Soluble adenylyl cyclase contributes to imiquimod-mediated inflammation and is a potential therapeutic target in psoriasis.
Jaewon YouMichael D ReillyMahmoud EljalbyRohan BarejaMaftuna YusupovaNikki S VyasJakyung BangWanhong DingGarrett DesmanLloyd S MillerOlivier ElementoRichard D GransteinJonathan H ZippinPublished in: Experimental dermatology (2023)
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 reduced CD4+ IL17+ cell numbers in the draining lymph nodes, compared with wild-type mice after induction of psoriasiform dermatitis with imiquimod. Keratinocyte-specific knock out of Adcy10 had no effect on imiquimod-induced ear swelling suggesting keratinocyte sAC has no role in imiquimod-induced inflammation. During Th17 polarization in vitro, naive T cells from Adcy10 -/- mice exhibited reduced IL17 secretion and IL-17+ T-cell proliferation suggesting that differentiation into Th17 cells is suppressed without sAC activity. Interestingly, loss of sAC did not impact the expression of Th17 lineage-defining transcription factors (such as Rorc and cMaf) but rather was required for CREB-dependent gene expression, which is known to support Th17 cell 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 important for psoriasiform dermatitis in mouse skin. sACi may provide an alternative class of topical therapeutics for Th17-mediated skin diseases.
Keyphrases
- gene expression
- wild type
- small molecule
- wound healing
- oxidative stress
- single cell
- diabetic rats
- atopic dermatitis
- high glucose
- dna methylation
- soft tissue
- cell proliferation
- cell therapy
- lymph node
- binding protein
- high fat diet induced
- transcription factor
- induced apoptosis
- genome wide
- drug induced
- protein kinase
- cell cycle arrest
- signaling pathway
- endothelial cells
- copy number
- hiv infected
- stem cells
- climate change
- endoplasmic reticulum stress
- stress induced
- mesenchymal stem cells
- bone marrow
- early stage
- skeletal muscle
- dna binding
- nk cells