Abstract: The skin acts as the body’s primary physical and immune barrier, maintaining the skin microbiome and providing a physical, chemical, and immune barrier. A disrupted skin barrier plays a critical role in the onset and advancement of inflammatory skin conditions such as atopic dermatitis (AD) and contact dermatitis. This narrative review outlines the relationship between AD and skin barrier function in preparation for the search for possible markers for the treatment of AD.
WeissRA, EichnerR, SunTT. Monoclonal antibody analysis of keratin expression in epidermal diseases: A 48- and 56-kdalton keratin as molecular markers for hyperproliferative keratinocytes. J Cell Biol. 1984; 98(4):1397–1406.
3.
WawersikM, CoulombePA. Forced expression of keratin 16 alters the adhesion, differentiation, and migration of mouse skin keratinocytes. Mol Biol Cell. 2000; 11(10):3315–3327.
YangLL, JiangB, ChenSH, et al.Abnormal keratin expression pattern in prurigo nodularis epidermis. Skin Health Dis. 2022; 2(1):e75.
6.
SchleiferSG, VersteegSA, van OostB, et al.Familial footpad hyperkeratosis and inheritance of keratin 2, keratin 9, and desmoglein 1 in two pedigrees of Irish Terriers. Am J Vet Res. 2003; 64(6):715–720.
7.
CaoW, YanM, HaoQ, et al.Autosomal-dominant Meesmann epithelial corneal dystrophy without an exon mutation in the keratin-3 or keratin-12 gene in a Chinese family. J Int Med Res. 2013; 41(2):511–518.
8.
BloorBK, SeddonSV, MorganPR. Gene expression of differentiation-specific keratins (K4, K13, K1 and K10) in oral non-dysplastic keratoses and lichen planus. J Oral Pathol Med. 2000; 29(8):376–384.
9.
BloorBK, SeddonSV, MorganPR. Gene expression of differentiation-specific keratins in oral epithelial dysplasia and squamous cell carcinoma. Oral Oncol. 2001; 37(3):251–261.
10.
Ishida-YamamotoA, McGrathJA, ChapmanSJ, et al.Epidermolysis bullosa simplex (Dowling-Meara type) is a genetic disease characterized by an abnormal keratin-filament network involving keratins K5 and K14. J Invest Dermatol. 1991; 97(6):959–968.
11.
LeighIM, NavsariaH, PurkisPE, et al.Keratins (K16 and K17) as markers of keratinocyte hyperproliferation in psoriasis in vivo and in vitro. Br J Dermatol. 1995; 133(4):501–511.
12.
SandilandsA, SmithFJ, LunnyDP, et al.Generation and characterisation of keratin 7 (K7) knockout mice. PLoS One. 2013; 8(5):e64404.
13.
ParkY, JungJG, YuZC, et al.A novel human endometrial epithelial cell line for modeling gynecological diseases and for drug screening. Lab Invest. 2021; 101(11):1505–1512.
14.
SatoR, ImamuraK, SembaT, et al.TGFbeta signaling activated by cancer-associated fibroblasts determines the histological signature of lung adenocarcinoma. Cancer Res. 2021; 81(18):4751–4765.
15.
SurI, RozellB, JaksV, et al.Epidermal and craniofacial defects in mice overexpressing Klf5 in the basal layer of the epidermis. J Cell Sci. 2006; 119(Pt 17):3593–3601.
16.
BuschT, ArmackiM, EiselerT, et al.Keratin 8 phosphorylation regulates keratin reorganization and migration of epithelial tumor cells. J Cell Sci. 2012; 125(Pt 9):2148–2159.
17.
StenvallCA, TayyabM, GronroosTJ, et al.Targeted deletion of keratin 8 in intestinal epithelial cells disrupts tissue integrity and predisposes to tumorigenesis in the colon. Cell Mol Life Sci. 2021; 79(1):10.
18.
AndolinoC, HessC, PrinceT, et al.Drug-induced keratin 9 interaction with Hsp70 in bladder cancer cells. Cell Stress Chaperones. 2018; 23(5):1137–1142.
19.
LiuX, QiuC, HeR, et al.Keratin 9 L164P mutation in a Chinese pedigree with epidermolytic palmoplantar keratoderma, cytokeratin analysis, and literature review. Mol Genet Genomic Med. 2019; 7(11):e977.
20.
PorterRM, LunnyDP, OgdenPH, et al.K15 expression implies lateral differentiation within stratified epithelial basal cells. Lab Invest. 2000; 80(11):1701–1710.
21.
BernotKM, CoulombePA, McGowanKM. Keratin 16 expression defines a subset of epithelial cells during skin morphogenesis and the hair cycle. J Invest Dermatol. 2002; 119(5):1137–1149.
22.
KimS, WongP, CoulombePA. A keratin cytoskeletal protein regulates protein synthesis and epithelial cell growth. Nature. 2006; 441(7091):362–365.
23.
FortierAM, AsselinE, CadrinM. Keratin 8 and 18 loss in epithelial cancer cells increases collective cell migration and cisplatin sensitivity through claudin1 up-regulation. J Biol Chem. 2013; 288(16):11555–11571.
24.
LuMH, YangPC, ChangLT, et al.Temporal and spatial sequence expression of cytokeratin K19 in cultured human keratinocyte. Proc Natl Sci Counc Repub China B. 2000; 24(4):169–177.
25.
ZhouQ, CadrinM, HerrmannH, et al.Keratin 20 serine 13 phosphorylation is a stress and intestinal goblet cell marker. J Biol Chem. 2006; 281(24):16453–16461.
26.
MaissE, IvanovaL, BreyelE, et al.Cloning and sequencing of the S RNA from a Bulgarian isolate of tomato spotted wilt virus. J Gen Virol. 1991; 72 (Pt 2):461–464.
PerkinsJP, MooreMM, KaliskerA, et al.Regulation of cyclic AMP content in normal and malignant brain cells. Adv Cyclic Nucleotide Res. 1975; 5:641–658.
29.
Birkenkamp-DemtroderK, HahnSA, MansillaF, et al.Keratin23 (KRT23) knockdown decreases proliferation and affects the DNA damage response of colon cancer cells. PLoS One. 2013; 8(9):e73593.
30.
MinM, ChenXB, WangP, et al.Role of keratin 24 in human epidermal keratinocytes. PLoS One. 2017; 12(3):e174626.
31.
LangbeinL, RogersMA, Praetzel-WunderS, et al.K25 (K25irs1), K26 (K25irs2), K27 (K25irs3), and K28 (K25irs4) represent the type I inner root sheath keratins of the human hair follicle. J Invest Dermatol. 2006; 126(11):2377–2386.
32.
LangbeinL, RogersMA, Praetzel-WunderS, et al.Novel type I hair keratins K39 and K40 are the last to be expressed in differentiation of the hair: Completion of the human hair keratin catalog. J Invest Dermatol. 2007; 127(6):1532–1535.
33.
TakadaT, ShitaraH, MatsuokaK, et al.A novel hairless mouse model on an atopic dermatitis-prone genetic background generated by receptor-mediated transgenesis. Transgenic Res. 2008; 17(6):1155–1162.
34.
ZihniC, MillsC, MatterK, et al.Tight junctions: from simple barriers to multifunctional molecular gates. Nat Rev Mol Cell Biol. 2016; 17(9):564–580.
35.
AndersonJM, Van ItallieCM. Physiology and function of the tight junction. Cold Spring Harb Perspect Biol. 2009; 1(2):a2584.
36.
WeberCR, LiangGH, WangY, et al.Claudin-2-dependent paracellular channels are dynamically gated. Elife. 2015; 4:e9906.
37.
AhmadS, EvansWH. Post-translational integration and oligomerization of connexin 26 in plasma membranes and evidence of formation of membrane pores: Implications for the assembly of gap junctions. Biochem J. 2002; 365(Pt 3):693–699.
38.
EvansWH, MartinPE. Gap junctions: Structure and function (Review). Mol Membr Biol. 2002; 19(2):121–136.
39.
ZeitzMJ, SmythJW. Gap junctions and ageing. Subcell Biochem. 2023; 102:113–137.
40.
DiWL, RuggEL, LeighIM, et al.Multiple epidermal connexins are expressed in different keratinocyte subpopulations including connexin 31. J Invest Dermatol. 2001; 117(4):958–964.
41.
LairdDW, CastilloM, KasprzakL. Gap junction turnover, intracellular trafficking, and phosphorylation of connexin43 in brefeldin A-treated rat mammary tumor cells. J Cell Biol. 1995; 131(5):1193–1203.
42.
SolanJL, LampePD. Spatio-temporal regulation of connexin43 phosphorylation and gap junction dynamics. Biochim Biophys Acta Biomembr. 2018; 1860(1):83–90.
43.
LairdDW, PuranamKL, RevelJP. Turnover and phosphorylation dynamics of connexin43 gap junction protein in cultured cardiac myocytes. Biochem J. 1991; 273(Pt 1)(Pt 1):67–72.
44.
AuA, ShaoQ, WhiteKK, et al.Comparative analysis of Cx31 and Cx43 in differentiation-competent rodent keratinocytes. Biomolecules. 2020; 10(10)
45.
ChansonM, WatanabeM, O’ShaughnessyEM, et al.Connexin communication compartments and wound repair in epithelial tissue. Int J Mol Sci. 2018; 19(5)
46.
NugentL, Ofori-FrimpongB, MartinPE, et al.Cx31.1 expression is modulated in HaCaT cells exposed to UV-induced damage and scrape-wounding. J Cell Physiol. 2021; 236(2):911–920.
47.
Prost-SquarcioniC. Histology of skin and hair follicle. Med Sci (Paris). 2006; 22(2):131–137.
48.
WangY, XuR, HeW, et al.Three-dimensional histological structures of the human dermis. Tissue Eng Part C Methods. 2015; 21(9):932–944.
49.
SorrellJM, CaplanAI. Fibroblast heterogeneity: More than skin deep. J Cell Sci. 2004; 117(Pt 5):667–675.
50.
FraynKN, KarpeF. Regulation of human subcutaneous adipose tissue blood flow. Int J Obes (Lond). 2014; 38(8):1019–1026.
51.
BruggenMC, StinglG. Subcutaneous white adipose tissue: The deepest layer of the cutaneous immune barrier. J Dtsch Dermatol Ges. 2020; 18(11):1225–1227.
52.
Ramirez-MarinHA, SilverbergJI. Differences between pediatric and adult atopic dermatitis. Pediatr Dermatol. 2022; 39(3):345–353.
53.
TokuraY, HayanoS. Subtypes of atopic dermatitis: from phenotype to endotype. Allergol Int. 2022; 71(1):14–24.
54.
GuoY, LiP, TangJ, et al.Prevalence of atopic dermatitis in Chinese children aged 1-7 ys. Sci Rep. 2016; 6:29751.
OwenJL, VakhariaPP, SilverbergJI. The role and diagnosis of allergic contact dermatitis in patients with atopic dermatitis. Am J Clin Dermatol. 2018; 19(3):293–302.
57.
HamannCR, HamannD, EgebergA, et al.Association between atopic dermatitis and contact sensitization: A systematic review and meta-analysis. J Am Acad Dermatol. 2017; 77(1):70–78.
58.
SilnyP, Czarnecka-OperaczM, SilnyW. Clinical assessment and evaluation of total immunoglobulin E concentrations in blood of atopic dermatitis patients with allergy to airborne allergens. Pol Merkur Lekarski. 2004; 17(102):608–614.
59.
ZhangS, EdwardsTN, ChaudhriVK, et al.Nonpeptidergic neurons suppress mast cells via glutamate to maintain skin homeostasis. Cell. 2021; 184(8):2151–2166.e16.
60.
RohYJ, NohHH, KooNY, et al.Development of in vitro co-culture model to mimic the cell to cell communication in response to urban PM(2.5). Ann Dermatol. 2022; 34(2):110–117.
61.
YuYY, JinH, LuQ. Effect of polycyclic aromatic hydrocarbons on immunity. J Transl Autoimmun. 2022; 5:100177.
62.
MuZ, ZhangJ. The role of genetics, the environment, and epigenetics in atopic dermatitis. Adv Exp Med Biol. 2020; 1253:107–140.
DrislaneC, IrvineAD. The role of filaggrin in atopic dermatitis and allergic disease. Ann Allergy Asthma Immunol. 2020; 124(1):36–43.
65.
EngebretsenKA, BandierJ, KezicS, et al.Concentration of filaggrin monomers, its metabolites and corneocyte surface texture in individuals with a history of atopic dermatitis and controls. J Eur Acad Dermatol Venereol. 2018; 32(5):796–804.
66.
FujiiM. The pathogenic and therapeutic implications of ceramide abnormalities in atopic dermatitis. Cells. 2021; 10(9)
67.
FeingoldKR. Thematic review series: Skin lipids. The role of epidermal lipids in cutaneous permeability barrier homeostasis. J Lipid Res. 2007; 48(12):2531–2546.
68.
DansoM, BoitenW, van DrongelenV, et al.Altered expression of epidermal lipid bio-synthesis enzymes in atopic dermatitis skin is accompanied by changes in stratum corneum lipid composition. J Dermatol Sci. 2017; 88(1):57–66.
69.
TawadaC, KanohH, NakamuraM, et al.Interferon-gamma decreases ceramides with long-chain fatty acids: Possible involvement in atopic dermatitis and psoriasis. J Invest Dermatol. 2014; 134(3):712–718.
70.
GolevaE, BerdyshevE, LeungDY. Epithelial barrier repair and prevention of allergy. J Clin Invest. 2019; 129(4):1463–1474.
71.
GriceEA, SegreJA. The skin microbiome. Nat Rev Microbiol. 2011; 9(4):244–253.
72.
WollenbergA, BarbarotS, BieberT, et al.Consensus-based European guidelines for treatment of atopic eczema (atopic dermatitis) in adults and children: Part II. J Eur Acad Dermatol Venereol. 2018; 32(6):850–878.
73.
PallerAS, KongHH, SeedP, et al.The microbiome in patients with atopic dermatitis. J Allergy Clin Immunol. 2019; 143(1):26–35.
74.
AlbanesiC, FairchildHR, MadonnaS, et al.IL-4 and IL-13 negatively regulate TNF-alpha- and IFN-gamma-induced beta-defensin expression through STAT-6, suppressor of cytokine signaling (SOCS)-1, and SOCS-3. J Immunol. 2007; 179(2):984–992.
75.
NguyenH, Trujillo-PaezJV, UmeharaY, et al.Role of antimicrobial peptides in skin barrier repair in individuals with atopic dermatitis. Int J Mol Sci. 2020; 21(20)
BergmannS, von BuenauB, Vidal-Y-SyS, et al.Claudin-1 decrease impacts epidermal barrier function in atopic dermatitis lesions dose-dependently. Sci Rep. 2020; 10(1):2024.
78.
LeeSY, HongSH, KimHI, et al.Paeonia lactiflora Pallas extract alleviates antibiotics and DNCB-induced atopic dermatitis symptoms by suppressing inflammation and changing the gut microbiota composition in mice. Biomed Pharmacother. 2022; 154:113574.
79.
KlechevskyE, MoritaR, LiuM, et al.Functional specializations of human epidermal Langerhans cells and CD14+ dermal dendritic cells. Immunity. 2008; 29(3):497–510.
80.
OsabeM, TajikaT, TohkinM. Allopurinol suppresses expression of the regulatory T-cell migration factors TARC/CCL17 and MDC/CCL22 in HaCaT keratinocytes via restriction of nuclear factor-kappaB activation. J Appl Toxicol. 2018; 38(2):274–283.
81.
ZhouS, QiF, GongY, et al.Biological therapies for atopic dermatitis: A systematic review. Dermatology. 2021; 237(4):542–552.
82.
TangTS, BieberT, WilliamsHC. Does “autoreactivity” play a role in atopic dermatitis?J Allergy Clin Immunol. 2012; 129(5):1209–1215.e2.
83.
EzzatMH, HasanZE, ShaheenKY. Serum measurement of interleukin-31 (IL-31) in paediatric atopic dermatitis: Elevated levels correlate with severity scoring. J Eur Acad Dermatol Venereol. 2011; 25(3):334–339.