Fig. 2. Therapeutic strategies for atopic dermatitis.
Multiple strategies aimed at correcting the skin dysbiosis by microbiome manipulation are currently in development either by topical application or by oral administration. The aim is to reduce the overgrowth of Staphylococcus aureus (S.a.) and/or to favour the recovery of the commensals Staphylococcus hominis (S.h.) and Staphylococcus epidermidis (S.e.). The innate immune response is assumed to be instrumental at the very early stage of AD, and targeting the aryl-hydrocarbon receptor (AhR) and alarmins represents an appealing strategy of intervention. The complexity of the adaptive immune response offers multiple opportunities for targeted therapies using biologics against cytokines and their respective receptors. As T cells are the effectors in the inflammatory reaction, impacting on their migratory activity from the lymph nodes via modulation of the sphingosine 1-phosphate receptor (S1PR) or into the skin via the C-C chemokine receptor 4 (CCR4) is an emerging approach. Besides biologics, another strategy to affect the pathways involved in the generation of inflammation is the use of kinase inhibitors that are differentially selective for Janus kinases (JAKs) (JAKi) involved in the signal transduction of cytokine receptors. Other inhibitors address kinases involved in pathways related to the nerve growth factor, such as the tropomyosin receptor kinase (TRK) or Bruton tyrosine kinase (BTK) involved in the signal transduction of the B cell receptor or the high-affinity receptor for IgE expressed in mast cells and dendritic cells. Histamine receptor 4 (H4R) is widely expressed and is an interesting target as it is involved in immunomodulatory mechanisms. Another popular approach to reduce inflammation in AD is to use inhibitors of phosphodiesterase 4 (PDE4) as they increase the cellular levels of cAMP and thereby contribute to the generation of anti-inflammatory cytokines. As sensing neurons in the skin can be activated by multiple mediators generated during the inflammatory reaction, several strategies targeting the generation of itching have been developed, including blockade of IL-31 receptor (IL-31R), neurokinin 1 receptor (NK1R) and purinoreceptor 3 (P2X3). LXR, liver X receptor; mIgE, membrane form of IgE; OX40L, OX40 ligand; TH cell, T helper cell; TSLP, thymic stromal lymphopoietin.