IL-23, and TNF-␣ 25-27 while DCs present in atopic dermatitis lesions express low or undetectable levels of these cytokines. 25 DCs from each of these diseases also differentially express cell surface molecules such as DC-SIGN. 21 However, the cell types and/or factors that influence the generation of these DC subsets remain elusive.Given that memory T H cells and monocytes rapidly infiltrate inflamed tissues 2 and that activated T H cells secrete high levels of GM-CSF, 28 a cytokine that mediates DC differentiation from monocytes, 29,30 we hypothesized that T H cells instruct monocytes to differentiate into DCs. Our data demonstrate that not only do T H cells direct monocytes to differentiate into DCs, but that each T H cell subset drives the formation of phenotypically and functionally distinct DC subsets that resemble DCs previously identified in atopic dermatitis and psoriatic lesions. 21,24,25 These data support the hypothesis that memory T H cells influence t...

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Increased expression of IL-12p70 and IL-23 by multiple dendritic cell and macrophage subsets in plaque psoriasis

Cited by 95 publications

References 22 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

Rapid Downregulation of Innate Immune Cells, Interleukin-12 and Interleukin-23 in Generalized Pustular Psoriasis with Infliximab in Combination with Acitretin

TH1, TH2, and TH17 cells instruct monocytes to differentiate into specialized dendritic cell subsets

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Increased expression of IL-12p70 and IL-23 by multiple dendritic cell and macrophage subsets in plaque psoriasis

Cited by 95 publications

References 22 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

Rapid Downregulation of Innate Immune Cells, Interleukin-12 and Interleukin-23 in Generalized Pustular Psoriasis with Infliximab in Combination with Acitretin

TH1, TH2, and TH17 cells instruct monocytes to differentiate into specialized dendritic cell subsets

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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