Skin Barrier Insights: From Bricks and Mortar to Molecules and Microbes

January 2019 | Volume 18 | Issue 1 | Supplement Individual Articles | 63 | Copyright © January 2019


Carol A. Bosko PhD

Unilever Research & Development, Trumbull, CT

for antimicrobial defense, enzyme activity, and cytokine activation. Elevated SC pH is associated with perturbations in barrier function as many enzymes involved in lipid metabolism and CD degradation require an acidic environment.44 Elevated pH is also associated with shifts in the microbial composition toward potentially pathogenic organisms.45 These findings provide support for use of acid-neutral pH cleansers and moisturizers in the prevention and treatment of barrier deficiencies.46 Microbiome The skin harbors a diverse population of microbes whose composition is largely determined by site-specific factors such as moisture and sebum content.47 The skin’s invaginations and appendages harbor a large number of microorganisms but microbial DNA has also been found deep within the dermis.48 This surprising finding challenges many existing concepts of skin, its microflora, and the mechanisms by which the host immune system is educated by the microbiome.The SC provides a formidable barrier to microbial colonization due to the physical barrier, low water and nutrient content, acidic pH, and antimicrobial lipids (AML) and peptides (AMP). Sphingosine and free fatty acids are potent AMLs and are found in ample concentrations in SC.49 AMPs are a diverse, yet highly conversed set of proteins belonging to the host innate immune system that kill microbes primarily through disruption of the cell membrane. The predominant AMPs of skin belong to the cathecidin and defensin classes and are delivered to the SC via LGs or glandular secretions.50 However, microbes can also produce AMP-like proteins. S. epidermidis produces AMPs that inhibit colonization of S. aureus,51 however strain variation is significant, and the commensals in some AD patients lack the ability to produce AMPs selective for S. aureus.52 Microbial AMPs also synergize with host AMPs, thus the secretome of commensals could be viewed as an integral part of most innate defense system.53 There exists a complex interplay between the microbiome and the host immune system. The innate and adaptive arms of the immune system modulate the composition of the microbiome and in turn, the microflora communicates with and directs the host immune response.54 Propionibacteria acnes induces expression of AMPs and inflammatory cytokines in keratinocytes in a toll-like receptor-dependent (TLR) fashion.55 Staphylococcal lipoteichoic acid blunts inflammation via interaction with TLR3 and stimulates wound healing.56 These are but a few examples that illustrate how the microflora directly modulates both the innate and adaptive arms of the host immune response. The complexity of this interaction suggests a coevolution of host and microbes and this balance may be disrupted by our rapidly changing environment; diet, hygiene, and antibiotics could affect the microbiome at a faster rate than the microbiota can adapt. This has led some researchers to speculate that these changes are responsible for the dramatic increase in the incidence of inflammatory diseases such as AD.Barrier perturbations can drive changes in the skin’s microbiota, ie, dysbiosis. There is now a strong recognition that barrier dysfunction is a driving element in many inflammatory skin disorders and not merely a bothersome sequela. Most notably patients with AD tend to be at increased risk of infection and colonization by S. aureus.57 In contrast to the many microbiome studies on AD patients, definitive studies on microbial changes that might accompany cosmetic dry skin are yet to be published.58 On the other hand, mild cleansers have been shown to help restore normal flora.59 The use of mild cleansers that protect the skin’s barrier lipids60,61 would be expected to help maintain a “healthy” microbiome.

CONCLUSIONS

Barrier impairment, whether the result of genetic or environmental influences, increases the flux of water out of and exogenous materials in to the skin. The consequences of this increased permeation will depend, in large part, on the host response to that stimulus. In some instances, the host response can further degrade barrier function leading to a vicious cycle of stimulus and response. Optimizing a skin care regime to support the skin’s own barrier repair mechanisms is an integral part of any successful therapy. Continued research efforts are necessary to provide the scientific foundation for identifying new therapies and optimal skin care regimes.

DISCLOSURES

Carol Bosko is an employee of Unilever.

REFERENCES

  1. Elias PM. Epidermal lipids barrier function and desquamation. J Invest Dermatol. 1983;80(Suppl):44-49.
  2. Grice EA, Segre JA. The skin microbiome. Nat Rev Microbiol. 2011;9:244-253.
  3. Serre G, Mils V, Haftek M, et al. Identification of late differentiation antigens of human cornified epithelia, expressed in re-organized desmosomes and bound to cross-linked envelope. J Invest Dermatol. 1991;97:1061-1072.
  4. Harding CR, Long S, Richardson J, et al. The cornified cell envelope: an important marker of stratum corneum maturation in healthy and dry skin. Int J Cosmet Sci. 2003;25:157-167.
  5. Guneri D, Voegeli R, Gurgul SJ, et al. A new approach to assess the effect of photodamage on corneocyte envelope maturity using combined hydrophobicity and mechanical fragility assays. Int J Cosmet Sci. 2018;40:207-216.
  6. Brattsand M, Stefansson K, Lungh C, et al. A proteolytic cascade of kallikreins in the stratum corneum. J Invest Dermatol. 2005;124:198-203
  7. Ishida-Yamamoto A, Kishibe M. Involvement of corneodesmosome degradation and lamellar granule transportation in the desquamation process. Med Mol Morpho. 2011;44:1-6
  8. Singh B, Haftek M, Harding CR. Retention of corneodesmosomes and increased expression of protease inhibitors in dandruff. Br J Dermatol. 2014;171:760-770.
  9. Has C. Peeling skin disorders. J Invest Dermatol. 2018;138:1689-1691.
  10. Deraison C, Bonnart C, Lopez F, et al. LEKT1 fragments specifically inhibit KLK5,KLK7, and KLK14 and control desquamation through pH-dependet interaction. Mol Cell Biol. 2007;18:3607-3619.
  11. Kitajima Y. Desmosomes and corneodesmosomes are enclosed by tight junctions at the periphery of granular cells and corneocytes, suggesting a role in generation of a peripheral distribution of corneodesmosomes in corenocytes. J Dermatol Sci. 2016;83:73-75.
  12. Igawa S, Kishibe M, Murakami M, et al. Tight junctions in the stratum corneum explain spatial differences in corneodesmosome degradation. Exp Dermatol. 2011;20:53-57.
  13. Harding CR, Aho S, Bosko CA. Filaggrin - revisited. Int J Cosmet Sci. 2013;35:412-23.
  14. Scott I, Harding C. Studies on the synthesis and degradation of a histidine-rich phosphoprotein from mammalian epidermis. Biochim Biophys Acta. 1982;719:110-117.
  15. Paternoster L, Standl M, Waage J, et al. Multi-ancestry genome-wide association study of 21,000 cases and 95,000 controls identifies new risk loci for atopic dermatitis. Nat Genet. 2015;47:1449-1456.
  16. Bin L, Leung DY. Genetic and epigenetic studies of atopic dermatitis. Allergy Asthma Clin Immunol. 2016;12:52-66.
  17. Irvine AD, McLean WH. Breaking the (un)sound barrier:filaggrin is a major gene for atopic dermatits. J Invest Dermatol. 2006; 126:200-1202.
  18. Nutten S. Atopic Dermatitis: global epidemiology and risk factors. Ann Nutr Metab. 2015;66(suppl):8-16.
  19. Kezic S, O'Regan GM, Yau N, et al. Levels of filaggrin degradation products are influenced byboth filaggrin genotype and atopic dermatitis severity. Allergy. 2011;66:934-940.
  20. Honzke S, Wallmeyer L, Ostrowski A, et al. Influence of Th2 cytokines on the cornified envelope, tight junction proteins, and beta-defensins in filaggrin-deficient skin equivalents. J Invest Dermatol. 2016;136:631-639.
  21. Danso MO, van Drongelen V, Mulder A, et al. TNF-alpha and Th2 cytokines induce atopic dermatitis-like features on epidermal differentiation proteins and stratum corneum lipids in human skin equivalents. J Invest Dermatol. 2014;134:1941-1950.
  22. Elias PM, Cullander C, Mauro T, et al. The secretory granular cell: the outermost granular cell as a specialized secretory cell. J Invest Dermatol Symp Proc. 1998;3:87-100
  23. Elias PM. Lipid abnormalities and lipid-based repair strategies in atopic dermatitis. Biochim Biophys Acta. 2014;1841:323-330
  24. Elias PM. Epidermal barrier function, intercellular lamellar lipid structures, origin, composition and metabolism. J Control Release. 1991;15:199-208.
  25. Rawlings AV, Hope J, Rogers J, et al. Abnormalities in stratum corneum structure, lipid composition and desmosomal degradation in soap-induced winter xerosis. J Soc Cosmet Chem. 1994;45:203-220.
  26. Rogers J, Harding C, Mayo A, et al. Stratum corneum lipids: the effect of ageing and the seasons. Arch Dermatol Res. 1996;288:765-770.
  27. Tfayli A, Guillard E, Manfait M, Baillet-Guffroy A. Raman spectroscopy: feasibility of in vivo survey of stratum corneum lipids, effect of natural aging. Eur J Dermatol. 2012;22:36-41.
  28. Imokawa G, Abe A, Jin K, et al. Decreased level of ceramides in stratum corneum of atopic dermatitis: an etiologic factor in atopic dry skin? J Invest Dermatol. 1991;96:523- 526.
  29. Bleck O, Abeck D, Ring U, et al. Two ceramide subfractions detectable in Cer (AS) position by HPTLC in skin surface lipids of non-lesional skin in atopic eczema. J Invest Dermatol. 1999;113: 894- 900.
  30. van Smeden J, Janssens M, Kaye EC, et al. The importance of free fatty acid chain length for the skin barrier function in atopic dermatitis patients. Exp Dermatol. 2014;23:45-52.
  31. Janssens M, van Smeden J, Gooris GS, et al. Increase in short-chain ceramides correlates with an altered lipid organization and decrease barrier function in atopic eczema patients. J Lipid Res. 2012; 53:2755-2766.
  32. Lu N, Chandar P, Tempesta D, et al. Characteristic differences in barrier and hygroscopic properties between normal and cosmetic dry skin. I. Enhanced barrier analysis with sequential tape-stripping. Int J Cosmet Sci. 2014;36:167-174.
  33. Matsukawa Y, Narita H, Sato H, et al. Comprehensive quantification of ceramide species in human stratum corneum. J Lipid Res. 2009;50:1708-1719.
  34. Laffet GP, Genette A, Gamboa B, et al. Determination of fatty acid and sphingoid base composition of eleven cermaide subclasses in stratum corneum by UHPLC/scheduled-MRM. Metabolomics. 2018;14:69.
  35. van Smeden J, Bolten WA, Hankemeier T, et al. Combined LC/MS-platform for analysis of all major stratum corneum lipids and the profiling of skin substitutes. Biochem Biophys Acta. 2014;1841:70-79.
  36. Bouwstra JA, Gooris GS, Dubbelaar F E, Ponec M. Phase behaviour of stratum corneum lipid mixtures based on human ceramides: the role of natural and synthestic ceramide 1. J Invest Dermatol. 2002;118:606-617.
  37. Zheng Y, Yin H, Boeglin WE, et al. Lipooxygenases mediate the effect of essential fatty acid in skin barrier formation: a proposed role in releasing omega-hydroxyceramide for construction of the corneocyte lipid envelope. J Biol Chem. 2011;286:24046-24056.
  38. Houben E, Holleran WM, Yaginuma T, et al. Differentiation-associated expression of cermaidase isoforms in cultured keratincytes and epidermis. J Lipid Res. 2006;47:1063-1070.
  39. Iwai I, Han H, Hollander LD, et al. The human skin barrier is organized as stacked bilayers of fully extended ceramides with cholesterol molecules associated with the ceramide sphingoid moiety. J Invest Dermatol. 2012;132:2215-2225.
  40. Skolova B, Hudska K, Pullmannova P, et al. Different phase behavior and packing of ceramides with long (C16) and very long (C24) acyls in modle membranses: infrared spectroscopy of deuterated lipids. J Phys Chem B. 2014;118:10460-10470.
  41. Bouwstra J, Gooris G, Ponec M. The lipid organisation of the skin barrier: liquid and crystalline domains coexist in lamellar phases. J Biol Phys. 2002;28:211-223
  42. Berkers T, van Dijk L, Absalah S, et al. Topically applied fatty acids are elongated before incorporation in the stratum corneum lipid matrix in compromised skin. Exper Dermatol. 2017;26:36-43.
  43. Elias PM. Stratum corneum acidification, how and why? Exper Dermatol. 2015;24:179-180.
  44. Hachem JP, Man MQ, Crumine D, et al. Sustained serine proteases activity by prolonged increase in pH leads to degradation of lipid processing enzymes and profound alterations of barrier function and stratum corneum integrity. J Invest Dermatol. 2005;125:510-520.
  45. Korting HC, Hubner K, Greiner K, et al. Differences in skin surface pH and bacterial microflora due to long-term application of synthetic detergent preparations of pH 5.5 and pH 7.0. Acta Derm Venereol. 1990;7:429-431.
  46. Lee HJ, Yoon NY, Lee SH, et al. Topical acidic cream prevents the developme nt of atopic dermatitis-and asthma-like lesions in murine model. Exp Dermatol. 2014;23:736-741.
  47. Belkaid Y, Segre JA. Dialogue between skin microbiota and immunity. Science. 2014;21:954-959.
  48. Nakatsuji. The microbiome extends to subepidermal compartments of normal skin. Nature Communications. 2013;1431.
  49. Bibel DJ, Aly R, Shah S, Shinefield HR. Sphingosines: antimicrobial barriers of the skin. Acta Derm Venerol. 1993;73:407-411.
  50. Radek K, Gallo R. Antimicrobial peptides: natural effectors of the innate immune system. Semin Immunopathol. 2007;29:27-43
  51. Iwase T, Uehara Y, Shinji H, et al. Staphylococcus epidermidis Esp inhibits Staphylococcus aureus biofil formation and nasal colonization. Nature. 2010;465:346-351.
  52. Nakatsuji T. Antimicrobials from human skin commensal bacteria protect aggainst Staphylococcus aureus and are deficient in atopic dematitis. Science Trans Med. 2017;9:eaah4680.
  53. Cogen AL, Yamasaki K, Sanchez KM, et al. Selective antimicrobial action is provided by phenol-soluble modulins derived from Staphylococcus epidermidis, a normal resident of the skin. J Invest Dermatol. 2010;130:192-200.
  54. Grice EA, Kong HH, Conlan S, et al. Topographical and temporal diversity of the human skin microbiome. Science. 2009;324:1190-1192.
  55. Nagy I, Pivarcsi A, Koreck A, et al. Distinct strains of Propionibacterium acnes induces selective human β-defensin-2 and interleukin-8 expression in human keratinocytes through Toll-like receptors. J Invest Dermatol. 2005;124:931-938.
  56. Lai Y, DiNardo A, Nakatsuji T, et al. Commensal bacteria regulate Toll-like receptor 3–dependent inflammation after skin injury. Nat Med. 2009;15:1377-1382
  57. Kong H, Oh J, Deming C, et al. Temporal shifts in the skin microbiome associated with disease flares and treatment in children with atopic dermatits. Genome Res. 2012;22:850-859.
  58. Ballesteros A, Tierney NK, Rush A. Fundamental assessment of skin microbiome diversity in three subject populations: normal skin, dry skin, and dry skin with a history of itch. J Amer Acad Dermatol. 2018;6631
  59. Fukui S, Morikawa T, Hirahara M, et al. A mild hand cleanser, alkyl ether sulphate supplemented with alkyl ether carboxylic acid and alkyl glucoside, improves eczema on the hand and prevents the growth of Staphylococcus aureus on the skin surface. Int J Cosmet Sci. 2016;38:599-606.
  60. Ananthapadmanabhan KP, Yang L, Vincent C, et al. A novel technology in mild and moisturizing cleansing liquids. Cosmetic Dermatol. 2009;22:307-316.
  61. Mukherjee S, Edmunds M, Lei X, et al. Stearic acid delivery to corneum

AUTHOR CORRESPONDENCE

Carol A. Bosko PhD Carol.Bosko@unilever.com
Close Menu