A Critical Role of the IL-1β–IL-1R Signaling Pathway in Skin Inflammation and Psoriasis Pathogenesis

Cai, Yihua; Xue, Feng; Chen, Quan; Qu, Minye; Liu, Na; Zhang, Yuan; Fleming, Christopher; Hu, Xiaoling; Zhang, Huang Ge; Weichselbaum, Ralph; Fu, Yang–Xin; Tieri, David; Rouchka, Eric C.; Zheng, Jie; Yan, Jun

doi:10.1016/j.jid.2018.07.025

Cited by 190 publications

(161 citation statements)

References 35 publications

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“…Psoriasis is a chronic autoimmune disease in which T cells are known to play an important role in its pathogenesis. The participation of macrophages in the pathogenesis of psoriasis has been previously suggested with a key role for TNF and IL-1β (12,13). In a mouse model of psoriasis, depletion of macrophages led to a decrease in severity of the disease (14).…”

Section: Discussionmentioning

confidence: 92%

Mononuclear Phagocyte Activation Is Associated With the Immunopathology of Psoriasis

Costa

Paixão²,

Viana³

et al. 2020

Front. Immunol.

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Psoriasis is a chronic, inflammatory disease affecting the skin and joints. The pathogenesis of this disease is associated with genetic, environmental and immunological factors, especially unbalanced T cell activation and improper keratinocyte differentiation. Psoriatic lesion infiltrate is composed of monocytes and T cells, and most studies have focused on the participation of T cells in the pathogenesis of this disease. Here we investigated the contribution of mononuclear phagocytes in the immunopathology observed in psoriatic patients. Significant increases in the levels of TNF, IL-1β, CXCL9, as well as the soluble forms of CD14 and CD163, were observed within the lesions of psoriatic patients compared to skin biopsies obtained from healthy individuals. Moreover, we found an association between the levels of CCL2, a monocyte attractant chemokine, and disease severity. In conclusion, our findings suggest a potential role for mononuclear phagocytes in the pathogenesis of psoriasis.

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Section: Discussionmentioning

confidence: 92%

Mononuclear Phagocyte Activation Is Associated With the Immunopathology of Psoriasis

Costa

Paixão²,

Viana³

et al. 2020

Front. Immunol.

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“…Considering the evidence that AMPK, SIRT1 and autophagy are coordinately regulated 56 , and that autophagy induction negatively regulates NLRP3 inflammasome activation [57][58][59] , there is a possibility that autophagy through AMPK and SIRT1 activation may be involved in the lowered caspase-1 protein expression induced by metformin, contributing to the inhibition of NLRP3 activation and IL-1β secretion (mature IL-1β); however, to demonstrate this, further studies are required. Recently, the IL-1β-IL-1R signalling pathway controlled by NLPR3 inflammasome has been reported to play a critical role in the pathogenesis of psoriasis in humans and induced by IMQ in mice 60 . Our results show that metformin treatment inhibited IL-1β secretion in vitro and prevented the development of IMQ-induced psoriasis in vivo, suggesting that metformin administration may impair the IL-1β-IL-1R signalling pathway controlled by NLPR3 inflammasome, leading to the prevention of psoriasis.…”

Section: Discussionmentioning

confidence: 99%

Metformin inhibits IL-1β secretion via impairment of NLRP3 inflammasome in keratinocytes: implications for preventing the development of psoriasis

Tsuji

Hashimoto-Hachiya

et al. 2020

Cell Death Discov.

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Psoriasis is a systemic inflammatory disease significantly associated with comorbidities including type 2 diabetes mellitus (T2DM). Metformin is utilized as a first-line agent for treating T2DM. Although metformin reportedly inhibits mature IL-1β secretion via NLRP3 inflammasome in macrophages of T2DM patients, it remains unclear whether it affects skin inflammation in psoriasis. To test this, we analysed normal human epidermal keratinocytes (NHEKs), a major skin component, stimulated with the key mediators of psoriasis development, TNF-α and IL-17A. This stimulation induced the upregulation of pro-IL-1β mRNA and protein levels, and subsequently mature IL-1β secretion, which was inhibited by metformin treatment. To further reveal the mechanism involved, we examined how metformin treatment affected NLRP3 inflammasome activated by TNF-α and IL-17A stimulation. We found that this treatment downregulated caspase-1 expression, a key mediator of NLRP3 inflammasome. Furthermore, inhibitors of AMPK and SIRT1 abrogated the downregulation of caspase-1 induced by metformin treatment, indicating that AMPK and SIRT1 are essential for the inhibitory effect on NLRP3 inflammasome in NHEKs. As IL-1β stimulation induced upregulation of IL-36γ, CXCL1, CXCL2, CCL20, S100A7, S100A8 and S100A9 mRNA and protein levels in NHEKs, we examined whether metformin treatment affects such gene expression. Metformin treatment inhibited upregulation of IL-36γ, CXCL1, CXCL2, CCL20, S100A7, S100A8 and S100A9 mRNA and protein levels induced by TNF-α and IL-17A stimulation. Finally, we examined whether metformin administration affected psoriasis development in an imiquimod-induced mouse psoriasis model. Oral metformin treatment significantly decreased ear thickness, epidermal hyperplasia and inflammatory cell infiltration. A cytokine profile in the epidermis under metformin treatment showed that IL-1β, Cxcl1, Cxcl2, S100a7, S100a8 and S100A9 mRNA levels were downregulated compared with control levels. These results indicate that metformin administration prevented psoriasis development in vivo. Collectively, our findings suggest that metformin-mediated anti-psoriatic effects on the skin have the potential for treating psoriasis in T2DM patients.

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“…Another mechanism which is considered to have a major role in the psoriasis pathogenesis and its related inflammatory skin dermatoses is the IL-1β-IL-1R signaling pathway which may be involved in the amplification of the skin inflammatory cascade through the regulation of dermal IL-17producing cells and stimulation of keratinocytes [12,13]. However, plaque and guttate psoriasis show important differences between the phenotype and function of T lymphocytes, IFN-γ and IL-17 from CD4+T cells being involved in guttate psoriasis, while IFN-γ and IL-17 from CD8+T cells are essential in the pathogenesis of plaque psoriasis [3,14,15].…”

Section: Pathogenesismentioning

confidence: 99%

The histopathological landscape of the major psoriasiform dermatoses

et al. 2019

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Psoriasiform dermatoses represent a wide spectrum of inflammatory conditions, with several major forms represented by psoriasis, as the prototype of this category, followed by pustular psoriasis, Reiter's syndrome, pityriasis rubra pilaris, lichen simplex chronicus and large-plaques parapsoriasis. They create a diagnostic challenge, both clinical and histopathological, because of their complexity and frequent overlapping of the microscopical features. The characteristic histopathological features of psoriasiform reaction comprise extensive hyperkeratosis, with horizontally confluent but vertically intermittent parakeratosis, which alternate with orthokeratosis, thin granular layer, with relative frequent mitoses, uniform elongated and fused rete ridges, edematous superficial papillary dermis, with dilated capillaries, perivascular lymphocytic infiltrate, Munro's microabscesses, and spongiform pustules of Kogoj. Our paper aims to review the histopathology of major form of psoriasiform dermatoses and to emphasize the characteristic microscopical differences between them, for a better approach of the diagnosis as an important key for clinical and therapeutical management. Using the clinicopathological correlations, a thoroughly evaluation of the microscopical features and compartments distribution or special stainings and techniques, the range of differential diagnosis can be decreased and a more accurate diagnostic can be usually achieved. The insights into the pathogenic mechanisms can lead to new therapeutic opportunities targeted to the specific type of inflammatory lesion.

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A Critical Role of the IL-1β–IL-1R Signaling Pathway in Skin Inflammation and Psoriasis Pathogenesis

Cited by 190 publications

References 35 publications

Mononuclear Phagocyte Activation Is Associated With the Immunopathology of Psoriasis

Mononuclear Phagocyte Activation Is Associated With the Immunopathology of Psoriasis

Metformin inhibits IL-1β secretion via impairment of NLRP3 inflammasome in keratinocytes: implications for preventing the development of psoriasis

The histopathological landscape of the major psoriasiform dermatoses

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