Crisaborole efficacy in murine models of skin inflammation and Staphylococcus aureus infection
Christine Youn
Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
Search for more papers by this authorDustin A. Dikeman
Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
Search for more papers by this authorEvelyn Chang
Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
Search for more papers by this authorHaiyun Liu
Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
Search for more papers by this authorSabrina J. Nolan
Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
Search for more papers by this authorMartin P. Alphonse
Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
Search for more papers by this authorDaniel P. Joyce
Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
Search for more papers by this authorQi Liu
Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
Search for more papers by this authorJames Meixiong
The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
Search for more papers by this authorXinzhong Dong
Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
Search for more papers by this authorLloyd S. Miller
Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
Search for more papers by this authorCorresponding Author
Nathan K. Archer
Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
Correspondence
Nathan K. Archer, PhD, Johns Hopkins Department of Dermatology Cancer Research Building II, Suite 2M04 1550 Orleans Street Baltimore, MD 21231 USA.
Email: [email protected]
Search for more papers by this authorChristine Youn
Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
Search for more papers by this authorDustin A. Dikeman
Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
Search for more papers by this authorEvelyn Chang
Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
Search for more papers by this authorHaiyun Liu
Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
Search for more papers by this authorSabrina J. Nolan
Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
Search for more papers by this authorMartin P. Alphonse
Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
Search for more papers by this authorDaniel P. Joyce
Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
Search for more papers by this authorQi Liu
Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
Search for more papers by this authorJames Meixiong
The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
Search for more papers by this authorXinzhong Dong
Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
Search for more papers by this authorLloyd S. Miller
Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
Search for more papers by this authorCorresponding Author
Nathan K. Archer
Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
Correspondence
Nathan K. Archer, PhD, Johns Hopkins Department of Dermatology Cancer Research Building II, Suite 2M04 1550 Orleans Street Baltimore, MD 21231 USA.
Email: [email protected]
Search for more papers by this authorAbstract
Phosphodiesterase 4 (PDE4) is highly expressed in keratinocytes and immune cells and promotes pro-inflammatory responses upon activation. The activity of PDE4 has been attributed to various inflammatory conditions, leading to the development and approval of PDE4 inhibitors as host-directed therapeutics in humans. For example, the topical PDE4 inhibitor, crisaborole, is approved for the treatment of mild-to-moderate atopic dermatitis and has shown efficacy in patients with psoriasis. However, the role of crisaborole in regulating the immunopathogenesis of inflammatory skin diseases and infection is not entirely known. Therefore, we evaluated the effects of crisaborole in multiple mouse models, including psoriasis-like dermatitis, AD-like skin inflammation with and without filaggrin mutations, and Staphylococcus aureus skin infection. We discovered that crisaborole dampens myeloid cells and itch in the skin during psoriasis-like dermatitis. Furthermore, crisaborole was effective in reducing skin inflammation in the context of filaggrin deficiency. Importantly, crisaborole reduced S. aureus skin colonization during AD-like skin inflammation. However, crisaborole was not efficacious in treating S. aureus skin infections, even as adjunctive therapy to antibiotics. Taken together, we found that crisaborole reduced itch during psoriasis-like dermatitis and decreased S. aureus skin colonization upon AD-like skin inflammation, which act as additional mechanisms by which crisaborole dampens the immunopathogenesis in mouse models of inflammatory skin diseases. Further examination is warranted to translate these preclinical findings to human disease.
CONFLICT OF INTEREST
LSM is a full-time employee of Janssen Pharmaceuticals and holds Johnson & Johnson stock. LSM performed all work at his previous affiliation at Johns Hopkins University School of Medicine and has received previous grant support from AstraZeneca, Pfizer, Boehringer Ingelheim, Regeneron Pharmaceuticals, and Moderna Therapeutics; was a paid consultant for Almirall and Janssen Research and Development; was on the scientific advisory board of Integrated Biotherapeutics; and is a shareholder of Noveome Biotherapeutics, which are all developing therapeutics against infections (including Staphylococcus aureus and other pathogens) and/or inflammatory conditions. XD is a co-founder and a scientific advisory board member of Escient Pharmaceuticals, a company focussed on developing small molecules targeting MRGPRs. NKA has received previous grant support from Pfizer and Boehringer Ingelheim; and was a paid consultant for Janssen Pharmaceuticals. The remaining authors state no conflict of interest.
Open Research
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Supporting Information
| Filename | Description |
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| exd14722-sup-0001-FigureS1.docxWord 2007 document , 533.3 KB |
Figure S1. Flow cytometric gating strategy from a vehicle-treated mouse. Representative flow cytometric gating strategy of live myeloid immune cells (CD45+CD11b+) cells for identification of eosinophils (Siglec-F+), monocytes (Ly6GloLy6Chi), neutrophils (Ly6GhiLy6Clo) and macrophages (CD115+F4/80+). |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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