As the largest organ and outermost layer of the human body, the skin serves as the first-line defense against various external pathogenic factors, including physical, chemical, and biological stresses, and plays a pivotal role in preventing dehydration. Maintenance of these functions relies primarily on a sound skin barrier; any functional or structural defect of the skin barrier may induce various skin diseases such as atopic dermatitis (AD) (1) and psoriasis (2). In addition to the skin physical barrier, which mainly consists of keratinocytes and their products, skin barrier immunity is also recently found to play an important role in maintaining integrity of skin barrier (3). Recent studies found that skin-resident immune cells, including Langerhans cells (LCs), dendritic cells (DCs), innate lymphoid cells (ILCs), and T cells, work along with the skin-resident structural cells, such as keratinocytes and fibroblasts to protect the homeostatic balance of skin barrier immunity (4). The integrity of skin barrier closely depends on the homeostasis of skin barrier immunity and challenged when homeostasis is irreversibly compromised. During the last few years, it has been recognized that skin-associated adipocytes, which located in the subcutis and at the bottom of the dermis, may play important roles in modulating skin immunity by producing various cytokines, adipokines, and antimicrobial peptides (AMPs) (5). Studying of the effect of skin-associated adipocytes on skin barrier immunity may deepen our understanding of skin barrier system (4, 6, 7). Therefore, this mini-review will summarize the recent developments and current understanding of how the skin-associated adipocytes mediate multiple facets of skin barrier immunity.

Skin barrier can be functionally divided into four levels, namely, the microbiome barrier, the chemical barrier, the physical barrier, and the immune barrier (8). As the outermost layer, the microbiome barrier is composed of abundant microbial communities which act as the first line of defense. The commensal microbes play important roles in inhibiting the colonization of pathogenic bacteria (9) and in suppressing inflammatory cytokines released by skin-resident cells (10). The chemical barrier commonly refers to a series of protective molecules produced by different types of skin cells, including AMPs (11), natural moisturizing factors (NMFs) (12), epidermal lipids (13), and cutaneous pH-contributing factors. With regard to the physical barrier, the stratum corneum (SC) and tight junctions (TJs) are the most important components. The SC consists of several layers of denucleated and flattened cornified cells, which result from the terminal differentiation of keratinocytes (14), the TJs are transmembrane proteins expressed by keratinocytes in the stratum granulosum (SG) and function as connections between adjacent keratinocytes (15). The immune barrier is composed of various resident immune cells in the epidermis and dermis. In addition, other skin structural cells exert immunologic functions and work together with immune cells to maintain immune barrier integrity. These four elements of the skin barrier are not independent of one another. Instead, they are inextricably interconnected, and each element influences the others. Any dysfunction in the barrier compartment may lead to a vicious circle, compounding damage to the barrier and resulting in various dermatoses.

The skin consists of several distinct layers and a series of cutaneous appendages, of which the epidermis forms the outermost layer and accounts for the majority of the barrier function. The next layer is the dermis, which can be subdivided into papillary and reticular dermis (16). Skin-associated adipocytes reside in the reticular dermis and subcutis, where they form dermal white adipose tissue (dWAT) and subcutaneous white adipose tissue (sWAT), respectively. In mice and rats, these two layers are clearly separated by a thin layer of skeletal muscle called the panniculus carnosus (17). However, in human skin, there is no distinct demarcation between dWAT and sWAT, and the existence of dWAT has not yet been confirmed because of the difficulty in tracing (18).

WAT used to be merely considered as an energy storage site with simple functions, such as mechanical protection and thermal insulation (6). However, recent studies demonstrated that adipose tissue acts as an endocrine organ with a pivotal role in the regulation of immune responses (19). Adipocyte is the most common cell type in WAT; however, adipose tissue also contains a variety of immune cells. The cross-talk between adipocytes and immune cells remarkably affects the local inflammatory state. For instance, receptors for the macrophage-derived factors interleukin (IL)-1β and tumor necrosis factor (TNF), as well as receptors for the cytokine IL-17 produced by helper T (Th) 17 cells, are expressed on the surface of adipocytes and mediate downstream pro-inflammatory signals (20, 21). In addition, receptors for the anti-inflammatory cytokine IL-10 are enriched in mature adipocytes and contribute to the creation of an anti-inflammatory milieu (22). Moreover, adipocytes produce an array of inflammatory cytokines and chemokines, including several ILs, notably IL-6, IL-1β, TNF-α, and monocyte chemoattractant protein-1 (MCP-1) (23, 24). In addition, the immunoregulatory potency of skin-associated adipocytes depends on adipokines, a series of small bioactive proteins produced by adipocytes (25). Based on their inflammatory properties, adipokines can be classified as pro-inflammatory and anti-inflammatory (26, 27) ( Table 1 ).

Skin-derived AMPs are small peptides secreted primarily by keratinocytes that form the first line of defense against microbial pathogens (11). They act as multifunctional biomolecules that maintain the integrity and stability of the skin barrier in several ways. The AMPs exert antibiotic-like activity that directly kills pathogens (81) and act as effector molecules that play a vital role in balancing immune responses and modulating cell activities (82, 83). Recent studies have identified the role of skin-associated adipocytes in barrier immunity as a significant source of AMPs. When the skin suffers from inflammation, injury, and infection, the lesion site enters a state called reactive adipogenesis, characterized by a local increase in dermal adipocytes from which AMPs are responsively produced to suppress infection (84, 85). Using a Staphylococcus aureus-induced skin infection mouse model, Zhang et al. (86) indicated that newly differentiating preadipocytes could directly contribute to host defense by producing cathelicidin, which is one of the best characterized AMPs. This defense effect was inhibited in Zfp423-deficient mice and in the mice treated with inhibitors of PPAR-γ, which further confirmed the antimicrobial role of adipocytes. The mechanisms by which adipocytes recognize and respond to bacteria were subsequently uncovered possibly involving a TLR2-mediated pathway (87).

In addition to classic AMPs, some adipokines secreted by skin-associated adipocytes exert antimicrobial activities. In a study by Mancuso et al. (35), the authors found that low levels of circulatory leptin induced by starvation resulted in the impairment of bacterial clearance in a Streptococcus pneumoniae infected mouse model. This defective function was restored by administration of exogenous leptin, indicating the antimicrobial ability of leptin. Structural homology between chemerin and cathelicidin has been predicted (40, 88). Based on this prediction, Kulig et al. (44) tested the antibacterial capacity of chemerin against Escherichia coli and Klebsiella pneumoniae. The results showed that although the antimicrobial effects of chemerin on E. coli and K. pneumoniae were less potent than those of the classic AMP LL-37, chemerin displayed a certain degree of bactericidal capacity, especially the isoforms truncated by the cysteine proteases cathepsin L and K.

Moreover, skin-associated adipocytes can induce AMP secretion from other skin cells via adipokines. Leptin can enhance the production of human beta-defensin-2 (hBD-2) in human keratinocytes in vitro (36). Another in vitro experiment showed that visfatin activated the secretion of a series of AMPs, including cathelicidin, S100A7, hBD-2, and hBD-3, in normal human keratinocytes (48).

Skin surface lipids are comprised of extracellular and sebaceous lipids. Extracellular lipids, also called keratinocyte-derived lipids, are found predominantly in the SC, and mainly consist of ceramides (45–50%), cholesterol (25%), and free fatty acid (10–15%) (13). Lipid precursors and lipid synthases are secreted by lamellar bodies, from which extracellular lipids are synthesized in the extracellular spaces of the stratum corneum. Sebaceous lipids are sebum molecules secreted by sebaceous glands and include cholesteryl esters, triglycerides, squalene, and wax esters. Together with sweat secreted by sweat glands, sebaceous lipids form a hydrolipidic film on the skin surface that plays a role in skin protection. Lipids are important components of the physical barrier of the skin. Additionally, some skin lipids contribute to skin barrier maintenance by acting as bioactive mediators in cutaneous immunity and inflammation (89). Alteration of skin lipid contents and compositions can cause skin barrier dysfunction and skin immunity dysregulation, resulting in various dermatoses such as psoriasis (90), AD (91), and acne vulgaris (92).

Adipocytes, being the energy storage vault of the body, store excess energy in the form of triglycerides. In addition, adipocytes contain many ceramides and a number of other lipid species. Numerous studies have investigated the role of adipocyte-derived lipids in the development of multiple metabolic diseases such as diabetes, insulin resistance, cardiomyopathy, atherosclerosis, and hepatic-steatosis (93). Whereas the effect of adipocyte-derived lipids on the skin barrier has seldom been studied. Although most of the studies that focused on metabolic diseases have indicated the deleterious effects resulting from excessive accumulation of triglycerides and ceramides in adipocytes. In view of the particular role of lipids in the maintenance of the skin barrier, adipocyte-derived lipids might, to some extent, possess the capacity for skin barrier protection.

In this review, we attempted to summarize and highlight the important role of skin-associated adipocytes in skin barrier immunity, either by the production of biomolecules (cytokines, adipokines, and AMPs) or by direct interaction with skin-resident cells ( Figure 1 ). In addition, the abundant storage of lipid species in skin-associated adipocytes may indicate a potential role in skin barrier maintenance. The pathogenesis of inflammatory skin diseases, such as AD and psoriasis, involves complex interactions between abnormal immunity, dysbacteriosis, and skin barrier defects, indicating therapeutic agents with comprehensive efficacy are required. On account of the comprehensive effects of skin-associated adipocytes on skin barrier immunity, they might be potential therapeutic agents for this kind of skin disease. As a matter of fact, the therapeutic effect of preadipocytes (adipose-derived mesenchymal stem cells) has been determined by various research teams. However, the effects of adipocytes on immunity are two-sided. Although an increasing number of anti-inflammatory biomolecules have been identified in adipocytes, adipocyte-derived pro-inflammatory factors cannot be ignored. Therefore, pretreatment of adipose tissue or adipocytes, such as by extracting anti-inflammatory components and excluding pro-inflammatory elements, would be needed to enhance their effect in maintaining skin barrier homeostasis.

JG and CW drafted the review. YH and FL revised the manuscript. All authors contributed to the article and approved the submitted version.