Inhibition of p38 kinase suppresses the development of psoriasis-like lesions in a human skin transplant model of psoriasis

Mihara, Katsuhiro; Elliott, Graham R.; Boots, A.; Nelissen, R.L.H.

doi:10.1111/j.1365-2133.2012.10939.x

Cited by 9 publications

(8 citation statements)

References 9 publications

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“…There is an increasing number of studies providing evidence that p38 plays a key role in the pathogenesis of a growing number of chronic inflammatory diseases including inflammatory skin diseases, and consequently that p38, as key signaling molecule, may be a promising therapeutic target in such diseases (Cuenda andRousseau, 2007, Kumar et al, 2003). For instance, while p38g is poorly expressed in epidermal keratinocytes (Dashti et al, 2001) and likely has marginal roles in these cells, the kinase activity of p38a, b, and d has been reported to be increased in the lesional epidermis of patients suffering from psoriasis (Johansen et al, 2005;Yu et al, 2007), and that inhibition of p38 suppresses the development of psoriasis-like lesions in a human skin transplant model of psoriasis (Mihara et al, 2012). p38 MAPKs also play an important role in inflammation induced by UVB, where they have been shown to exhibit increased activity in human and mouse keratinocytes , and where UVB has been shown to induce IL-6 and IL-8 expression in keratinocytes in a cyclooxygenase-2-and p38-dependent manner (Chen et al, 2001;Kim et al, 2005).…”

Section: G Fenini Et Almentioning

confidence: 99%

The p38 Mitogen-Activated Protein Kinase Critically Regulates Human Keratinocyte Inflammasome Activation

Fenini

Grossi

Gehrke

et al. 2018

Journal of Investigative Dermatology

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Inflammasomes are key intracellular signaling platforms involved in innate immune responses to micro-organisms and danger signals. Extracellular signal-regulated kinase, Jun N-terminal kinase, and p38 mitogen-activated protein kinase family members are activated by numerous environmental stresses. Recently, it has been reported that Jun N-terminal kinase is involved in inflammasome activation in myeloid immune cells. To date, the role of mitogen-activated protein kinase in inflammasome activity in keratinocytes has not been investigated. Here, we show that, in primary human keratinocytes, p38 mitogen-activated protein kinase is required for inflammasome activation and IL-1β secretion. Using selective small molecule inhibitors, small interfering RNA gene silencing, and CRISPR/Cas9-based deletion, we demonstrate the above and identify p38α and p38δ as critical regulators of ASC oligomerization, inflammasome activation, and IL-1β secretion in keratinocytes. Furthermore, our data suggest that the nature of the mitogen-activated protein kinase regulating inflammasome activity exhibits a certain cell specificity, with p38 playing a predominant role in keratinocytes and Jun N-terminal kinase 1 in cells of myeloid origin.

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Section: G Fenini Et Almentioning

confidence: 99%

The p38 Mitogen-Activated Protein Kinase Critically Regulates Human Keratinocyte Inflammasome Activation

Fenini

Grossi

Gehrke

et al. 2018

Journal of Investigative Dermatology

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“…These findings indicate that targeting p38 could be a promising strategy to treat psoriasis (29). Un fortunately, p38 inhibitors have not shown efficacy in the treatment of psoriasis, and many have been withdrawn from clinical trials because of adverse side effects (28). Thus, it would be useful to define the cell types in which p38 is active in psoriasis.…”

Section: Introductionmentioning

confidence: 99%

p38α signaling in Langerhans cells promotes the development of IL-17–producing T cells and psoriasiform skin inflammation

Zheng

Zhao

et al. 2018

Sci. Signal.

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Dendritic cells (DCs) contribute to psoriasis pathogenesis. In a mouse model of imiquimod-induced psoriasiform skin inflammation, we found that p38α activity in Langerhans cells (LCs), a skin-resident subset of DCs, promoted the generation of T cells that produce IL-17, a proinflammatory cytokine that is implicated in autoimmune disease. Deletion of p38α in LCs, but not in other skin or circulating DC subsets or T cells, decreased T cell-mediated psoriasiform skin inflammation in mice. The activity of p38α in LCs specifically promoted IL-17 production from γδ and CD4 T cells by increasing the abundance of IL-23 and IL-6, two cytokines that stimulate IL-17 secretion. Inhibition of p38 activity through either pharmacological inhibition or genetic deletion also reduced the severity of established psoriasiform skin inflammation. Together, our findings indicate a critical role for p38α signaling in LCs in promoting inflammatory responses in the skin and suggest that targeting p38α signaling in LCs may offer an effective therapeutic approach to treat psoriasis.

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“…To investigate whether KdPT might be able to ameliorate ongoing psoriasis in human skin, a psoriasis xenograft transplantation model, where non‐lesional skin biopsies from individuals with psoriasis were transplanted onto immunodeficient BNX mice, was used . Three weeks after surgery, the human skin transplants were injected with PBMC from the same individuals and characteristic hallmarks of psoriasis, such as acanthosis or hyperkeratosis, started developing in the transplants (Fig.…”

Section: Resultsmentioning

confidence: 99%

The tripeptide KdPT ameliorates ongoing psoriasis‐like skin inflammation in murine and human skin

Mykicki

Klenner

Baumann

et al. 2016

Experimental Dermatology

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Psoriasis is a chronic inflammatory disease appearing as scaly erythematous cutaneous lesions, which are characterized by parakeratosis and acanthosis as well as the infiltration of immune cells, such as T helper-1 and T helper-17 cells. Here, we demonstrated that KdPT, a tripeptide structurally related to the C-terminal amino acids of alpha-melanocyte-stimulating hormone, which was previously shown to exhibit anti-inflammatory effects in intestinal inflammation, ameliorated ongoing disease in the mouse model of imiquimod-induced psoriasis-like skin inflammation and in the small xenotransplant mouse model of psoriasis. We could show that systemic KdPT treatment significantly reduced hyperkeratosis and acanthosis in murine as well as human skin. Moreover, KdPT upregulated Foxp3 in CD4 T cells from mice and from peripheral blood of individuals with psoriasis and decreased the expression of type 1 inflammatory cytokines, indicating that the beneficial effect of KdPT was, at least in part, mediated by the induction of functional regulatory T cells that suppressed the activation of pathogenic CD4 IFN-γ and CD4 IL-17 T cells. Thus, these data might suggest KdPT as a potential novel therapeutic alternative for the treatment of psoriasis.

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Inhibition of p38 kinase suppresses the development of psoriasis-like lesions in a human skin transplant model of psoriasis

Cited by 9 publications

References 9 publications

The p38 Mitogen-Activated Protein Kinase Critically Regulates Human Keratinocyte Inflammasome Activation

The p38 Mitogen-Activated Protein Kinase Critically Regulates Human Keratinocyte Inflammasome Activation

p38α signaling in Langerhans cells promotes the development of IL-17–producing T cells and psoriasiform skin inflammation

The tripeptide KdPT ameliorates ongoing psoriasis‐like skin inflammation in murine and human skin

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