Skin barrier immunology from early life to adulthood

Our skin has a unique barrier function, which is imperative for the body’s protection against external pathogens and environmental insults. Although interacting closely and sharing many similarities with key mucosal barrier sites, such as the gut and the lung, the skin also provides protection for internal tissues and organs and has a distinct lipid and chemical composition. Skin immunity develops over time and is influenced by a multiplicity of different factors, including lifestyle, genetics, and environmental exposures. Alterations in early life skin immune and structural development may have long-term consequences for skin health. In this review, we summarize the current knowledge on cutaneous barrier and immune development from early life to adulthood, with an overview of skin physiology and immune responses. We specifically highlight the influence of the skin microenvironment and other host intrinsic, host extrinsic (e.g. skin microbiome), and environmental factors on early life cutaneous immunity. Our skin has a unique barrier function, which is imperative for the body’s protection against external pathogens and environmental insults. Although interacting closely and sharing many similarities with key mucosal barrier sites, such as the gut and the lung, the skin also provides protection for internal tissues and organs and has a distinct lipid and chemical composition. Skin immunity develops over time and is influenced by a multiplicity of different factors, including lifestyle, genetics, and environmental exposures. Alterations in early life skin immune and structural development may have long-term consequences for skin health. In this review, we summarize the current knowledge on cutaneous barrier and immune development from early life to adulthood, with an overview of skin physiology and immune responses. We specifically highlight the influence of the skin microenvironment and other host intrinsic, host extrinsic (e.g. skin microbiome), and environmental factors on early life cutaneous immunity. The skin is an active immune-rich barrier tissue, which also acts as the outermost barrier of the human body and is thus one of the first lines of defense against exogenous threats. The physical, chemical, microbial, and immune barrier components of the skin form an interactive system, which contributes to cutaneous host defense and skin homeostasis as a whole. Skin barrier immunology has been well-defined and described in the adult setting. However, limited knowledge is available on the development of skin barrier immunity in early life due to technical challenges and ethical concerns related to early life skin sampling (Box 1). Here, we provide an overview of the current knowledge on skin immune and structural development from early life to adulthood, with a focus on the timing of immune cell seeding and their localization, and alterations in physical, chemical, and microbial properties. We highlight the similarities or differences between human and rodent skin.Box 1Sampling techniques for assessment of skin immunological responsesThe pathophysiology of skin diseases, including atopic dermatitis (AD), has been extensively studied using skin biopsies. Due to the invasive nature of skin biopsy sampling and associated ethical issues, skin biopsies for diagnostic and research purposes in healthy infants and children and those with a skin disease are very limited. Hence, skin immune profiling in healthy subjects or in children with a skin disease is very limited. In addition, sampling limitations may bias our knowledge of skin immune responses as only localized sampling can be done in case of biopsies, and gene expression and lipid composition analysis of tape strips may only reflect the upper layers of the skin176Berdyshev E. et al.Lipid abnormalities in atopic skin are driven by type 2 cytokines.JCI Insight. 2018; 3: e98006Crossref PubMed Scopus (148) Google Scholar, 177Broccardo C.J. Mahaffey S.B. Strand M. Reisdorph N.A. Leung D.Y. Peeling off the layers: skin taping and a novel proteomics approach to study atopic dermatitis.J. Allergy Clin. Immunol. 2009; 124 (1113–5.e1-11)Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar, 178Dyjack N. et al.Minimally invasive skin tape strip RNA sequencing identifies novel characteristics of the type 2-high atopic dermatitis disease endotype.J. Allergy Clin. Immunol. 2018; 141: 1298-1309Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar, 179Kezic S. et al.Levels of filaggrin degradation products are influenced by both filaggrin genotype and atopic dermatitis severity.Allergy. 2011; 66: 934-940Crossref PubMed Scopus (216) Google Scholar, 180Li S. et al.Altered composition of epidermal lipids correlates with Staphylococcus aureus colonization status in atopic dermatitis.Br. J. Dermatol. 2017; 177: e125-e127Crossref PubMed Scopus (51) Google Scholar. However, side-by-side comparison of skin tape stripping and skin biopsies of taped skin and adjacent non-taped skin in adult healthy controls and subjects with AD, indicated that consecutive skin tape stripping removed the stratum corneum and the upper part of the granular layer181Kim B.E. et al.Side-by-side comparison of skin biopsies and skin tape stripping highlights abnormal stratum corneum in atopic dermatitis.J. Invest. Dermatol. 2019; 139: 2387-2389.e1Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar. Moreover, gene expression levels of epidermal differentiation markers (filaggrin, corneodesmosin, loricrin, involucrin, and keratin-1) from skin tape stripping samples positively correlated with staining intensities of these markers in matching skin biopsies following immunostaining, suggesting that skin tape stripping is reliable for the evaluation of epidermal differentiation markers181Kim B.E. et al.Side-by-side comparison of skin biopsies and skin tape stripping highlights abnormal stratum corneum in atopic dermatitis.J. Invest. Dermatol. 2019; 139: 2387-2389.e1Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar. Analysis of stratum corneum biomarkers in skin tape strips from children were performed using proteomic, transcriptomic and quantitative real-time polymerase chain reaction (qRT-PCR) analysis182Hulshof L. et al.A minimally invasive tool to study immune response and skin barrier in children with atopic dermatitis.Br. J. Dermatol. 2019; 180: 621-630Crossref PubMed Scopus (48) Google Scholar, 183McAleer M.A. et al.Systemic and stratum corneum biomarkers of severity in infant atopic dermatitis include markers of innate and T helper cell-related immunity and angiogenesis.Br. J. Dermatol. 2019; 180: 586-596Crossref PubMed Scopus (57) Google Scholar, 184Leung D.Y.M. et al.The nonlesional skin surface distinguishes atopic dermatitis with food allergy as a unique endotype.Sci. Transl. Med. 2019; 11, eaav2685Google Scholar, 185Guttman-Yassky E. et al.Use of tape strips to detect immune and barrier abnormalities in the skin of children with early-onset atopic dermatitis.JAMA Dermatol. 2019; 155: 1358-1370Crossref PubMed Scopus (84) Google Scholar, 186Renert-Yuval Y. et al.Tape strips capture atopic dermatitis-related changes in nonlesional skin throughout maturation.Allergy. 2022; 77: 3445-3447Crossref PubMed Scopus (1) Google Scholar. The latter provided strong evidence that qRT-PCR analysis of minimally invasive skin tape strips across pediatric age groups can be used for identification of biomarkers associated with AD. In addition, this method may benefit clinical trials in which repeated measures are required to predict for example the course of the disease. The pathophysiology of skin diseases, including atopic dermatitis (AD), has been extensively studied using skin biopsies. Due to the invasive nature of skin biopsy sampling and associated ethical issues, skin biopsies for diagnostic and research purposes in healthy infants and children and those with a skin disease are very limited. Hence, skin immune profiling in healthy subjects or in children with a skin disease is very limited. In addition, sampling limitations may bias our knowledge of skin immune responses as only localized sampling can be done in case of biopsies, and gene expression and lipid composition analysis of tape strips may only reflect the upper layers of the skin176Berdyshev E. et al.Lipid abnormalities in atopic skin are driven by type 2 cytokines.JCI Insight. 2018; 3: e98006Crossref PubMed Scopus (148) Google Scholar, 177Broccardo C.J. Mahaffey S.B. Strand M. Reisdorph N.A. Leung D.Y. Peeling off the layers: skin taping and a novel proteomics approach to study atopic dermatitis.J. Allergy Clin. Immunol. 2009; 124 (1113–5.e1-11)Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar, 178Dyjack N. et al.Minimally invasive skin tape strip RNA sequencing identifies novel characteristics of the type 2-high atopic dermatitis disease endotype.J. Allergy Clin. Immunol. 2018; 141: 1298-1309Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar, 179Kezic S. et al.Levels of filaggrin degradation products are influenced by both filaggrin genotype and atopic dermatitis severity.Allergy. 2011; 66: 934-940Crossref PubMed Scopus (216) Google Scholar, 180Li S. et al.Altered composition of epidermal lipids correlates with Staphylococcus aureus colonization status in atopic dermatitis.Br. J. Dermatol. 2017; 177: e125-e127Crossref PubMed Scopus (51) Google Scholar. However, side-by-side comparison of skin tape stripping and skin biopsies of taped skin and adjacent non-taped skin in adult healthy controls and subjects with AD, indicated that consecutive skin tape stripping removed the stratum corneum and the upper part of the granular layer181Kim B.E. et al.Side-by-side comparison of skin biopsies and skin tape stripping highlights abnormal stratum corneum in atopic dermatitis.J. Invest. Dermatol. 2019; 139: 2387-2389.e1Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar. Moreover, gene expression levels of epidermal differentiation markers (filaggrin, corneodesmosin, loricrin, involucrin, and keratin-1) from skin tape stripping samples positively correlated with staining intensities of these markers in matching skin biopsies following immunostaining, suggesting that skin tape stripping is reliable for the evaluation of epidermal differentiation markers181Kim B.E. et al.Side-by-side comparison of skin biopsies and skin tape stripping highlights abnormal stratum corneum in atopic dermatitis.J. Invest. Dermatol. 2019; 139: 2387-2389.e1Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar. Analysis of stratum corneum biomarkers in skin tape strips from children were performed using proteomic, transcriptomic and quantitative real-time polymerase chain reaction (qRT-PCR) analysis182Hulshof L. et al.A minimally invasive tool to study immune response and skin barrier in children with atopic dermatitis.Br. J. Dermatol. 2019; 180: 621-630Crossref PubMed Scopus (48) Google Scholar, 183McAleer M.A. et al.Systemic and stratum corneum biomarkers of severity in infant atopic dermatitis include markers of innate and T helper cell-related immunity and angiogenesis.Br. J. Dermatol. 2019; 180: 586-596Crossref PubMed Scopus (57) Google Scholar, 184Leung D.Y.M. et al.The nonlesional skin surface distinguishes atopic dermatitis with food allergy as a unique endotype.Sci. Transl. Med. 2019; 11, eaav2685Google Scholar, 185Guttman-Yassky E. et al.Use of tape strips to detect immune and barrier abnormalities in the skin of children with early-onset atopic dermatitis.JAMA Dermatol. 2019; 155: 1358-1370Crossref PubMed Scopus (84) Google Scholar, 186Renert-Yuval Y. et al.Tape strips capture atopic dermatitis-related changes in nonlesional skin throughout maturation.Allergy. 2022; 77: 3445-3447Crossref PubMed Scopus (1) Google Scholar. The latter provided strong evidence that qRT-PCR analysis of minimally invasive skin tape strips across pediatric age groups can be used for identification of biomarkers associated with AD. In addition, this method may benefit clinical trials in which repeated measures are required to predict for example the course of the disease. The development of skin immunity starts in utero alongside its structural development1Visscher M.O. Carr A.N. Narendran V. Epidermal immunity and function: origin in neonatal skin.Front. Mol. Biosci. 2022; 9894496Crossref PubMed Scopus (2) Google Scholar, 2Botting R.A. Haniffa M. The developing immune network in human prenatal skin.Immunology. 2020; 160: 149-156Crossref PubMed Scopus (0) Google Scholar and continues to mature and expand throughout early life and into adulthood. Adequate immune development in early life is imperative for establishing cutaneous homeostasis, which sets the tone for long-term skin health. In early life, the skin contains a diverse range of immune cell populations, despite having significantly fewer in total than mature adult skin3Hornef M.W. Torow N. 'Layered immunity' and the 'neonatal window of opportunity' - timed succession of non-redundant phases to establish mucosal host-microbial homeostasis after birth.Immunology. 2020; 159: 15-25Crossref PubMed Scopus (0) Google Scholar, an observation made both in mice4Ubags N.D. et al.Microbiome-induced antigen-presenting cell recruitment coordinates skin and lung allergic inflammation.J. Allergy Clin. Immunol. 2021; 147: 1049-1062.e7Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar and in humans5Antolin-Amerigo et al.In-vitro tests suitability in severe systemic reaction due to several drugs.J. Clin. Exp. Dermatol. Res. 2012; S2: 005Google Scholar. The two main skin layers, the epidermis, a stratified structure composed of 90%–95% keratinocytes (KCs)6Wikramanayake T.C. Stojadinovic O. Tomic-Canic M. Epidermal differentiation in barrier maintenance and wound healing.Adv. Wound Care (New Rochelle). 2014; 3: 272-280Crossref PubMed Google Scholar, and the dermis, which lies underneath the latter, develop throughout multiple gestational stages7Coolen N.A. Schouten K.C. Middelkoop E. Ulrich M.M. Comparison between human fetal and adult skin.Arch. Dermatol. Res. 2010; 302: 47-55Crossref PubMed Scopus (118) Google Scholar, 8Holbrook K.A. Odland G.F. The fine structure of developing human epidermis: light, scanning, and transmission electron microscopy of the periderm.J. Invest. Dermatol. 1975; 65: 16-38Abstract Full Text PDF PubMed Google Scholar. The epidermis layer is maintained through continuous proliferation and differentiation of epidermal KCs in the basal layers and desquamation of corneocytes (dead, terminally-differentiated KCs) on the skin surface. Tight junctions hold these cells together, and degradation of these tight junctions is required during the termination of this dynamic process (i.e. exfoliation of dead skin cells)9Brandner J.M. et al.Organization and formation of the tight junction system in human epidermis and cultured keratinocytes.Eur. J. Cell Biol. 2002; 81: 253-263Crossref PubMed Scopus (243) Google Scholar. While undergoing terminal differentiation, KCs produce two key components: (i) structural proteins [e.g. filaggrin (FLG)] and (ii) lipids (mainly ceramides) that are equally essential for the formation of the stratum corneum (SC), the uppermost layer of the epidermis10Candi E. Schmidt R. Melino G. The cornified envelope: a model of cell death in the skin.Nat. Rev. Mol. Cell Biol. 2005; 6: 328-340Crossref PubMed Scopus (1304) Google Scholar. This process is often described as a brick-and-mortar model, where the corneocytes represent the bricks and the intercellular lipid matrix, in which the corneocytes are embedded, symbolizes the mortar11Elias P.M. Epidermal lipids, barrier function, and desquamation.J. Invest. Dermatol. 1983; 80: 44s-49sAbstract Full Text PDF PubMed Google Scholar, 12Nemes Z. Steinert P.M. Bricks and mortar of the epidermal barrier.Exp. Mol. Med. 1999; 31: 5-19Crossref PubMed Google Scholar. The SC, which allows tightly-controlled permeability, is the cornerstone of skin barrier function13Elias P.M. Skin barrier function.Curr. Allergy Asthma Rep. 2008; 8: 299-305Crossref PubMed Scopus (127) Google Scholar. The structural maturation of the skin, and particularly that of the epidermis, is achieved by 34 weeks of gestational age14Evans N.J. Rutter N. Development of the epidermis in the newborn.Biol. Neonate. 1986; 49: 74-80Crossref PubMed Google Scholar, whereas functional maturation [e.g. hydration, skin surface pH, and transepidermal water loss (TEWL)] starts in utero and continues into adult life15Leung A. Crombleholme T.M. Keswani S.G. Fetal wound healing: implications for minimal scar formation.Curr. Opin. Pediatr. 2012; 24: 371-378Crossref PubMed Scopus (87) Google Scholar, 16Méhul B. et al.Noninvasive proteome analysis of psoriatic stratum corneum reflects pathophysiological pathways and is useful for drug profiling.Br. J. Dermatol. 2017; 177: 470-488Crossref PubMed Scopus (22) Google Scholar, 17Yamazaki T. et al.Differentiation induction of human keratinocytes by phosphatidylethanolamine-binding protein.J. Biol. Chem. 2004; 279: 32191-32195Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar (see Table 1). Visscher and colleagues recently reported on the transcriptomics analysis of human newborn (6–10 weeks old), adult (20–24 years old), and elderly (60–65 years old) skin. Gene ontology analysis revealed differences in genes associated with epidermal development, keratinocyte differentiation, and immune function (antigen processing and presentation of exogenous antigen) with higher expression in adults than in infants18Visscher M.O. et al.Biomarkers of neonatal skin barrier adaptation reveal substantial differences compared to adult skin.Pediatr. Res. 2021; 89: 1208-1215Crossref PubMed Scopus (1) Google Scholar. Interestingly, similar findings have been reported comparing neonatal and adult murine skin4Ubags N.D. et al.Microbiome-induced antigen-presenting cell recruitment coordinates skin and lung allergic inflammation.J. Allergy Clin. Immunol. 2021; 147: 1049-1062.e7Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar. This age-dependent maturation process is critical for establishing the physical and functional barrier properties of the skin. The cross talk between these different barriers is fundamental for their own development and maintenance but is also pivotal for the establishment of the so-called immune barrier and ultimately contribute to adequate maturation of the cutaneous immune system.Table 1Evolution of the main structural and functional factors of human skin over time.NewbornInfant (<1 y)AdultTEWL (g/m2/h)18Visscher M.O. et al.Biomarkers of neonatal skin barrier adaptation reveal substantial differences compared to adult skin.Pediatr. Res. 2021; 89: 1208-1215Crossref PubMed Scopus (1) Google Scholar, 187Nikolovski J. Stamatas G.N. Kollias N. Wiegand B.C. Barrier function and water-holding and transport properties of infant stratum corneum are different from adult and continue to develop through the first year of life.J. Invest. 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Barrier function and water-holding and transport properties of infant stratum corneum are different from adult and continue to develop through the first year of life.J. Invest. Dermatol. 2008; 128: 1728-1736Abstract Full Text Full Text PDF PubMed Scopus (273) Google Scholar, 189Hoeger P.H. Enzmann C.C. Skin physiology of the neonate and young infant: a prospective study of functional skin parameters during early infancy.Pediatr. Dermatol. 2002; 19: 256-262Crossref PubMed Scopus (162) Google Scholar++++++NMF component levels18Visscher M.O. et al.Biomarkers of neonatal skin barrier adaptation reveal substantial differences compared to adult skin.Pediatr. Res. 2021; 89: 1208-1215Crossref PubMed Scopus (1) Google Scholar++++++Microbiome composition (predominant genera)115Chu D.M. et al.Maturation of the infant microbiome community structure and function across multiple body sites and in relation to mode of delivery.Nat. Med. 2017; 23: 314-326Crossref PubMed Scopus (603) Google ScholarNatural birth: Lactobacillus1.Staphylococcus 2.Corynebacterium 3.Cutibacterium1.Cutibacterium 2.Staphylococcus 3.CorynebacteriumC-section: Streptococcus and CutibacteriumNMF = natural moisturizing factor; TEWL = transepidermal water loss. Open table in a new tab NMF = natural moisturizing factor; TEWL = transepidermal water loss. Innate immunity is of paramount importance to protect the body from environmental aggression and infection, particularly at birth when the newborn emerges from the womb. Hence, achieving adequate epidermal barrier formation at birth is pivotal for the newborn, an event that is attained by 34 weeks of gestational age14Evans N.J. Rutter N. Development of the epidermis in the newborn.Biol. Neonate. 1986; 49: 74-80Crossref PubMed Google Scholar. Despite having a thin epidermis19Stamatas G.N. Nikolovski J. Luedtke M.A. Kollias N. Wiegand B.C. Infant skin microstructure assessed in vivo differs from adult skin in organization and at the cellular level.Pediatr. Dermatol. 2010; 27: 125-131Crossref PubMed Scopus (185) Google Scholar, the skin from term newborns is characterized by low TEWL, indicative of low skin permeability, which is similar to that of adults20Cunico R.L. Maibach H.I. Khan H. Bloom E. Skin barrier properties in the newborn.Neonatology. 1977; 32: 177-182Crossref Scopus (54) Google Scholar, 21Yosipovitch G. Maayan-Metzger A. Merlob P. Sirota L. Skin barrier properties in different body areas in neonates.Pediatrics. 2000; 106: 105-108Crossref PubMed Google Scholar. However, TEWL in premature babies (25–32 weeks of gestational age) is elevated22Harpin V.A. Rutter N. Barrier properties of the newborn infant's skin.J. Pediatr. 1983; 102: 419-425Abstract Full Text PDF PubMed Scopus (251) Google Scholar, 23Mathanda T.R. Bhat M.R. Hegde P. Anand S. Transepidermal water loss in neonates: baseline values using a closed-chamber system.Pediatr. Dermatol. 2016; 33: 33-37Crossref PubMed Scopus (6) Google Scholar. KCs, the predominant cell type in the epidermal layer, play a critical role in innate immunity and act as bona fide immune sentinels. KCs produce antimicrobial peptides and are equipped with Toll-like receptors (TLRs). Moreover, they not only participate in the regulation of the skin microbiota but can also recognize microbial components and initiate cascades of immune responses both in infants and adults24Frohm M. et al.The expression of the gene coding for the antibacterial peptide LL-37 is induced in human keratinocytes during inflammatory disorders.J. Biol. Chem. 1997; 272: 15258-15263Abstract Full Text Full Text PDF PubMed Scopus (674) Google Scholar, 25Marchini G. et al.The newborn infant is protected by an innate antimicrobial barrier: peptide antibiotics are present in the skin and vernix caseosa.Br. J. 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In another study, Kobayashi et al. demonstrated that by secreting interleukin (IL)-7, thymic stromal lymphopoietin protein (TSLP), and the chemokine CCL20, adult murine KCs can regulate the development and localization of cutaneous innate lymphoid cells (ILCs)29Kobayashi T. et al.Homeostatic control of sebaceous glands by innate lymphoid cells regulates commensal bacteria equilibrium.Cell. 2019; 176: 982-997.e16Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar. KCs also produce kallikreins (KLKs), which are essential for skin desquamation. KLK5 and KLK7 regulate skin innate immunity by controlling the activity of the antimicrobial peptide LL-37 both in humans (in vitro) and in mice (in vivo)30Yamasaki K. et al.Kallikrein-mediated proteolysis regulates the antimicrobial effects of cathelicidins in skin.FASEB J. 2006; 20: 2068-2080Crossref PubMed Scopus (369) Google Scholar. 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KCs and sebaceous glands are responsible for the production of skin lipids (e.g. ceramides, wax esters, and cholesterol esters) and sebum. Newborn skin contains high levels of skin surface lipids, particularly sebum33Agache P. Blanc D. Barrand C. Laurent R. Sebum levels during the first year of life.Br. J. Dermatol. 1980; 103: 643-649Crossref PubMed Scopus (83) Google Scholar. Subsequently, sebum levels diminish within the first 6 months of life before increasing again during pre-adolescence and reaching adult levels33Agache P. Blanc D. Barrand C. Laurent R. Sebum levels during the first year of life.Br. J. Dermatol. 1980; 103: 643-649Crossref PubMed Scopus (83) Google Scholar, 34Stamatas G.N. Nikolovski J. Mack M.C. Kollias N. Infant skin physiology and development during the first years of life: a review of recent findings based on in vivo studies.Int. J. Cosmet. Sci. 2011; 33: 17-24Crossref PubMed Scopus (146) Google Scholar, 35Pochi P.E. Strauss J.S. Downing D.T. Age-related changes in sebaceous gland activity.J. Invest. Dermatol. 1979; 73: 108-111Abstract Full Text PDF PubMed Google Scholar. Notably, it was shown that keratinocyte-derived lipids promote the survival of skin-resident memory T cells in both mouse and human settings36Pan Y. et al.Survival of tissue-resident memory T cells requires exogenous lipid uptake and metabolism.Nature. 2017; 543: 252-256Crossref PubMed Scopus (406) Google Scholar, whereas human sebocytes produce lipids with immunomodulatory properties promoting the differentiation of monocytes into alternatively activated macrophages in vitro37Lovászi M. et al.Sebum lipids influence macrophage polarization and activation.Br. J. Dermatol. 2017; 177: 1671-1682Crossref PubMed Scopus (49) Google Scholar. However, modulation of skin immunity by lipids warrants further investigation. Interestingly, using targeted proteomic analysis of human skin, Visscher and colleagues demonstrated that newborn and infant skin contains elevated keratinocyte-derived biomarkers related to skin barrier function and innate immunity (e.g. antimicrobial peptides) compared with adult skin1Visscher M.O. Carr A.N. Narendran V. Epidermal immunity and function: origin in neonatal skin.Front. Mol. Biosci. 2022; 9894496Crossref PubMed Scopus (2) Google Scholar, confirming the age-dependent differences in epidermal maturation and the necessity for an accelerated differentiation status and effector function of epidermal KCs in early life. Newborn skin has an alkaline pH at birth21Yosipovitch G. Maayan-Metzger A. Merlob P. Sirota L. Skin barrier properties in different body areas in neonates.Pediatrics. 2000; 106: 105-108Crossref PubMed Google Scholar, 38Lund C. Kuller J. Lane A. Lott J.W. Raines D.A. Neonatal skin care: the scientific basis for practice.Neonatal Netw. 1999; 18: 15-27Crossref PubMed Scopus (0) Google Scholar, which progressively decreases to adult levels39Schmid-Wendtner M.H. Korting H.C. The pH of the skin surface and its impact on the barrier function.Skin Pharmacol. Physiol. 2006; 19: 296-302Crossref PubMed Scopus (566) Google Scholar (pH of 5.4–5.9) during the first 2–3 months of life40Fluhr J.W. et al.Infant epidermal skin physiology: adaptation after birth.Br. J. Dermatol. 2012; 166: 483-490Crossref PubMed Scopus (125) Google Scholar (Table 1). Thi