The CDK4/6-EZH2 pathway is a potential therapeutic target for psoriasis.

Psoriasis is a frequent, inflammatory skin disease characterized by keratinocyte hyperproliferation and a disease-related infiltration of immune cells. Here, we identified a novel proinflammatory signaling pathway driven by cyclin-dependent kinase 4 (CDK4) and CDK6 and the methyltransferase EZH2 as a valid target for psoriasis therapy. Delineation of the pathway revealed that CDK4/6 phosphorylated EZH2 in keratinocytes, thereby triggering a methylation-induced activation of STAT3. Subsequently, active STAT3 resulted in the induction of IκBζ, which is a key proinflammatory transcription factor required for cytokine synthesis in psoriasis. Pharmacological or genetic inhibition of CDK4/6 or EZH2 abrogated psoriasis-related proinflammatory gene expression by suppressing IκBζ induction in keratinocytes. Importantly, topical application of CDK4/6 or EZH2 inhibitors on the skin was sufficient to fully prevent the development of psoriasis in various mouse models by suppressing STAT3-mediated IκBζ expression. Moreover, we found a hyperactivation of the CDK4/6-EZH2 pathway in human and mouse psoriatic skin lesions. Thus, this study not only identifies a novel psoriasis-relevant proinflammatory pathway, but also proposes the repurposing of CDK4/6 or EZH2 inhibitors as a new therapeutic option for patients with psoriasis.

Keratinocyte-derived IκBζ drives psoriasis and associated systemic inflammation.

The transcriptional activator IκBζ is a key regulator of psoriasis, but which cells mediate its pathogenic effect remains unknown. Here we found that IκBζ expression in keratinocytes triggers not only skin lesions but also systemic inflammation in mouse psoriasis models. Specific depletion of IκBζ in keratinocytes was sufficient to suppress the induction of imiquimod- or IL-36-mediated psoriasis. Moreover, IκBζ ablation in keratinocytes prevented the onset of psoriatic lesions and systemic inflammation in keratinocyte-specific IL-17A-transgenic mice. Mechanistically, this psoriasis protection was mediated by IκBζ deficiency in keratinocytes abrogating the induction of specific proinflammatory target genes, including Cxcl5, Cxcl2, Csf2, and Csf3, in response to IL-17A or IL-36. These IκBζ-dependent genes trigger the generation and recruitment of neutrophils and monocytes that are needed for skin inflammation. Consequently, our data uncover a surprisingly pivotal role of keratinocytes and keratinocyte-derived IκBζ as key mediators of psoriasis and psoriasis-related systemic inflammation.

Replacement of brain-resident myeloid cells does not alter cerebral amyloid-ß deposition in mouse models of Alzheimer's disease.

Immune cells of myeloid lineage are encountered in the Alzheimer's disease (AD) brain, where they cluster around amyloid-ß plaques. However, assigning functional roles to myeloid cell subtypes has been problematic, and the potential for peripheral myeloid cells to alleviate AD pathology remains unclear. Therefore, we asked whether replacement of brain-resident myeloid cells with peripheral monocytes alters amyloid deposition in two mouse models of cerebral ß-amyloidosis (APP23 and APPPS1). Interestingly, early after repopulation, infiltrating monocytes neither clustered around plaques nor showed Trem2 expression. However, with increasing time in the brain, infiltrating monocytes became plaque associated and also Trem2 positive. Strikingly, however, monocyte repopulation for up to 6 mo did not modify amyloid load in either model, independent of the stage of pathology at the time of repopulation. Our results argue against a long-term role of peripheral monocytes that is sufficiently distinct from microglial function to modify cerebral ß-amyloidosis. Therefore, myeloid replacement by itself is not likely to be effective as a therapeutic approach for AD.

Proton pump inhibitors inhibit metformin uptake by organic cation transporters (OCTs).

Metformin, an oral insulin-sensitizing drug, is actively transported into cells by organic cation transporters (OCT) 1, 2, and 3 (encoded by SLC22A1, SLC22A2, or SLC22A3), which are tissue specifically expressed at significant levels in various organs such as liver, muscle, and kidney. Because metformin does not undergo hepatic metabolism, drug-drug interaction by inhibition of OCT transporters may be important. So far, comprehensive data on the interaction of proton pump inhibitors (PPIs) with OCTs are missing although PPIs are frequently used in metformin-treated patients. Using in silico modeling and computational analyses, we derived pharmacophore models indicating that PPIs (i.e. omeprazole, pantoprazole, lansoprazole, rabeprazole, and tenatoprazole) are potent OCT inhibitors. We then established stably transfected cell lines expressing the human uptake transporters OCT1, OCT2, or OCT3 and tested whether these PPIs inhibit OCT-mediated metformin uptake in vitro. All tested PPIs significantly inhibited metformin uptake by OCT1, OCT2, and OCT3 in a concentration-dependent manner. Half-maximal inhibitory concentration values (IC(50)) were in the low micromolar range (3-36 µM) and thereby in the range of IC(50) values of other potent OCT drug inhibitors. Finally, we tested whether the PPIs are also transported by OCTs, but did not identify PPIs as OCT substrates. In conclusion, PPIs are potent inhibitors of the OCT-mediated metformin transport in vitro. Further studies are needed to elucidate the clinical relevance of this drug-drug interaction with potential consequences on metformin disposition and/or efficacy.

[The English Sweating Sickness' of 1529 in Augsburg: a challenge to body and soul and the printer]. / "Englischer Schweiss" 1529 in Augsburg: "Suchet man leybsärtzney, warumb sucht man nit artzney der seelen"?

In 1529, Sudor anglicus, the 'English Sweating Sickness', spread from England to Germany reaching the city of Augsburg. Its exact nature is unclear: the symptoms were profuse sweating, uncontrollable thirst, and headaches, with death occurring within hours of infection. Those who survived the first twenty-four hours returned to health. According to one source the fever arrived in Autumn 1529 and in September there were 800 deaths; another source gives November as the onset with 600 deaths. While these death rates were in fact relatively low compared with the plague, for instance, people were particularly frightened by the sudden appearance of an unknown fever and the speed of death. Augsburg was aware that the 'English Sweating Sickness' was spreading in Germany. What is remarkable was the quick reaction of the printing trade. Two related types of handbooks so on appeared; whichwill serve as the subject of this paper. Firstly, handbooks dealing with the fever as a medical issue, and secondly, those dealing with the fever as an issue of theology. An illustrative example of each handbook is discussed here. Authored at speed and quickly published, they reflect the urgent response to the outbreak. What is demonstrated is the need to attend both to body and soul, that the 'English Sweating Sickness' was a challenge not just to physicians but also to theologians. The printing trade seized the opportunity to meet both needs.