Commensal microbes modulate the immune system in the colon through short-chain fatty acids, which induce regulatory T cells (Treg). Accordingly, the short-chain fatty acid sodium butyrate (SB) suppressed allergic contact dermatitis in mice through the activation of Treg. There is evidence that Treg exert the capacity to control inflammation in psoriasis. Thus, we were interested in studying the effect of SB in psoriasis, utilizing the imiquimod-induced psoriasis-like skin inflammation model. Topical application of imiquimod induced thickening of the skin, scales, and inflammation. This was associated with an upregulation of IL-17 and downregulation of IL-10 and FOXP3. Topically applied SB reduced imiquimod-induced inflammation and downregulated IL-17 and induced IL-10 and FOXP3 transcripts. The mitigating effect of SB was due to Treg because it was lost upon depletion of Treg in the depletion of regulatory T cell mice. Treg isolated from the blood of patients with psoriasis were reduced in their suppressive activity, which was normalized by SB. The fewer Treg numbers in the biopsies of psoriatic lesions as well as enhanced IL-17e and IL-6eexpression levels and reduced IL-10e and FOXP3eexpression levels were restored by SB. These data indicate that psoriasis is associated with an impairment of Treg and an altered cytokine milieu. Short-chain fatty acids appear to restore these alterations, thereby harboring a therapeutic potential for psoriasis.

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The organ-specific microbiome plays a crucial role in tissue homeostasis, among other things by inducing regulatory T cells (Treg). This applies also to the skin and in this setting short chain fatty acids (SCFA) are relevant. It was demonstrated that topical application of SCFA controls the inflammatory response in the psoriasis-like imiquimod (IMQ)-induced murine skin inflammation model. Since SCFA signal via HCA2, a G-protein coupled receptor, and HCA2 expression is reduced in human lesional psoriatic skin, we studied the effect of HCA2 in this model. HCA2 knock-out (HCA2-KO) mice reacted to IMQ with stronger inflammation, presumably due to an impaired function of Treg. Surprisingly, injection of Treg from HCA2-KO mice even enhanced the IMQ reaction, suggesting that in the absence of HCA2 Treg switch from a suppressive into a proinflammatory type. HCA2-KO mice differed in the composition of the skin microbiome from wild type mice. Co-housing reversed the exaggerated response to IMQ and prevented the alteration of Treg, implying that the microbiome dictates the outcome of the inflammatory reaction. The switch of Treg into a proinflammatory type in HCA2-KO mice could be a downstream phenomenon. This opens the opportunity to reduce the inflammatory tendency in psoriasis by altering the skin microbiome.

Psoriasis is a common skin inflammatory disorder known for its hallmark of having abnormal keratinocyte differentiation. In psoriatic skin, the expression of liver X receptors (LXRa and LXRb), a nuclear receptor family of transcription factors has shown to be down-regulated. In addition, LXR plays an integral part in the control of keratinocyte differentiation. However, very few studies have been conducted to understand the role of LXRs during skin inflammation. We hypothesized that LXRs in the skin can interfere the immune cascade in the induction of psoriatic inflammation. We first evaluated imiquimod (IMQ)-induced psoriatic inflammation in murine ear skin that was simultaneously treated with or without an LXR agonist (GW3965) for 11 days. We found that IMQ-induced skin inflammation was milder in mice treated with GW3965 than in mice treated with its vehicle. In addition, qPCR analysis demonstrated that the gene expression levels of pro-resolution mediators (ABCA1, MerTK and TGF-b) in the IMQ-treated skin were higher in the LXR agonist-treated group than in the control group. We also performed lipidomics analysis to understand the role of the LXR agonist for the generation of lipid mediators in the skin. The levels of key immune recruitment lipid mediators (leukotriene D4 and prostaglandin E2) in the skin lesions were lower in the LXR agonist-treated group than in the control group. To further illustrate the role of LXRs for the immune cell recruitment in psoriatic skin inflammation, we performed whole mount skin imaging. We observed that neutrophil recruitment in the IMQ-treated skin were markedly lower in the LXR agonist-treated group compared to the control group. These results suggest that the activation of LXRs can alleviate psoriatic skin inflammation via the generation of proresolving molecules and the regulation of the synthesis of lipid mediators.

Necroptosis is a form of programmed necrosis dependent on Receptor Interacting Protein Kinase 3 (RIPK3) and Mixed Lineage Kinase domain Like pseudokinase (MLKL). It is antagonised by apoptotic effectors FADD and caspase-8. Necroptosis has been shown previously to trigger psoriasis-like skin inflammation in mice upon epidermal-specific deletion of FADD or caspase-8 (FADD or caspase-8 EKO ). Here, we show that alarmin IL-33 is highly expressed in necroptotic epidermis of caspase-8 EKO mice and induces the inflammatory cascade upon keratinocyte necroptosis. Genetic ablation of IL-33 or its receptor ST2 (or IL-33R) dramatically delays lesion development and improves survival in caspase-8 EKO animals. Interestingly, impairment of the IL33-IL33R axis does not affect epidermal necroptosis but reduces immune cell recruitment and subsequent amplification of inflammation. Recent data in the literature have highlighted expression IL-33 in the epidermis of psoriasis patients. Taken together, our findings highlight a pivotal role of IL-33 in necroptosis-induced psoriasis-like skin inflammation.