Exploring SIK2-CXCL5 interactions in neutrophils: A novel mechanism for modulating IL-23 and psoriasis progression

Psoriasis, a chronic inflammatory skin disease, involves dysregulated immune responses and keratinocyte hyperproliferation. The role of salt-inducible kinase 2 (SIK2) in modulating interleukin-23 (IL-23) secretion via C-X-C motif chemokine ligand 5 (CXCL5) in neutrophils has not been fully explored. We combined in vivo and in vitro approaches to examine SIK2's role in an imiquimod (IMQ)-induced psoriasis model and activated neutrophils. Mice underwent intradermal injections of lentiviruses overexpressing SIK2, CXCL5, or both, while in vitro experiments involved transfecting activated neutrophils with these constructs. Assessments included ear thickness, cellular and neutrophil infiltration through histological and immunofluorescence techniques, and analysis of gene and protein expressions via quantitative real-time PCR (qRT-PCR), immunohistochemistry (IHC), and Western blot. Additionally, cell viability, proliferation, and cytokine levels in N-formylmethionyl-leucyl-phenylalanine (fMLF) treated neutrophils were evaluated using cell-counting kit-8 (CCK8), 5-ethynyl-2'-deoxyuridine (EdU) incorporation, and Enzyme-Linked Immunosorbent Assay (ELISA). Overexpression of SIK2 significantly reduced ear thickness, cellular and neutrophil infiltration, IL-1β, tumor necrosis factor-alpha (TNF-α), CXCL5, IL-23 and phosphorylated Yes-associated protein (p-YAP) levels, and increased SIK2 levels in IMQ mice model, but overexpression of CXCL5 reversed these effects. In vitro, SIK2 overexpression resulted in reduced cell viability and proliferation, with corresponding reductions in IL-1β, IL-17, IL-23, and Matrix Metallopeptidase 9 levels, whereas overexpression of CXCL5 reversed these effects. Our findings suggest that SIK2 acts as a critical modulator in psoriasis by influencing CXCL5-mediated IL-23 secretion in neutrophils, underscoring the potential of SIK2 as a therapeutic target to alleviate the inflammatory responses in psoriasis.