505 Evolution and Challenges of Sustainability
These AMPs help protect the skin from colonization and infection by transient
microorganisms and pathogens.
6. Commensal skin microflora may promote immunological quiescence by up-regulating
production of IL-10 (an anti-inflammatory cytokine) by dendritic cells.
Each microorganism in any environment—including the skin—is in a constant, life-
and-death struggle with other organisms in this environment as they compete for the
available nutrients needed for survival and growth. Microorganisms can make free fatty
acids, enzymes, and virulence factors including toxins, bacteriocins, AMPs, and antibiotics
that help them compete and survive, as illustrated by the following examples. C. acnes,
S. epidermidis, S. aureus, and Malassezia spp. secrete lipases that hydrolyze triglycerides in
sebum to produce free fatty acids that lower the pH of the skin surface and make it more
difficult for non-acid-tolerant microorganisms to grow, and stimulate epithelial cells and
neutrophils to express HBD2, which has antimicrobial activity against Gram-negative
bacteria and Candida spp.84-86 Many fatty acids upregulate AMPs and cytokines in sebaceous
glands, and sebaceous-gland-rich sites have higher levels of AMPs (e.g., psoriasin S100A7,
HBD2, and lipocalin than sebum-poor sites.87-90 Most Corynebacterium spp. contain mycolic
acid in the cell envelope. Mycolic acid can promote γδTcell accumulation with release of
IL-23, an inflammatory cytokine. Some strains of C. acnes produce cutimycin, a thiopeptide
antibiotic that limits S. aureus colonization.89,91 Staphylococcus lugdunensis produces lugdunin,
an antimicrobial peptide that induces keratinocytes to produce AMPs (cathelicidin LL-37
and CXCL8). CXCL8 is a neutrophil chemoattractant produced through the TLR-myeloid
differentiation response protein 88 (TLR-Myd88) pathway.92 S. epidermidis produces
bacteriocins, several types of AMPs, and stimulates keratinocytes and Langerhans cells
to produce AMPs to prevent the growth of other microorganisms. S. epidermidis produces
succinic acid (from fermentation of glycerol) which inhibits some strains of C. acnes.87,93-95
S. epidermidis also produces a serine protease, Esp, that is able to inhibit S. aureus biofilm
formation and colonization.96 Biofilm is involved in the pathogenicity and antimicrobial
susceptibility of C. acnes,97and it is likely that Esp produced by S. epidermidis, or proteases
produced by other microorganisms, may help control biofilm formation of C. acnes, which
in turn decreases C. acnes colonization to decrease the severity of acne.
Skin colonization with commensal microorganisms shapes immunity through activation
of cellular pattern recognition receptors, with distinct activation signatures defining skin
physiology.98 Commensal S. epidermidis, induces IL-17A+ CD8+ T cells that home to the
epidermis, enhance innate barrier immunity, and help prevent pathogen attachment and
colonization.99 Commensals also trigger activation of cellular Toll-like receptors (TLRs)
to enhance immunity and facilitate wound repair.100 Keratinocytes express TLRs and
other immunomodulatory proteins, such as nucleotide-binding oligomerization domain-
containing protein 2 (NOD2), that can recognize pathogenic substances, such as pathogen-
associated molecular patterns including bacterial cell wall peptidoglycans, and stimulate an
immune reaction to them.101,102 Immune response pathways are activated in a TLR-specific
process, which causes the release of cytokines, chemokines, and AMPs to attract circulating
immune cells (e.g., neutrophils and Langerhans cells). Keratinocytes constitutively express
certain AMPs, such as HBD1, while other AMPs are induced in response to injury or
infection.103-105 The Firmicutes and Actinobacteria produce lipoteichoic acid (LTA), which
is a major constituent of Gram-positive bacterial cell walls. LTA is a Toll-like receptor 2
(TLR2) ligand that down-regulates skin inflammation, which in turn, supports barrier
function.82,106

506 JOURNAL OF COSMETIC SCIENCE
Up-regulation of HBD2 is believed to play an important role in cutaneous immune
defense, and expression of this AMP appears to be localized to the upper Malpighian layer
of the epidermis and stratum corneum.107,108 S. epidermidis is a good inducer of HBD2 and
is tolerant to it, which enables S. epidermis to colonize skin. Streptococcus pyogenes is known to
be a poor/variable inducer of HBD2, which means that S. pyogenes can reside on skin and
mucous membranes without stimulating skin cells to release substantial amounts of HBD2.
However, S. pyogenes is reported to be significantly more sensitive to killing by HBD2 than
S. epidermidis.107 Consequently, the growth of S. epidermidis on skin up-regulates HBD2
which helps limit S. pyogenes colonization of skin.
Phenol-soluble modulins (PSMs) are AMPs which are small peptides with an amphipathic
α-helical structure and strong surfactant-like properties. PSMs are produced by most
staphylococci and can induce the production of proinflammatory cytokines, recruit, activate,
and lyse neutrophils to help staphylococci evade destruction by these neutrophils. For
example, PSMs facilitate the detachment and dissemination of staphylococcal biofilms.66
PSMα elicits a keratinocyte Myd88 signaling response that drives an IL-17-mediated skin
inflammatory response to S. aureus colonization of skin, and PSMε enhances production
of IL-8—neutrophil chemotactic factor—a proinflammatory mediator that recruits and
activates neutrophils to kill competing microorganisms.109-111
The normally functioning skin microbiome assists the body’s immune barrier however,
dysbiosis (i.e., disruption of the microbiome with changes composition and/or metabolic
activities) may lead to inflammatory skin disorders.112 For example, C. acnes is involved
directly or indirectly in the pathogenesis of acne vulgaris. The free fatty acids and porphyrins
produced by C. acnes cause skin inflammation.68,82,113 S. epidermidis, and to a lesser extent,
S. aureus normally colonize human skin without any negative health effects, but these
bacteria may worsen atopic dermatitis (AD) in some patients. It is not known whether over-
colonization by staphylococci in AD is the cause or the consequence of inflammation.74,114,115
Malassezia yeasts are residents of healthy skin, but Malassezia spp. may cause dandruff
and seborrheic dermatitis in susceptible individuals.116 The microbiome of patients with
psoriasis has higher numbers of Malassezia spp. and Streptococcus spp. and lower numbers of
Cutibacterium spp. compared to healthy individuals.117
The crosstalk between commensals and the skin may involve microbial metabolite-mediated
interactions with cells in the immune system. Mucosal-associated invariant T (MAIT) cells
constitute a subset of αβT lymphocytes characterized by a semi-invariant T cell receptor
alpha (TCRα) chain. MAIT cells have innate, T cell effector-like qualities.118,119 Microbial
exposure that occurs during early life imprints MAIT cell abundance for life. MAIT cells
represent a dominant type-17 effector subset in the skin, they are involved with immune
surveillance, and they defend against microbial infection. MAIT cells require vitamin B2
metabolites that are only produced by bacteria and fungi.86 The major histocompatibility
complex (MHC) class I-like protein, MR1, is responsible for presenting bacterially-produced
riboflavin (vitamin B2) and folic acid (vitamin B9) metabolites to MAIT cells.118,120-122 After
the presentation of foreign antigen by MR1, MAIT cells produce the proinflammatory
cytokines, interferon-γ (IFN-γ) and tumor necrosis factor, and they are cytolytic.118
Most species within the dominant bacterial taxa Corynebacteriaceae, Propionibacteriaceae,
and Staphylococcaceae in the skin microbiome encode Vitamin B2 biosynthesis therefore,
MAIT cell specific immunity through recognition of riboflavin biosynthesis intermediates
produced by the skin microflora is an example of crosstalk between commensals and the
skin that plays an important role in skin barrier immunology.123-127