Doxycycline, a tetracycline antibiotic, is widely used in the field of dermatology for its antibiotic properties, anti-inflammatory properties and good safety profile. Over the past decades, numerous studies have clarified some of the anti-inflammatory mechanisms of doxycycline. In this review article, we aimed to provide an update on recent data on the anti-inflammatory properties of doxycycline and its potential role in cutaneous inflammatory diseases. Better understanding of these mechanisms might offer the practicing clinicians a better use of this therapeutic tool. In addition, research in this field could help clarify pathogenic aspects of inflammatory dermatologic diseases responsive to this medication. Further research is needed to fully elucidate the potential of doxycycline as an anti-inflammatory agent, and the development of new topical vehicles could open ways to new therapeutic possibilities for dermatologists.

Protease‐activated receptor 2 (PAR2) is a transmembrane receptor expressed by multiple tissues, including skin, with rapidly expanding knowledge regarding its roles. In the skin, PAR2 has extensively documented effects in promoting Th2 inflammation and pruritus; and its role in atopic dermatitis continues to be thoroughly studied. Numerous new investigations have shown a more complex range of activities potentially related to dermatologic diseases. Goal of this review is to outline emerging effects of PAR2 activation in the skin other than those related to immunologic and pruritic functions. Specifically, this work seeks to summarize current knowledge (and gaps) of PAR2 as a regulator of epidermal barrier, keratinocyte differentiation, cutaneous tumorigenesis and pigmentation. Additional focus will be placed on possible involvement in dermatologic disease and emergence as a therapeutic target.

Dogs were topically challenged with HDM extract and symptoms of itching were monitored by videotaping for 6 hours on the third day after the challenge and counting the time the dogs spent scratching. While active and placebo dogs showed similar itching before immunization, immunized dogs showed clearly reduced symptoms of itching, in particular early after immunization, when antibody titers were high (Fig 2, A). Assuming that dogs showing more than 50% reduced scratching compared with the average of the placebo dogs, 4 to 5 out of 6 dogs were responders whereas 0 to 1 dog was a responder in the placebo group (Fig 2, B). Reduced scratching correlated well with antibody titers induced (Fig 2, C and D, for the first 2 time points), supporting the mechanism of action. At a later time point, when antibody responses declined, reduced scratching was less pronounced (Fig 2, B). Allergic dermatitis is a major health issue in dogs. Most current treatment options are either ineffective or may be associated with serious side effects. Allergen-specific immunotherapy is safe but not effective in all dogs and compliance is low. Here, we describe a novel treatment option consisting of active vaccination against IL-31, a major cause of itching in dogs and other mammals, such as humans and mice. IL-31 is currently targeted by 2 different drugs, namely, Apoquel and an mAb directed against IL-31. 1 In contrast to these 2 existing modalities to block IL-31, which require frequent administration, vaccination offers the advantage of high specificity combined with infrequent administration of small amounts of antigen; in the present study, a 100-mg dose followed by two 300-mg doses were tested. Two important points emerged, namely, that the vaccine was (1) well tolerated and (2) induced protective antibody levels in most dogs. In summary, the present study lays the foundation of a novel breakthrough therapeutic modality for the treatment of AD in dogs. Next studies will be performed to increase and prolong efficacy by studying dose responses and the role of adjuvants in more detail. The insights we gain here for the treatment of dogs may be harnessed for the development of a homologous vaccine for use in humans. We thank Linda J€ ohr and Marianne Zwicker for excellent technical assistance and Mona Mohsen and Monique Vogel for critically reading the manuscript.

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The type I keratin 14 (K14) is mainly expressed in the basal layer of epidermis and related stratified epithelia. Previous work revealed a role for inter-keratin disulfide bonding involving residue cysteine (Cys) 367 of human K14 toward the assembly, organization, and dynamics of keratin filaments in skin keratinocytes in culture. To define the function of K14-dependent disulfide bonding in skin epithelia in vivo, we generated Krt14C373A mice using the Crispr/ Cas9 technology (mouse Cys373 is orthologous to human Cys367). Western blotting revealed a marked decrease in disulfide-bonded K14 species in Krt14C373A ear and tail skin relative to control. Morphological analyses revealed a state of hyperproliferation and hyperkeratosis, dysregulated keratinocyte differentiation, and abnormal cornified envelopes in Krt14C373A skin. Adult Krt14C373A mice show a skin barrier defect at baseline, reflected by increased trans-epidermal water loss. The latter trait is enhanced following topical acetone irritation. Mass spectrometry-based assays identified 14-3-3 as a major K14 interacting protein, and follow-up studies confirmed that 14-3-3 interacts with both WT and C373A mutant forms. 14-3-3 forms aggregates in Krt14C373A keratinocytes in situ, accompanied by abnormal nuclear localization of Yap1, a transcriptional effector of Hippo signaling, in suprabasal differentiated keratinocytes. Mutagenesis shows that the subcellular distribution and regulation of 14-3-3 and Yap1 is specifically regulated by residue Cys373 in mouse K14. The results obtained to date establish that K14-dependent disulfide bonding plays a physiologically important role in epidermal homeostasis and barrier function by impacting the solubility, regulation and function of 14-3-3/Yap1.

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