# Skin Barrier Function: The Interplay of Physical, Chemical, and Immunologic Properties
## 4 Significant Factors in the Disruption and Restoration of the Skin Barrier  
Dysfunction of the skin barrier is a hallmark of multiple dermatologic conditions, including psoriasis and atopic dermatitis [6; 7]. Many treatments, including certain formulations of emollients, contribute to the restoration of the barrier [58; 59]. Emollients with biochemical properties, such as ceramide-based mixtures, have had success in improving atopic dermatitis and psoriasis [60; 61]. Aside from helping maintain a physical skin barrier, ceramides also demonstrate a biochemical signaling component that is relevant to the skin barrier, influencing cellular pathways including those associated with cell differentiation [62]. Ceramides also stimulate the Th1 immune response that is mediated by IL-12, which plays a role in downregulating Th2- and Th17-driven inflammation [46; 53; 56]. The depletion of ceramides has also been shown to induce Th2 inflammatory responses in mouse models [63]. Ceramide-induced mitophagy contributes to an intact skin barrier, as dysfunctional mitochondria induce metabolic issues including excessive production of superoxide, which could kill cells that are needed to maintain a skin barrier [64]. Ceramide can be converted to sphingomyelin, which can be further metabolized to sphingosine-1-phosphate (S1P) [65]. Sphingosine-1-phosphate has demonstrated signaling, which controls proliferation and induces differentiation in keratinocytes, opposing the undifferentiated, uncontrolled keratinocyte proliferation that is characteristic of psoriasis [66]. Thus, the disruption of ceramides may lead to skin barrier disruption. However, sphingosine-1-phosphate has also been linked with inflammation through immune cell recruitment and angiogenesis, which could be disruptive to a healthy skin barrier [67]. Accordingly, ceramide analogs, which cannot be converted to S1P, have been synthesized as derivatives of solenopsin. These analogs, S12 and S14, result in a reduction in thickness of inflammatory lesions in mouse models, along with a reduced penetrance of CD4+, CD8+, and CD11c+ T cells. They have also demonstrated various biochemical signaling influences that highlight the role of biochemical pathways in skin barrier maintenance [57]. These include downregulation of IL-22, upregulation of IL-12, and decreases in immune cell recruitment [57]. By examining the effects on the skin barrier both in a physical and biochemical manner, further studies could use this dual-pronged concept to develop treatments with greater efficacy in restoring the skin barrier. Mitochondrial health also plays a large role in maintaining a healthy skin barrier. Skin cells with sufficient energy produced by healthy mitochondria maintain a barrier, while senescent cells could have mitochondrial dysfunction, which disrupts barrier function [68]. First, mitochondria generate ATP, which is used by the sodium-hydrogen exchanger isoform-1 protein, which helps export protons and decrease extracellular pH, contributing to skin acidity [18; 69]. Furthermore, cellular aging, associated with mitochondrial dysfunction, leads to other adverse effects that decrease the skin barrier effectiveness, including reduced rete ridges [68; 70]. Signals for cell senescence including elevated reactive oxygen/radicals from defective mitochondria can increase the expression of NFxB, which can lead to hyperproliferation of keratinocytes, leading to disrupted barrier function [71; 72; 73]. Furthermore, senescent cells can have adverse effects on the skin barrier by affecting the microenvironment: the senescence-associated secretory phenotype (SASP) produces many proinflammatory cytokines [74]. Mitochondrial function could possibly be preserved with SIRT3 activators, including honokiol, a small molecule polyphenol with anti-inflammatory properties, thus contributing to normal skin barrier function [75] (Figure 2). Targeting mitochondria could also alleviate oxidative stress and subsequently restore barrier function.