Psoriasiform Dermatitis Research Articles

036 CXCL10 expression is regulated by keratinocyte STAT3 signaling and inhibits skin inflammation

The role of STAT3 signaling in psoriasis is not entirely clear as transgenic mice that overexpress STAT3 in keratinocytes (K14-stat3c) spontaneously develop psoriasiform dermatitis whereas STAT3 is also thought to promote IL-17A/F production by T cells. Therefore, in this study, the relative contribution of STAT3 in keratinocytes versus T cells was evaluated in the imiquimod mouse model of psoriasiform dermatitis by evaluating cre/lox mice with either keratinocyte inducible deletion of STAT3 (K5-creERT2×STAT3fl/fl [K5-STAT3]) or specific deletion of STAT3 in T-cells (Lck-cre×STAT3 fl/fl [Lck-STAT3]). Unexpectedly, psoriasiform skin inflammation was diminished in K5-STAT3 mice whereas Lck-STAT3 mice developed similar skin inflammation as WT mice. In addition, K5-STAT3 mice had increased IFN-γ+ T cells but less IL-17+ T cells compared to wt mice, indicating that loss of STAT3 signaling in keratinocytes dampened inflammation by inhibiting IL-17 responses while promoting IFN-γ responses. Interestingly, mRNA and histologic expression of the interferon response gene, CXCL10, inversely correlated with the skin inflammation in deletion or overexpression of STAT3 in the K5-STAT3 or K14-stat3c mice, respectively. Additionally, we discovered that neutralizing CXCL10 signaling enhanced imiquimod-induced skin inflammation, suggesting that CXCL10 acts to inhibit skin inflammation in this model. Taken together, these findings define a novel mechanism by which keratinocyte but not T cell-intrinsic STAT3 signaling induces psoriasiform-like skin inflammation via regulation of CXCL10 expression, proinflammatory IL-17 and anti-inflammatory IFN-γ T cell responses.

656 Psoriasis and obesity: Stearoyl-CoA desaturase 1 deficient mice are resistant to imiquimod-induced psoriasiform dermatitis

Psoriasis is a chronic inflammatory skin condition whose severity has been linked with obesity. In patients with psoriasis, the likelihood of developing new-onset obesity is higher than those without psoriasis. Stearoyl-CoA desaturase (SCD), is an endoplasmic reticulum resident desaturase, that acts as a catalyst in the synthesis of monounsaturated fatty acids. Mice lacking SCD1 are insulin sensitive, resistant to development of obesity and exhibit suppressed fatty acid synthesis. We have earlier shown that skin specific deletion of SCD1 in mice (SKO) results in epidermal proliferation, sebaceous gland hypoplasia and elevated interleukin 6 levels. We hypothesized that SCD1 deficiency will render mice susceptible to imiquimod (IMQ)-induced psoriasiform dermatitis. A topical dose of 62.5 mg IMQ cream was applied daily to the shaved back region of SKO and SCD1 proficient FLOX counterparts for 14 days after which the mice were euthanized. Cumulative average skin thickness in SKO animals following IMQ application, measured prior to excision was significantly (36%) less than that in FLOX animals. Quantitation of epidermal thickness in H&E stained skin sections validated this observation. Further, histological analysis revealed that in spite of skin inflammation and hair follicle dysplasia associated with their genetic background, the degree of IMQ associated inflammatory changes in the SKO mice were remarkably less than that in FLOX counterparts. Keratin 14, the prototypic marker of dividing basal keratinocytes was elevated in IMQ-treated FLOX skin. Moreover, fatty acid binding protein 5, upregulated in psoriasis tissue was reduced in SKO skin. Our data suggests a complex relationship between fatty acid metabolism and cytoskeletal proteins driving aberrant cell proliferation in psoriatic skin. We propose that SCD1 inhibition could be a novel approach for the management of psoriasis, especially in obese individuals.

297 KCa3.1-overexpression in skin causes pruritic eczema and epidermal hyperplasia

Ion channels have emerged as potential mediators of chronic skin disease. Here, we explored the consequences of genetically encoded induction of the cell volume-regulating Ca2+-activated KCa3.1 channel (Kcnn4) for murine epidermal homeostasis. 800-fold channel overexpression in keratinocytes of doxycycline-treated KCa3.1+ mice produced strong KCa3.1-functions, epidermal spongiosis, progressive epidermal hyperplasia, hyperkeratosis, itch and ulcers, and high morbidity within two weeks. We found significant induction of pro-proliferative and pro-inflammatory cytokines, IL-β1 (60-fold over basal levels), IL-23 (34-fold), IL-6 (33-fold), and TNFα (26-fold) in the skin. In-vivo treatment with the KCa3.1-selective blocker, Senicapoc, significantly suppressed spongiosis, hyperplasia, and induction of IL-β1 (-88%), IL-23 (-77%), and IL-6 (-90%). In conclusion, KCa3.1-induction over basal levels in keratinocytes resulted in expression of several pro-proliferative and pro-inflammatory cytokines, spongiosis, hyperplasia, and hyperkeratosis, itch, and morbidity. This skin condition is similar to eczematous and psoriasiform dermatitis and identifies KCa3.1 as a key player in epidermal homeostasis and spongiosis. Clinically safe KCa3.1-blockers may be of therapeutic utility to treat spongiosis and itchy eczematous dermatitis.

457 Epidermal IκBζ is indispensable for induction of psoriasiform dermatitis and protection from bacterial infection

457 Epidermal IκBζ is indispensable for induction of psoriasiform dermatitis and protection from bacterial infection

721 Electrophilic nitro-fatty acids suppress psoriasiform dermatitis through the inhibition of NF-κB and STAT3

721 Electrophilic nitro-fatty acids suppress psoriasiform dermatitis through the inhibition of NF-κB and STAT3

617 Presentation of psoriasiform dermatitis in patients treated with dupilumab

617 Presentation of psoriasiform dermatitis in patients treated with dupilumab

650 IL-31 produced by Th17 cells contributes to psoriasiform dermatitis

650 IL-31 produced by Th17 cells contributes to psoriasiform dermatitis

712 Comparing RNAseq analysis of the mouse IL-23 minicircle model to human psoriasis and other preclinical models of skin inflammation

Hydrodynamic delivery of a single i.v. injection of IL-23 minicircles (MC) in male B10. RIII mice induces psoriasiform dermatitis. To further evaluate its similarity to human psoriasis, RNAseq was performed and the data used for pathway analysis. Injection of 3 μg IL-23 MC induced ear skin inflammation, and elevation of key IL-23/IL-17 pathway cytokines/chemokines over an 11 day study. The RNAseq analyses from MC mice revealed that 15 of the top 20 affected pathways were also amongst the top 20 pathways identified in human psoriasis (Li et al., 2014) including those related to the IL-17A/F pathways. Additional associations within the top 20 pathways for the MC model included neuroinflammation, IL-10 signaling, and dendritic cell maturation pathways. When comparing human alignment of the MC model to an IL-23 ear injection (4 daily injections) and other preclinical psoriasis models, including IMQ, both IL-23 models show the strongest alignment to human psoriasis. The MC model tended to have a more amplified signal compared to the IL-23 ear injection model. Shams in the IL-23 ear injection model also had transcriptome changes which are not typical of psoriasis nor found in the MC shams, and may have been related to needle stick injury. The type I interferon pathway was under represented in both IL-23 models relative to human psoriasis. Most upstream regulators were shared between human psoriasis and the MC model, and also to the IL-23 ear injection model, but to a lesser degree. Treatment with apremilast, as well as anti-IL-23p40, anti-IL-23p19, or anti-TNF mAbs suppressed most of the gene changes in the MC model. In summary, both IL-23 models align more closely with human psoriasis than other preclinical models reported in the literature. The IL-23 MC tends to have a more amplified signal of these key pathways relative to the IL-23 ear injection model, and does not induce changes that seem to be associated with needle stick injury.

022 Diet-induced obesity predisposes anti-PD-1 antibody-treated mice to imiquimod-mediated psoriasiform dermatitis: implications for immune-related adverse events in cancer patients treated with anti-PD-1

022 Diet-induced obesity predisposes anti-PD-1 antibody-treated mice to imiquimod-mediated psoriasiform dermatitis: implications for immune-related adverse events in cancer patients treated with anti-PD-1

How useful is periodic acid-Schiff stain to detect fungi in biopsies from dermatoses of the palms and soles?

Periodic acid-Shiff (PAS) stain may help to diagnose fungal infection in biopsies from dermatoses of the palms and soles. It is questionable whether PAS stain should be used routinely or only when tinea is suspected clinically. A total of 195 consecutive punch biopsies of dermatoses from the palms (90) or soles (105) were stained with PAS, regardless of the clinical differential diagnosis. PAS stain showed fungi in the corneal layer of 6 (3%) of the 195 biopsies. Tinea was included in the differential diagnosis in 48 cases, of which 3 (6%) were PAS positive. PAS stain was also positive in 3 (2%) of 147 cases in which tinea was not suspected clinically. All 6 PAS-positive cases were detected in reaction patterns not readily classified as particular diagnostic entities: non-inflammatory keratoderma (2, 11%), chronic lichenified dermatitis (2, 6%), spongiotic psoriasiform dermatitis (1, 2%), and spongiotic dermatitis (1, 4%). There is a low concordance rate between the clinical suspicion and the actual demonstration of fungi by PAS stain in dermatoses of the palms and soles. Routine PAS stains in non-suspected cases have a relatively low yield, which may be improved by limiting the PAS stain to reaction patterns not readily classified as particular diagnostic entities.

Efficacy of Chemokine Receptor Inhibition in Treating IL-36α-Induced Psoriasiform Inflammation.

Several types of psoriasiform dermatitis are associated with increased IL-36 cytokine activity in the skin. A rare, but severe, psoriasis-like disorder, generalized pustular psoriasis (GPP), is linked to loss-of-function mutations in the gene encoding IL-36RA, an important negative regulator of IL-36 signaling. To understand the effects of IL-36 dysregulation in a mouse model, we studied skin inflammation induced by intradermal injections of preactivated IL-36α. We found the immune cells infiltrating IL-36α-injected mouse skin to be of dramatically different composition than those infiltrating imiquimod-treated skin. The IL-36α-induced leukocyte population comprised nearly equal numbers of CD4+ αβ T cells, neutrophils, and inflammatory dendritic cells, whereas the imiquimod-induced population comprised γδ T cells and neutrophils. Ligands for chemokine receptors CCR6 and CXCR2 are increased in both GPP and IL-36α-treated skin, which led us to test an optimized small-molecule antagonist (CCX624) targeting CCR6 and CXCR2 in the IL-36α model. CCX624 significantly reduced the T cell, neutrophil, and inflammatory dendritic cell infiltrates and was more effective than saturating levels of an anti-IL-17RA mAb at reducing inflammatory symptoms. These findings put CCR6 and CXCR2 forward as novel targets for a mechanistically distinct therapeutic approach for inflammatory skin diseases involving dysregulated IL-36 signaling, such as GPP.

GPR15 is not critically involved in the regulation of murine psoriasiform dermatitis

BackgroundGPR15 has been implicated in the pathogenesis of T cell-driven inflammation of the skin and the gut. Expression levels of the GPR15 ligand GPR15 L are increased in psoriatic skin and considered as potential biomarker for the treatment response to anti-IL-17 antibody therapies. However, the significance of the GPR15 L/GPR15 for the pathogenesis of psoriasis and the mechanisms regulating GPR15 L expression are still elusive. ObjectiveTo determine the significance of GPR15 signaling in mouse models of psoriasis. MethodsWe addressed the role of the GPR15 L/GPR15 in the Aldara™-induced psoriasiform dermatitis (AIPD) and the IL-23-induced dermatitis model. In both models, we charted the expression levels of GPR15 L in the skin and assessed the significance of GPR15 L/GPR15 by examining Gpr15−/− mice. ResultsGPR15 L levels were increased in the AIPD, but not in the IL-23-induced dermatitis model. Deficiency in Gpr15 did not alter the course of disease neither in the AIPD, nor in the IL-23-induced dermatitis model. In neither model, deficiency in Gpr15 modulated disease on the histopathological or the molecular level. Despite the induction of GPR15 L in the AIPD model, GPR15+ cells did not accumulate in the skin. ConclusionGPR15 L expression is induced in psoriasiform dermatitis, but the activation of the IL-23/IL-17 axis alone is not sufficient for its induction. This restricts the potential use of GPR15 L levels as biomarker for the treatment response to anti-IL-17 antibody therapy. Our results leave a significant role of GPR15 in the pathogenesis of psoriasiform dermatitis rather unlikely. Hence, GPR15 L probably modulates psoriasiform dermatitis via GPR15-independent pathways.

Methodological refinement of Aldara-induced psoriasiform dermatitis model in mice

Imiquimod (IMQ)-induced skin inflammation is currently the most widely accepted psoriasis animal model, however, it features several limitations. We have modified the IMQ-model to minimize its systemic effects towards effectively maintaining the characteristic skin reactions. The original protocol (OP) uses 62.5 mg Aldara cream (or vaseline) on the shaved back skin of mice for 4 days. In contrast, in our modified protocol (MP) 25 mg Aldara and vaseline are applied simultaneously in separate Finn chambers over the dorsal skin of mice. In both the OP and MP groups, histology showed unequivocal hallmarks of psoriasiform dermatitis. Additionally, skin scaling and blood perfusion values were similar. While Aldara elicited significantly increased skin thickness in the MP group, significant weight loss, spleen enlargement, increased inflammatory cytokine levels in plasma, and treatment related death were only observed in the OP group. Our new method reproduces psoriatic skin alterations highlighting considerably reduced systemic inflammatory reactions. Possessing psoriasiform and control skin areas on the same mouse also reduces inter-individual differences. Additionally, the new method permits prolonged IMQ treatment studies to mimic the chronic nature of psoriasis. Finally, our experimental approach may also be used in other mouse models, to prevent the undesired systemic effects of topically applied drugs.

Cold atmospheric plasma ameliorates imiquimod-induced psoriasiform dermatitis in mice by mediating antiproliferative effects

Psoriasis is a chronic hyperproliferative skin disease characterised by excessive growth of keratinocytes. Indeed, inducing keratinocyte apoptosis is a key mechanism responsible for psoriatic plaques clearance following some important existing therapies, which display pro-oxidant activity. Cold atmospheric plasma (CAP), acting as a tuneable source of reactive oxygen and nitrogen species (RONS), can controllably transfer RONS to the cellular environment, deliver antiproliferative RONS concentrations and exert antiproliferative and proapoptotic effects. This study was undertaken to evaluate the therapeutic potential of CAP in psoriasis. We used cell models of psoriasis-like inflammation by adding lipopolysaccharide (LPS) or tumour necrosis factor alpha (TNF-α) to HaCaT keratinocytes. Indirect plasma, plasma-activated medium (PAM), was administered to HaCaT cells. Atmospheric pressure plasma jet (APPJ) was applied directly to imiquimod (IMQ)-induced psoriasiform dermatitis in mice. The results showed that PAM induced an increase in intracellular ROS and caused keratinocyte apoptosis. Moreover, cells under inflammation showed lesser viability and larger apoptosis rate. With repeated administration of APPJ, psoriasiform lesions showed ameliorated morphological manifestation and reduced epidermal proliferation. Overall, this study supports that CAP holds good potential in psoriasis treatment.

Human amnion-derived mesenchymal stem cells ameliorate imiquimod-induced psoriasiform dermatitis in mice.

Human amnion-derived mesenchymal stem cells ameliorate imiquimod-induced psoriasiform dermatitis in mice.

“Interface” Dermatoses: Revisited

“Interface dermatoses” are defined as inflammatory dermatoses primarily affecting the interface elements along the dermoepidermal junction, resulting in epidermal basal cell damage. This epidermal basal cell damage can be of two forms: vacuolar/hydropic degeneration and filamentous degeneration (resulting in Civatte bodies). This may be associated with a range of secondary epidermal (atrophy to hypertrophy) and dermal changes (varying from simple effacement of the rete ridges to the diffuse dermal fibrosis/sclerosis). With so many variables, “Interface dermatitis” per se is not a diagnosis by itself but simply a reaction pattern, similar to “psoriasiform dermatitis” or “spongiotic dermatitis.” One should never use these terms as the final sign out diagnosis in reports, though in difficult cases one may allude to the reaction pattern and discuss the possible differentials. This article analyzes and discusses in detail, the basic pathogenesis behind the primary/secondary features associated with interface dermatoses and the steps involved in their histopathological evaluation; thorough knowledge of which may help one arrive at a specific diagnosis.

Signs of chronic itch in the mouse imiquimod model of psoriasiform dermatitis: sex differences and roles of TRPV1 and TRPA1.

Plaque psoriasis is a chronic inflammatory skin disease that affects a substantial proportion of the world population. This disorder is characterized by scaly, thick skin, intense ongoing itch, and itch from light touch (such as clothing contacting skin, called “alloknesis”). Imiquimod is a topical treatment for basal cell carcinomas and warts that has been used to create a mouse model of plaque psoriasis. Imiquimod-treated male, but not female, wildtype B6 mice showed significant increases in spontaneous scratching, while both sexes exhibited increased alloknesis, indicative of chronic itch. TRPV1 and TRPA1 knockout (KO) mice all exhibited numeric increases in spontaneous scratching which were significant for TRPV1KO mice and TRPA1KO males. Female TRPV1KO and TRPA1KO mice exhibited imiquimod-induced increases in alloknesis scores that did not significantly differ from wildtypes, while alloknesis scores in imiquimod-treated male TRPV1KO and TRPA1KO mice were significantly lower compared with wildtypes, suggesting that these ion channels are necessary for the development of alloknesis in males but not females in this model. Curiously, none of the groups exhibited any significant overall change in chloroquine-evoked scratching following imiquimod treatment, indicating that hyperknesis does not develop in this mouse model. Overall, the data indicate that there are sex differences in this mouse model of psoriasis, and that TRPV1 and TRPA1 ion channels have a small role in promoting the development of itch sensitization. This contrasts with the far greater role these channels play in the manifestation of skin changes in psoriatic dermatitis.

IL-36 receptor antagonistic antibodies inhibit inflammatory responses in preclinical models of psoriasiform dermatitis.

Psoriasis vulgaris (PV) results from activation of IL-23/Th17 immune pathway and is further amplified by cytokines/chemokines from skin cells. Among skin-derived pro-inflammatory cytokines, IL-36 family members are highly upregulated in PV patients and play a critical role in general pustular psoriasis. However, there is limited data showing crosstalk between the IL-23 and IL-36 pathways in PV. Herein, potential attenuation of skin inflammation in the IL-23-induced mouse model of psoriasiform dermatitis by functional inhibition of IL-36 receptor (IL-36R) was interrogated. Anti-mouse IL-36R monoclonal antibodies (mAbs) were generated and validated in vitro by inhibiting IL-36α-induced secretion of CXCL1 from NIH 3T3 cells. Antibody target engagement was demonstrated by inhibition of CXCL1 production in a novel acute model of IL-36α systemic injection in mice. In addition, anti-IL-36R mAbs inhibited tissue inflammation and inflammatory gene expression in an IL-36α ear injection model of psoriasiform dermatitis demonstrating engagement of the target in the ear skin. To elucidate the possible role of IL-36 signalling in IL-23/Th17 pathway, the ability of anti-IL-36R mAbs to inhibit skin inflammation in an IL-23 ear injection model was assessed. Inhibiting the IL-36 pathway resulted in significant attenuation of skin thickening and psoriasis-relevant gene expression. Taken together, these data suggest a role for IL-36 signalling in the IL-23/Th17 signalling axis in PV.

A Western Diet, but Not a High-Fat and Low-Sugar Diet, Predisposes Mice to Enhanced Susceptibility to Imiquimod-Induced Psoriasiform Dermatitis

Author(s): Yu, Sebastian; Wu, Xuesong; Zhou, Yan; Sheng, Lili; Jena, Prasant Kumar; Han, Dan; Wan, Yu Jui Yvonne; Hwang, Samuel T

TRPV1 mediates inflammation and hyperplasia in imiquimod (IMQ)-induced psoriasiform dermatitis (PsD) in mice

BackgroundTransient Receptor Potential Vanilloid 1 (TRPV1) is known to mediate itch and neurogenic inflammation, but the role of TRPV1 in psoriasiform dermal inflammation is poorly understood. ObjectiveTo investigate the function of TRPV1 in imiquimod (IMQ)-induced psoriasiform dermatitis (PsD) in mice. MethodsFollowing daily treatment of topical IMQ cream for consecutive 5 days in C57BL/6 wide-type (WT) and TRPV1 gene knockout (KO) mice, we assessed the psoriasis severity index (PSI) scores, transepidermal water loss (TEWL), dermal inflammatory infiltrates, as well as gene expression levels for psoriasis related genes in mouse skin lesions. ResultsCompared with WT mice, the clinical and TEWL scores, the extent of skin hyperplasia, the area of Munro microabscesses (MM) and angiogenesis of psoriasis were all significantly decreased in TRPV1 KO mice triggered with IMQ, suggesting a reduction in skin inflammation and barrier defects. In addition, the infiltration of CD45+ leukocytes, mast cells as well as CD3+ T cells was all reduced in the IMQ-treated skin of TRPV1 KO mice. Quantitative Real-time PCR (RT-qPCR) revealed that expression levels of IL-1β, IL-6, IL-23, S100A8 were decreased while IL-10 was increased in TRPV1 KO mice. ConclusionsIn summary, key markers of psoriatic inflammation and epidermal hyperplasia are reduced in TRPV1 KO mice, indicating the involvement of TRPV1 in the psoriasiform inflammation and suggesting its potential as a therapeutic target.