Barrea et al., 2016 Barrea L.

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Di Somma C.

Savanelli M.C.

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et al. Environmental risk factors in psoriasis: the point of view of the nutritionistInt. Ford et al., 2018 Ford A.R.

Siegel M.

Bagel J.

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et al. Dietary recommendations for adults with psoriasis or psoriatic arthritis from the Medical Board of the National Psoriasis Foundation. Herbert et al., 2018 Herbert D.

Franz S.

Popkova Y.

Anderegg U.

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et al. High-fat diet exacerbates early psoriatic skin inflammation independent of obesity: saturated fatty acids as key players. Nakamizo et al., 2017 Nakamizo S.

Honda T.

Adachi A.

Nagatake T.

Kunisawa J.

Kitoh A.

et al. High fat diet exacerbates murine psoriatic dermatitis by increasing the number of IL-17-producing γδ T cells. Nutrition is considered an essential factor in the management of inflammatory skin diseases such as psoriasis (). A recent study identified saturated fatty acid (FA) intake as a significant risk factor for exacerbation of psoriasis, independent of adipocytokine levels, fat mass, and glucose homeostasis (). In line with this observation, another study showed that in mice fed a high-fat diet (60% of kcal from fat) in which there was still a substantial amount of carbohydrates (20% of kcal), T-cells accumulated in the skin and promoted psoriasis via IL-17A production ().

Locker et al., 2018 Locker F.

Vidali S.

Holub B.S.

Stockinger J.

Brunner S.M.

Ebner S.

et al. Lack of galanin receptor 3 alleviates psoriasis by altering vascularization, immune cell infiltration, and cytokine expression. Figure 1 Impact of dietary composition on severity of IMQ-induced inflammation and basal skin health in mice. (a) Semi-quantitative scoring of erythema, (b) scaling, (c) thickening of the skin and (d) cumulative scoring over time, and following IMQ and (g–j) vehicle treatment on day 4 in mice fed respective diets. Values are depicted as mean ± standard error of mean (n = 18 [day 2–3; IMQ], n = 12 [day 4; IMQ], n = 6 [day 7; IMQ], n = 7–9 [d4; vehicle]). Statistical significance was assessed using non-parametric Kruskal-Wallis test: *P < 0.05, **P < 0.01, ***P <0.001. (e, k) Representative images from day 4 and (f) day 7. (l) Representative images of hematoxylin and eosin-stained skin sections on day 4 in IMQ-treated mice (Bar = 40 μm). d, day; IMQ, imiquimod; LCT, long-chain triglycerides; MCT, medium-chain triglycerides; SD, standard diet; ω-3, omega-3. All animal experiments were approved by the local animal ethics committee according to Austrian legislation on animal experiments (20901-TVG/118/6-2017). Induction of psoriasis via IMQ () led to increased erythema in mice fed with an LCT/MCT diet compared to SD-fed mice on day 4 ( Figure 1 a). The LCT/MCT group showed a trend toward increased cumulative disease severity compared to the SD group (8.2 ± 1.1 vs. 6.2 ± 0.7; P = 0.07), which was significant in comparison with the LCT group (8.2 ± 1.1 vs. 5.9 ± 1.7; P < 0.05) after 4 days of IMQ treatment ( Figure 1 d). Inflammatory patterns were not affected by ω-3 supplementation, as evidenced by the high cumulative disease severity in the LCT/MCT + ω-3 group on day 4 compared to the SD + ω-3 group ( Figure 1 d, e, and l). Interestingly the LCT/MCT KD ± ω-3 FA supplementation induced skin inflammation, even in Vaseline-treated mice, as illustrated by the significant increase in erythema, scaling, and thickening ( Figure 1 g–i) as well as the cumulative disease severity score compared to Vaseline-treated SD-fed mice on day 4 ( Figure 1 j and k). Because the SD ± ω-3 FA-fed mice showed no signs of skin inflammation we cannot exclude that the LCT/MCT ± ω-3 FA diets can also affect normal skin.

Figure 2 Molecular and cellular effects of KD feeding on murine skin. Relative mRNA levels of (a) IL-17A, (b) IL-1β and (f) Vegf in skin sections of IMQ and (a, b) vehicle-treated mice on day 4. (c) MPO concentration (U/ml) in 8-mm skin punch biopsies, (d) number of NIMP-R14+-stained cells and (e) CD31-positive vessels in paraffin-embedded skin sections of IMQ and (c) vehicle-treated mice on day 4. (g) Cytokine levels of IFN-γ, (h) IL-6 and (i) IL-1β in blood plasma of vehicle (n = 7–9) and imiquimod-treated (n =10–12) mice on day 4. All values are depicted as mean ± standard error of mean. Statistical significance was assessed using one-way analysis of variance, Tukey's multiple comparison, and non-parametric Kruskal-Wallis test (mRNA analysis): *P < 0.05, **P < 0.01, ***P < 0.001. IMQ, imiquimod; LCT, long-chain triglycerides; MCT, medium-chain triglycerides; MPO, myeloperoxidase; SD, standard diet; ω-3, omega-3. LCT/MCT and LCT groups showed significantly higher skin levels of IL-17A mRNA than the SD group, after IMQ treatment ( Figure 2 a). Supplementation with ω-3 FA changed this pattern only slightly because the LCT + ω-3 group expressed higher levels of IL-17A mRNA compared to the SD + ω-3 control after IMQ treatment ( Figure 2 a). However, addition of ω-3 FAs to the LCT and LCT/MCT diets resulted in a significant increase of IL-1β mRNA compared with the SD + ω-3 group ( Figure 2 b), after IMQ treatment. The level of IL-12b mRNA was significantly lower only in the skin of the LCT/MCT + ω-3 group compared with the SD + ω-3 control ( Supplementary Figure S4 ). Interestingly, all skin biopsies of Vaseline-treated mice fed KDs with or without ω-3 FAs showed increased levels of IL-17A mRNA ( Figure 2 a). In contrast, IL-1β mRNA was upregulated only when ω-3 FAs were added to the LCT/MCT-KD compared with SD + ω-3 ( Figure 2 b).

+ neutrophils in LCT/MCT + ω-3 skin compared to SD + ω-3 skin (P < 0.05) ( LCT/MCT + ω-3 skin showed significantly higher neutrophil-derived myeloperoxidase levels in comparison with SD + ω-3 skin upon psoriasis induction and Vaseline treatment ( Figure 2 c). Accordingly, we detected a significantly higher number of NIMP-R14neutrophils in LCT/MCT + ω-3 skin compared to SD + ω-3 skin (P < 0.05) ( Figure 2 d and Supplementary Figure S3 ).

CD31-positive vessels in skin sections did not differ between LCT KD, LCT/MCT KD, and SD-fed mice (± ω-3) 4 days after IMQ treatment. However, there was a significant difference between the SD and SD + ω-3 groups (83.2 ± 12.3 vs. 71.9 ± 6.0, P = 0.012) ( Figure 2 e). Vegf mRNA levels were not altered after 4 days of IMQ treatment ( Figure 2 f).

Herbert et al., 2018 Herbert D.

Franz S.

Popkova Y.

Anderegg U.

Schiller J.

Schwede K.

et al. High-fat diet exacerbates early psoriatic skin inflammation independent of obesity: saturated fatty acids as key players. Croxford et al. (2014) Croxford A.L.

Karbach S.

Kurschus F.C.

Wörtge S.

Nikolaev A.

Yogev N.

et al. IL-6 regulates neutrophil microabscess formation in IL-17A-driven psoriasiform lesions. Our data indicate that the low carbohydrate content in the KD might protect from the previously reported pro-inflammatory effects of saturated FA intake (). However, the FA composition of KD needs to be taken in consideration, as supplementation with MCTs and ω-3 FAs exacerbate IMQ-induced psoriasis, as well as elicit basal skin alterations. As the IMQ model is transient future research should focus on the long-term effects of KDs in a chronic psoriasiform-like skin inflammation model such as the K14-IL-17A(ind/+) model, described by

Data availability statement Datasets related to this article can be found at https://doi.org/10.17632/mnb67rtr2v.2 , an open-source online data repository hosted at Mendeley Data.

Conflict of Interest The authors declare no conflict of interest.

Acknowledgments The study was supported by the Paracelsus Medical University Research Fund ( PMU-FFF E-16/24/125-LAL ), TRANSMIT project ( EU H2020-MSCA-ITN-2016-722605 ) and the Austrian Research Promotion Agency ( 822782 /THERAPEP). Author Contributions Conceptualization, FL, RL, BK; Methodology, FL, BK; Investigation, FL, JL, SA, PS, AK, DDW, RGF, RW; Formal Analysis, FL; Visualization, FL; Writing – Original Draft, FL, RL, BK; Writing – Review & Editing, FL, RL, BK; Funding. Acquisition, FL, RL, BK; Supervision, RL, BK

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