# Skin Barrier Function: The Interplay of Physical, Chemical, and Immunologic Properties
## 5 Interleukins and Toll-like Receptors in Skin Barrier Regulation
After stimulus impacting both the physical and immunological aspects of the skin barrier, as seen in radiation damage, IL-12 therapy was able to rescue aspects of the damaged skin. This included reduced water loss (indicating a physical barrier restoration) and an increased density of interstitial dendritic cells (indicating enhanced immunological barrier maintenance) compared with skin that was irradiated without IL-12 treatment [100]. Furthermore, IL-12 signaling has been reported to limit skin inflammation in psoriatic lesions [53]. Although IL-12/23 has been targeted by therapies to reduce inflammations in previous studies, more recent data suggest that IL-23, which shares the p40 subunit with IL-12, may play a greater role in inflammatory responses, while IL-12 exhibits some anti-inflammatory activity [53; 103; 104; 105; 106]. Because of this, treatments targeted at p40 inhibition, such as ustekinumab, may have efficacy by inhibiting IL-23 [107]. Indeed, IL-23 expression is enhanced in keratinocytes in psoriasis lesions compared with keratinocytes from healthy skin [108]. However, this also inhibits IL-12, which could render the treatment less effective than an IL-23-specific treatment [53]. IL-12 also helps inhibit the Th17 immune response, which can drive psoriasis through the production of IL-17 [92]. IL-12 has been shown to inhibit Th17 cells in the context of pulmonary disease through IL-10 signaling [109]. In the skin, IL-12 expression can induce stromal alterations, which can reduce Th17 levels [53]. S12 and S14, which have been shown to effectively restore the skin barrier, increase IL-12 expression in mouse models of psoriasis [57]. S14 also reduced the Th2 response in a mouse model of atopic dermatitis, with a decrease in the IL-4 expression associated with increased IL-12 [110]. Furthermore, solenopsin increases IL-12, possibly independently of upregulating the shared p40 subunit, as it does not influence IL-23 levels [57]. IL-1 family cytokines also mediate inflammation and atopy, with studies implicating the dysregulation of IL-1\(\alpha\), IL-1\(\beta\), IL-18, IL-33, IL-36\(\alpha\), IL-36\(\beta\), and IL-36\(\gamma\) in different processes of skin barrier disruption [111]. Keratinocyte IL-1\(\alpha\) secretion in filaggrin-deficient mouse models perpetuate chronic inflammation, while IL-1\(\beta\) signaling in mouse models induces IL-17 expression, indicating a role in psoriasis [111; 112]. Neutrophphics proteases, which may be found in higher concentration in psoriatic skin, truncate IL-1\(\alpha\)/\(\beta\), IL-33, and IL-36\(\alpha\)/\(\beta\)/\(\gamma\), which could further amplify inflammatory responses [113]. IL-33, which induces atopic dermatitis-like inflammation in mouse skin and is overexpressed in atopic dermatitis skin samples, can also be activated by environmental proteases, potentially exacerbating the response in atopic dermatitis [114; 115]. IL-18 induction using \(S\). _aureus_ in mouse models of atopic dermatitis may also mediate the inflammatory response [116]. IL-36\(\alpha\) and IL-36\(\gamma\) injection into wild-type mice led to an increased skin expression of IL-17 and IL-23, implicated in psoriasis, while the latter also induced neutrophil infiltration. These inflammatory effects were also inhibited by the IL-36 receptor blocking antibodies [117]. Notably, elevated IL-36 cytokine pathway activity is implicated in the pathogenesis of generalized postular psoriasis (GPP), as up to 1/3 of GPP patients have missense mutations in IL-36 RN, which inhibits IL-36 receptor activation [117]. Other mutations in GPP patients, such as in CARD14, AP1S3, SERPINA3, and MPO, also regulate the IL-36 signaling axis [118]. Recent anti IL-36 receptor antibodies, namely spesolimab, have been FDA-approved for treatment of generalized postular psoriasis [119]. Toll-like receptor 4 (TLR4) is another important regulatory factor that must be balanced to ensure an appropriate immune response. Overactivation of TLR4 is observed in psoriasis [120].