Session Type: Abstract Submissions (ACR)
Background/Purpose: IL-17 is elevated in both the lesional skin and arthritic joints of psoriatic arthritis (PsA) patients. Although the IL-23/IL-17 axis has been linked with PsA pathology the direct effect of IL-17 on myeloid cells in PsA is elusive.
Methods: We performed gene transfer of IL-17 and GFP control 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. Characterization of molecular pathways was also performed in Il23r-/-Rag-/- and Tcrd-/- transgenic mice.
Results: We have identified a unique IL-17RhiCD11b+Gr-1hi cell subset induced by IL-17 that is associated with epidermal hyperplasia. Specifically 4 days post-IL-17 gene transfer we observed evidence of exacerbated epidermal hyperplasia, acanthosis, parakeratosis and Munro microabscess formation that were absent in GFP control mice. Gene expression of keratinocyte proliferation and inflammation biomarkers such as Keratin 16 (K16), S100a7, S100a8, Cxcl1, Cxcr2 and Ltb4r1 were consistently elevated post-IL-17 gene transfer and this correlated with an increase of Cxcl1 (a neutrophil chemoattractant) in the serum. Utilizing Il23r-/-Rag-/- and Tcrd-/- mice, we demonstrated that genetic ablation of IL-23r, or the complete absence of T, B and γδ Τ cells did not affect the pathologic features induced by IL-17. On the contrary, depletion of CD11b+Gr-1hi cells resulted in a complete rescue of skin pathology as evidenced by histology and gene expression.
Conclusion: Herein we demonstrate that IL-17 induces the expansion of an IL-17RhiCD11b+Gr-1hi pathogenic cell subset, which is directly responsible for inducing a constellation of features that resemble human psoriatic disease. Collectively our data underscore the importance of innate immune cells in the pathogenesis of PsA and paves the way for the design of novel therapeutics to combat this disabling condition.
I. E. Adamopoulos,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/il-17-gene-transfer-induces-myeloid-precursor-cells-that-initiate-epidermal-hyperplasia-independently-of-il-23rcd4-and-%ce%b3%ce%b4-t-cells/