Science - USA (2019-01-18)

SCIENCE sciencemag.org

By Apollo Stacy1,2,3 and Yasmine Belkaid1,2

S

kin, our largest and outermost organ,

faces numerous challenges, includ-

ing wounds, infections, inflammatory

disorders, and cancer. Fortunately, it

does not meet these challenges alone.

Our skin is home to complex microbial

communities, the skin microbiota, that play

a fundamental role in the protection and

control of this barrier surface. Here, we focus

on Staphylococcus epidermidis as a “poster

child” of the skin microbiota to illustrate the

remarkable diversity of functions a microbe

can exert on skin physiology and health.

Some of the most abundant constituents

of the skin microbiota are the coagulase-neg-

ative staphylococci, a group of bacteria that

includes S. epidermidis. Although in the past

these microbes were merely considered fast-

growing “weeds” and potential pathogens, re-

cent studies highlight that, analogous to the

oft-studied gut microbiota, this group also

assumes prominent roles in promoting tissue

immunity, repair, and antimicrobial defense.

Of note, S. epidermidis is more than “one

microbe.” Individual strains vary dramati-

cally in their genome content, functional

potential, and relationship to the host im-

mune system. Furthermore, the context in

which S. epidermidis is sensed—for exam-

ple, by intact or inflamed skin—can have a

profound impact on interaction outcomes,

explaining in part the diverse effects that it

exerts on the host and on other microbes

( 1 , 2 ). These functions can be mediated by

defined microbial features (see the figure),

some of which are specific to S. epidermidis

[for example, unique cell wall products ( 2 )],

whereas others are shared among many

members of the skin microbiota [for ex-

ample, the ability to produce antimicrobials

( 3 ) or the ability to colonize particular skin

niches such as hair follicles ( 4 )].

As a skin inhabitant, S. epidermidis lives

in tight association with keratinocytes, the

cells that constitute the top layer of this or-

gan. Keratinocytes represent a first line of de-

fense, yet it remains poorly understood how

they peacefully coexist with the skin micro-

biota. Because unchecked immune tolerance

to the skin microbiota could lead to micro-

bial overgrowth, keratinocytes have likely

co-opted products of microbial metabolism

as cues to curb its proliferation. Short-chain

fatty acids (SCFAs) are released by S. epider-

midis and other skin microbes as metabolic

waste. As such, SCFAs serve as effective prox-

ies for the quantity of microbiota, and hence

its potential threat to skin integrity. For in-

stance, the SCFAs propionate and valerate

inhibit the activity of histone deacetylases

(HDACs) in keratinocytes. This promotes

gene expression and thereby enables higher

keratinocyte production of proinflammatory

cytokines ( 5 ). Thus, the metabolic activity of

the skin microbiota may calibrate the acti-

vation status of keratinocytes toward either

tolerance or inflammation.

In the context of tissue damage, the dialog

between the skin microbiota and keratino-

cytes is shaped by microbial products. Cer-

tain cell wall products are sensed by the host

through dedicated receptors, such as Toll-like

receptors (TLRs). In most host cells, micro-

bial cell wall products trigger inflammation,

but in keratinocytes, S. epidermidis TLR2

signaling can, in some contexts, dampen in-

flammation processes ( 2 , 6 ). This response

benefits not only S. epidermidis, by ensuring

its stable colonization on skin, but also the

host in contexts where excess inflammation

is deleterious. For instance, S. epidermidis

TLR 2 signaling can limit inflammation after

skin injury—an effect that promotes wound

healing ( 2 )—as well as during infection with

the acne-associated microbe Cutibacterium

acnes ( 6 ). This anti-inflammatory communi-

cation occurs through discrete mechanisms.

In the context of wounds, TLR 2 activation

by S. epidermidis inhibits proinflamma-

tory TLR 3 signaling in response to double-

stranded RNA from damaged host cells ( 2 ),

whereas in the context of C. acnes infection,

S. epidermidis TLR2 signaling induces a

microRNA that limits TLR 2 expression, coun-

teracting TLR 2 - driven inflammation ( 6 ).

Given the structural and metabolic complex-

ity of microbial cells, numerous microbiota-

derived ligands may yet be discovered that

are recognized by other host receptors.

Members of the skin microbiota such as

S. epidermidis can also fully engage com-

ponents of the adaptive immune system,

including different subsets of T cells. These

cells are noted for acquiring target specific-

ity and orchestrating highly dynamic im-

mune responses, ranging from effector (for

example, aimed at eliminating a pathogen)

to regulatory (suppressive). S. epidermidis

can finely tune both types of responses. In

early life, cells with regulatory function [for

example, regulatory T cells (Tregs)] migrate

to skin after the skin microbiota colonizes

hair follicles. As these Tregs are microbiota-

specific, they are instrumental to establish-

ing tolerance to skin microbes including S.

epidermidis ( 4 ).

The two major subsets of effector T cells

are helper (TH) and cytotoxic (TC) cells. Al-

though many skin microbes can promote

the accumulation of TH cells, S. epidermidis

is rare in its ability to recruit and license the

function of TC cells ( 1 ). Remarkably, TC cells

acquire specificity to S. epidermidis through

an evolutionarily ancient arm of immunity.

This pathway involves the presentation of S.

epidermidis peptides on nonclassical antigen-

presenting molecules by dendritic cells to TC

cells ( 7 ). S. epidermidis–specific TC cells can

provide multiple benefits to the host through

their ability to alter the behavior of keratino-

cytes. These benefits include protecting the

skin against foreign pathogens ( 8 ) and accel-

erating the healing of skin wounds ( 7 ).

Antimicrobial peptides (AMPs) are se-

creted by keratinocytes to fortify the skin

against pathogens. Notably, their production

can be augmented by cues from S. epider-

midis. These cues can be sensed directly via

TLR2 ( 2 ) or transduced by S. epidermidis–

specific TC cells that instruct keratinocytes

to express AMPs ( 1 ). Both pathways promote

keratinocyte AMP expression and killing of

diverse microbial pathogens, including bac-

teria and fungi ( 1 , 2 ). Because S. epidermidis

has built-in defenses, such as modifying its

cell wall with positively charged residues that

repel AMPs ( 9 ), these responses may benefit

not only the host but also S. epidermidis by

eliminating its potential competitors.

S. epidermidis also interacts with other

microbes directly, independently of the host.

Often, these interactions are antagonistic,

revolving around competition for space and

nutrients. Antagonism is especially promi-

nent in the nasal cavity, a primary reservoir

of the pathogen S. aureus. In this niche, S.

epidermidis can displace S. aureus by secret-

ing the protease Esp that degrades S. aureus

adherence proteins ( 3 ). Microbes can further

MICROBIOLOGY

Microbial guardians of skin health

Skin microbes can promote skin immunity, repair, and antimicrobial defense

(^1) Metaorganism Immunity Section, Laboratory of Immune System
Biology, National Institute of Allergy and Infectious Diseases,
Bethesda, MD 20892 , USA.^2 NIAID Microbiome Program, National
Institute of Allergy and Infectious Diseases, Bethesda, MD
20892 , USA.^3 Postdoctoral Research Associate Training Program,
National Institute of General Medical Sciences, Bethesda, MD
20892 , USA. Email: [email protected]
1 8 JANUARY 2 019 • VOL 363 ISSUE 6424 227
Published by AAAS
on January 21, 2019^
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