IL-17 Induces Skin Inflammation Independently of IL-23R+ T Cells and Is Protected By Conditional Deletion of Wdfy3 in Neutrophils

Erika Suzuki¹, Emanual Maverakis², Laura Bouchareychas¹, Vijay K. Kuchroo³, Frank Nestle⁴ and Iannis E. Adamopoulos¹, ¹Internal Medicine, University of California, Davis, Sacramento, CA, ²Dermatology, University of California, Davis, Sacramento, CA, ³Center of Neurological Disease, Harvard Medical School, Boston, MA, ⁴Mary Dunhill Chair of Cutaneous Medicine and Immunotherapy Division of Genetics and Molecular Medicine St Johns Institute of Dermatology, King's College London, London, England

Meeting: 2015 ACR/ARHP Annual Meeting

Date of first publication: September 29, 2015

Keywords: Neutrophils and psoriatic arthritis

Session Information

Date: Tuesday, November 10, 2015

Title: Spondylarthropathies and Psoriatic Arthritis Pathogenesis, Etiology Poster I

Session Type: ACR Poster Session C

Session Time: 9:00AM-11:00AM

Background/Purpose: IL-17 is elevated in both the lesional skin and arthritic joints of psoriatic arthritis (PsA) patients, however, the direct effect of IL-17 on myeloid cells in PsA is less understood. We recently identified a unique molecule, Wdfy3, associated with IL-17 and neutrophil-driven epidermal hyperplasia. Using a cre-lox system to selectively ablate Wdfy3 in myeloid cells, we report the effect of Wdfy3 in protecting against epidermal hyperplasia.

Methods: We performed gene transfer of IL-17 by hydrodynamic delivery of minicircle (MC) DNA in control (C57BL/6) mice and mice treated with topical imiquimod. The psoriatic features were analyzed and scored for disease progression histologically. Further phenotypic analysis of cell populations was performed by flow cytometry, RT-qPCR, and in vivo imaging using nanoprobes in Il23r^-/-Rag^-/-, Tcrd^-/- and Wdfy3-LysM^Cre transgenic mice.

Results: Histological analysis of dorsal skins from IL-17 MC-injected Wdfy3-LysM^Cre at day 4 revealed reduced skin thickness and absence of epidermal hyperplasia and Munro’s microabscesses in contrast to IL-17 MC-injected WT controls. Consistent with the histology findings we observed a reduction in gene expression of K16, S100a8, Cxcl1, Cxcr2 and Ltb4r1 in IL-17 MC-injected Wdfy3-LysM^Cre dorsal skins compared to IL-17 MC-injected WT mice. Histological analysis of dorsal skins from IL-17 MC-injected Wdfy3-LysM^Cre at day 4 showed reduced apoptotic cells compared to IL-17 MC-injected WT controls. We found that deletion of Wdfy3 in Ly6G⁺ cells resulted in reduced NET formation, which was consistent with a reduction in NET-associated neutrophil elastase compared to WT or LysM^Cre controls.

Conclusion: Collectively, our data underscore the importance of IL-17 in IL-23 and T cell independent skin pathology and its direct association with neutrophil activation and Wdfy3 in epidermal hyperplasia; a pathological feature of various skin diseases and paves the way for the design of novel therapeutics to combat this disabling condition.

Disclosure: E. Suzuki, None; E. Maverakis, None; L. Bouchareychas, None; V. K. Kuchroo, None; F. Nestle, None; I. E. Adamopoulos, None.

To cite this abstract in AMA style:

Suzuki E, Maverakis E, Bouchareychas L, Kuchroo VK, Nestle F, Adamopoulos IE. IL-17 Induces Skin Inflammation Independently of IL-23R+ T Cells and Is Protected By Conditional Deletion of Wdfy3 in Neutrophils [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/il-17-induces-skin-inflammation-independently-of-il-23r-t-cells-and-is-protected-by-conditional-deletion-of-wdfy3-in-neutrophils/. Accessed .

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