|
| Status |
Public on Oct 01, 2021 |
| Title |
Soluble adenylyl cyclase induces type 17 inflammation and is a potential therapeutic target in psoriasis |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
Cyclic AMP (cAMP) has a key role in psoriasis pathogenesis, as indicated by the therapeutic efficacy of phosphodiesterase inhibitors that prevent the degradation of cAMP. However, whether soluble adenylate cyclase (sAC) (encoded by the ADCY10 gene), which is an important source for cAMP, is involved in Th17 cell-mediated inflammation or could be an alternative therapeutic target in psoriasis is unknown. We have utilized the imiquimod model of murine psoriasiform dermatitis to address this question. Adcy10-/- mice had reduced erythema, scaling and swelling in the skin and Th17 cell numbers in the draining lymph nodes, compared with wild-type mice after induction of psoriasiform dermatitis with imiquimod. During Th17 polarization in vitro, naïve T cells from Adcy10-/- mice were unable to differentiate to Th17 cells and RNA-seq analysis revealed that sAC was also essential for Th17 cell activation. Interestingly, sAC did not impact Th17 lineage-defining transcription factors (such as RORc and cMAF) but rather was required for CREB-dependent gene expression. Finally, topical application of small molecule sAC inhibitors (sACi) reduced imiquimod-induced psoriasiform dermatitis and IL17 gene expression in the skin. Collectively, these findings demonstrate that sAC is a key factor for inducing type 17 inflammation in the skin and sACi could provide an alternative class of topical therapeutics for psoriasis.
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| |
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| Overall design |
Wild Type vs Adcy10-/- T cells following differentiation to Th17 cells in vitro, without or with polarizing cytokines
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| |
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| Contributor(s) |
Zippin J, Reilly MD, Eljalby M, Elemento O, Bareja R |
| Citation missing |
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| |
| Submission date |
May 24, 2021 |
| Last update date |
Oct 02, 2021 |
| Contact name |
Olivier Elemento |
| E-mail(s) |
ole2001@med.cornell.edu
|
| Organization name |
WEILL MEDICAL COLLEGE OF CORNELL UNIV
|
| Street address |
1305 York Avenue
|
| City |
New York |
| State/province |
NY |
| ZIP/Postal code |
10021 |
| Country |
USA |
| |
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| Platforms (1) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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| Samples (12)
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| Relations |
| BioProject |
PRJNA732444 |
| SRA |
SRP321189 |
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