Inhibition of CDK4/6 boosts immune responses against epicutaneous S.aureus infections
FISCHER B. 1, KRAMER D. 1,2
1 Department of Dermatology, University Medical Center of the Johannes Gutenberg-University of Mainz, Germany, Mainz, Germany; 2 Research Center for Immunotherapy, University Medical Center of the Johannes Gutenberg-University of Mainz, Germany, Mainz, Germany
Recently, we uncovered that topical application of inhibitors against cyclin-dependent kinases 4 and 6 (CDK4/6) resolves experimentally induced psoriasis in mice. This was due to the inhibition of IκBζ expression in IL-17A- or IL-36-treated keratinocytes, a known transcriptional co-factor that mediates the induction of a variety of pro-inflammatory cytokines (e.g. IL36G or IL1B), chemokines (CXCL2, CXCL5) and antimicrobial peptides (e.g. DEFB4) in psoriasis.
Though this new treatment approach is very effective due to its immunosuppressive effects on psoriatic skin, CDK4/6 inhibitors might potentially also increase the risk for bacterial skin infections at the same time. Especially skin infections with multiresistant Staphylococcus aureus (S.aureus) strains constitute a major health risk for patients, potentially leading to non-healing wounds, systemic inflammation, and sepsis.
Therefore we wanted to investigate the consequences of IκBζ deletion or CDK4/6 inhibition on S.aureus infections of either human keratinocytes in vitro or epicutaneous S.aureus infections of mice in vivo. As expected, IκBζ deletion in S.aureus-infected keratinocytes or skin abrogated the expression of antimicrobial peptides and mediators of the innate immune responses, leading to insufficient clearance of S.aureus as well as to an increased systemic inflammation. This was due to an IκBζ-dependent induction of important NOD2 and TLR1/2-target genes in S.aureus-infected keratinocytes. In contrast, while CDK4/6 inhibition also quenched the expression of IκBζ in S.aureus-infected keratinocytes, CDK4/6 inhibitors could boost the immune responses against S.aureus at the same time, leading to a suppression of bacterial survival and internalization. Consequently, CDK4/6 inhibitors upregulated keratinocyte-derived expression of CXCL2 and CXCL1, leading to enhanced recruitment and activation of neutrophils at the site of infection.
Thus, we propose, that topical application of CDK4/6 inhibitors is not only suitable to inhibit psoriasis but might also be beneficial for the treatment of epicutaneous S.aureus infections.