Model Of Psoriasis-like Skin Inflammation Research Articles

Abstract # 1805 Peripheral cutaneous inflammation induces a brain chemokine response, immune cell infiltration and functional changes

There are now compelling data linking peripheral inflammation and depression. However, the mechanisms that underlie this relationship remain unclear. Using QPCR, we measured brain, lung, liver, skin and peripheral blood leukocyte responses to a well-characterised murine model of psoriasis-like skin inflammation, Aldara (containing the TLR-7 ligand, Imiquimod), in C57BL/6 female mice. We measured tissue responses across a number of time points (4 h, 12 h, 1 d, 3 d and 5 d) and confirmed qPCR findings with protein analysis of brain tissue. Further, we measured behavioural outcomes using burrowing, a rewarding behaviour, deficits in which can be construed as anhedonic. We found significant transcriptional upregulation of a number of chemokines and pro-inflammatory cytokines (including CCL2, CCL5, CXCL10, IL-1B, IL-6 and TNF-a) in the brain and systemic organs and concurrent upregulation of protein was confirmed in the brain. However, the brain response was temporally unique in that the peak transcriptional response was observed at 3 days compared to 12 h to 1 day in the peripheral tissues. Along with chemokine and cytokine induction, we observed the infiltration of immune cells into the brain, including T cells, NK cells and monocytes, particularly at day 3 and day 5. These data indicate that the brain mounts a unique response to peripheral inflammatory stimuli, including chemokine induction that may play a role in immune cell recruitment and subsequent behavioural deficits.

TLR7-mediated skin inflammation remotely triggers chemokine expression and leukocyte accumulation in the brain.

BackgroundThe relationship between the brain and the immune system has become increasingly topical as, although it is immune-specialised, the CNS is not free from the influences of the immune system. Recent data indicate that peripheral immune stimulation can significantly affect the CNS. But the mechanisms underpinning this relationship remain unclear. The standard approach to understanding this relationship has relied on systemic immune activation using bacterial components, finding that immune mediators, such as cytokines, can have a significant effect on brain function and behaviour. More rarely have studies used disease models that are representative of human disorders.MethodsHere we use a well-characterised animal model of psoriasis-like skin inflammation—imiquimod—to investigate the effects of tissue-specific peripheral inflammation on the brain. We used full genome array, flow cytometry analysis of immune cell infiltration, doublecortin staining for neural precursor cells and a behavioural read-out exploiting natural burrowing behaviour.ResultsWe found that a number of genes are upregulated in the brain following treatment, amongst which is a subset of inflammatory chemokines (CCL3, CCL5, CCL9, CXCL10, CXCL13, CXCL16 and CCR5). Strikingly, this model induced the infiltration of a number of immune cell subsets into the brain parenchyma, including T cells, NK cells and myeloid cells, along with a reduction in neurogenesis and a suppression of burrowing activity.ConclusionsThese findings demonstrate that cutaneous, peripheral immune stimulation is associated with significant leukocyte infiltration into the brain and suggest that chemokines may be amongst the key mediators driving this response.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-016-0562-2) contains supplementary material, which is available to authorized users.

Tumour necrosis factor-α plays a significant role in the Aldara-induced skin inflammation in mice.

Recently, the Aldara-induced psoriasis-like skin inflammation model in mice has attracted increased attention, due to its dependence on the same immunological pathways and cell types as in human psoriasis. To study the impact of constitutive deficiency of tumour necrosis factor (TNF)-α and its upstream regulator mitogen-activated protein kinase-activated protein kinase 2 (MAPKAPK-2, herein MK2) in the Aldara-induced psoriasis-like skin inflammation model. TNF-α knockout (KO), MK2 KO and wild-type (WT) mice divided into separate groups received either 45-mg Aldara cream or control cream for 5 consecutive days. The skin inflammation was evaluated clinically, histologically, and by quantitative reverse transcription-polymerase chain reaction. We found that TNF-α KO mice developed significantly less skin inflammation compared with WT mice, as evaluated clinically and histologically. At the molecular level, we demonstrated that the Aldara-induced mRNA expression of the psoriasis-related inflammatory markers interleukin (IL)-17C, IL-23p19, IL-12p40, IL-17A, IL-22 and S100A8 was significantly decreased in TNF-α KO mice compared with WT mice. No significant difference in the mRNA expression of these inflammatory markers between MK2 KO mice and WT mice was found, although Aldara-treated MK2 KO mice showed a tendency towards a lower mRNA expression of IL-17A and IL-22 compared with WT mice. We were able to demonstrate significantly lower levels of inflammation in TNF-α KO mice compared with WT mice, supporting the use of this model in future studies characterizing the role of TNF-α in psoriasis.

Decreased Expression of Caveolin-1 Contributes to the Pathogenesis of Psoriasiform Dermatitis in Mice

Psoriasis is a chronic inflammatory skin disease characterized by excessive proliferation and abnormal keratinocyte development, in which T helper type 17 cells and signal transducer and activator of transcription 3 (STAT3) activation have pivotal roles. Moreover, caveolin-1 (CAV-1) has been implicated in the regulation of signal transduction, and aberrant CAV-1 expression is involved in a variety of diseases. However, whether CAV-1 is involved in psoriasis is unknown. Here we examined CAV-1 expression in the psoriatic epidermis and investigated its role in the pathogenesis of psoriasis. CAV-1 was markedly reduced in lesional epidermis of psoriasis patients. CAV1 silencing in keratinocytes in vitro revealed significant activation of STAT3, leading to increased expression of keratin 16 and several cytokine/chemokines, such as IL-6, C-X-C chemokine ligand 8 (CXCL8), CXCL9, and C-C chemokine ligand 20. In addition, psoriasis-related cytokines, including tumor necrosis factor-α (TNF-α), decreased CAV-1 expression in keratinocytes. Finally, administration of CAV-1 scaffolding domain peptide in a murine model of psoriasis-like skin inflammation induced by imiquimod improved the skin phenotype and reduced epidermal thickness and infiltrating cell counts. Furthermore, expression of TNF-α, IL-17A, and IL-23 was significantly suppressed by this treatment. Collectively, our study indicated that CAV-1 participates in the pathogenesis of psoriasis by regulating the STAT3 pathway and cytokine networks.

Peripheral inflammation affects the central nervous system and biology of the brain

There is a growing pool of evidence to support the hypothesis that events in the periphery, particularly of an inflammatory nature, can have a profound effect on the central nervous system (CNS). Specifically, inflammatory cytokines have been shown to be important mediators of neuropsychiatric disorders and variations in their expression can affect the severity of both depression and disease score, if presenting with specific comorbidities. The mechanisms driving the relationship between the CNS and the periphery remain to be fully understood. To investigate this, we have used a well characterised model of psoriasis-like skin inflammation as a tool to examine the consequential effect of localised peripheral inflammation on the brain. Aldara cream, which contains 5% Imiquimod as the active component, has been shown to induce psoriasis-like skin inflammation when applied repeatedly to the dorsal skin of mice. We have already shown that this model leads to the transcriptional upregulation of a number of classic interferon-stimulated genes (ISGs) in the brain, a response that we do not see mimicked in the peripheral blood leukocytes (PBL) at the same time point. We have since identified the transcriptional upregulation of a number of chemokines in the CNS which may be important for instigating immune cell infiltration. Furthermore, we have found that Aldara treatment causes a reduction in the level of doublecortin staining in the dentate gyrus of the hippocampus, indicating a negative effect on neurogenesis. Finally, a basic behavioural model of anhedonia has allowed us to determine a phenotypic consequence of Aldaratreatment, whereby the burrowing activity of the treated group is significantly reduced compared with the control group.

Cutaneous Application of Leukotriene B4 as an in vivo Model of Psoriasis-Like Skin Inflammation: An Immunohistological Study

Background: Research has revealed new insights into the pathogenesis of psoriasis, leading to new therapeutic options. So far the order of changes in the pathogenesis of psoriasis is unclear. The responses to cutaneous leukotriene B₄ (LTB₄) application have been studied in the past as an in vivo model for inflammation. The aim of the present study is to find out the order of changes of key steps in inflammation, which all have been shown to be involved in mature psoriatic lesions. Objective: To study the dynamics of the consecutive stages of inflammation in challenged skin as a reflection of a psoriasis-like inflammatory response. Methods: We examined the dynamics of epidermal growth control and the key representatives of the innate and acquired immune system during the first 72 h after challenging the skin by LTB₄ application. Results: Interleukin 17-positive (IL-17+) cells dominate the acute phase of inflammation, whereas T-Bet+ cells seem to increase gradually during the entire observation period. This indicates a more important role for IL-17 in the unstable phase of inflammation and a more prominent role for T-Bet+ cells within the chronic phase. Conclusion: The present model is highly reproducible and is useful in studying the dynamics of a psoriasis-like inflammation with respect to key components of immunity. It could provide a useful tool to study the immediate biological effects of new therapies like anti-IL-17 drugs on IL-17 production and effects on cutaneous inflammation and epidermal proliferation in vivo.

α-MSH-Stimulated Tolerogenic Dendritic Cells Induce Functional Regulatory T Cells and Ameliorate Ongoing Skin Inflammation

The neuropeptide α-melanocyte-stimulating hormone (α-MSH) is a well-known mediator of skin pigmentation. More recently, it has been shown that α-MSH also exerts a strong anti-inflammatory and immunosuppressive activity. To elucidate the mechanisms underlying α-MSH-induced immunosuppression, we investigated whether α-MSH affects dendritic cell/T cell communication, as especially this interaction has an important role in the regulation of immune responses. Here, we show that α-MSH, by binding to MC-1R, induced tolerogenic dendritic cells, which were capable of expanding CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs) in vitro, as well as in vivo. Notably, those α-MSH-induced Tregs were functional as they efficiently inhibited cutaneous contact allergy and ongoing psoriasis-like skin inflammation in mice. Furthermore, α-MSH induced tolerogenic dendritic cells capable of generating functional Tregs in human blood. Interestingly, human Tregs expanded via α-MSH-stimulated dendritic cells suppressed the proliferation and cytokine secretion of pathogenic T-helper-17 (Th17) cells from individuals with psoriasis. Taken together, these data indicate that α-MSH induced immunosuppressive Tregs in vitro and in vivo, which inhibited disease progression in a mouse model of psoriasis-like skin inflammation and suppressed the activation and proliferation of effector T cells from subjects with psoriasis.

IL-22 is required for Th17 cell–mediated pathology in a mouse model of psoriasis-like skin inflammation

Psoriasis is a chronic skin disease resulting from the dysregulated interplay between keratinocytes and infiltrating immune cells. We report on a psoriasis-like disease model, which is induced by the transfer of CD4(+)CD45RB(hi)CD25(-) cells to pathogen-free scid/scid mice. Psoriasis-like lesions had elevated levels of antimicrobial peptide and proinflammatory cytokine mRNA. Also, similar to psoriasis, disease progression in this model was dependent on the p40 common to IL-12 and IL-23. To investigate the role of IL-22, a Th17 cytokine, in disease progression, mice were treated with IL-22-neutralizing antibodies. Neutralization of IL-22 prevented the development of disease, reducing acanthosis (thickening of the skin), inflammatory infiltrates, and expression of Th17 cytokines. Direct administration of IL-22 into the skin of normal mice induced both antimicrobial peptide and proinflammatory cytokine gene expression. Our data suggest that IL-22, which acts on keratinocytes and other nonhematopoietic cells, is required for development of the autoreactive Th17 cell-dependent disease in this model of skin inflammation. We propose that IL-22 antagonism might be a promising therapy for the treatment of human psoriasis.