Cell Host & Microbe
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Seeing Is Believing: Vitamin A Promotes
Skin Health through a Host-Derived Antibiotic
Jens-M. Schröder1,*
1Department of Dermatology, University-Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany
*Correspondence: jschroeder@dermatology.uni-kiel.de
https://doi.org/10.1016/j.chom.2019.05.011
In this issue of Cell Host & Microbe, Harris et al. (2019) show that members of the resistin-like molecule
(RELM) family are bactericidal, antimicrobial peptides that promote skin defenses in a vitamin-A-dependent
manner. Administration of vitamin A analogs triggers RELM, which improves host resistance against skin
pathogens in mice.
Body surfaces—including those of the gut,
the lung, and the skin—are intricate habi-
tats for numerous commensal and environ-
mental bacteria, fungi, and viruses. In
healthy skin, commensal bacteria reside
mainly within the different layers of the
dead keratinocyte-containing stratum cor-
neum (Zeeuwen et al., 2012) but also grow
within skin appendages like sweat glands
and hair follicles with sebaceous glands.
It is currently believed that—apart from
environmental conditions like nutrient
availability, salt, essential trace elements,
water, and the pH—antimicrobial compo-
nents of the host as well as the commensal
microflora shape the local microbiome.
Thus, the skin surface has to manage inter-
actions with this diverse microbial commu-
nity mainly through epidermal-cell-based
defense strategies with antimicrobial pep-
tides (AMPs) as effector molecules. In this
issue of Cell Host & Microbe, Harris et al.
(2019) explore a vitamin-A-dependent
role for murine resistin-like molecule a
(RELMa) and its human parlor resistin in
shaping the normal flora and its role as
AMP in skin defense against certain bacte-
rial infections.
Some epidermal AMPs are constitu-
tively produced and others need to be
induced, either upon infection, inflamma-
tion, or wounding. One strategy to under-
stand how the skin’s antimicrobial defense
is regulated by environmental factors is to
identify antimicrobial proteins whose
expression is inducible by bacteria. To
achieve this, Harris et al. (2019) used
whole-transcriptome RNA sequencing to
compare transcript abundances in the
skin of germ-free mice to those in the
skin of germ-free mice challenged with
the opportunistic skin pathogen Staphylo-
coccus aureus. The protein resistin-like
molecule a (RELMa), which belongs to
the protein family that encompasses resis-
tin and the resistin-like molecules
(RELMs), was found to be strongly
induced by bacterial exposure. Resistin
and other RELMs have been characterized
as hormones that modulate insulin pro-
duction. It, however, was recently found
that RELMb is a Gram-negative, bacteria-
killing AMP, promoting host-bacterial
mutualism in the intestine (Propheter
et al., 2017). Thus, Harris et al. (2019) hy-
pothesized that RELMa might be a bacte-
ricidal protein of the skin. They found it to
be expressed in mouse keratinocytes as
well as in sebocytes, cells of the seba-
ceous glands. While the mouse genome
encodes four RELM family members, the
human genome encodes only two RELM
proteins, resistin-like molecule b (RELMb)
and resistin (RETN). The location of
RELMa and RETN expression in keratino-
cytes and sebaceous glands—similar
to the lipophilic AMP cathelicidin—led
them hypothesize that mRELMa and
hRETN might function in antimicrobial de-
fense of the skin. With recombinant
mRELMa and hRETN, they identified
bactericidal activity for Streptococcus
pyogenes and Pseudomonas aeruginosa
and, of note, the highest sensitivity of Pro-
pionibacterium acnes, a skin commensal
linked to acne and residing in a lipid-rich
environment.
Whereas the skin commensal Staphylo-
coccus epidermidis is susceptible to
mRELMa and hRETN, a strain of the path-
ogen Staphylococcus aureus is unexpect-
edly resistant, a propensity attributed to
its production of staphyloxanthin (STX),
a yellow pigment that intercalates into
the S. aureus membrane and protects it
from attack by pore-forming antimicrobial
Cell Host & Microbe 25, June 12, 2019 ª 2019 Elsevier Inc. 769
proteins. Indeed, Harris et al. (2019)
demonstrated that a S. aureus mutant
lacking STX is more susceptible to killing
by mRELMa and hRETN, indicating that
STX is required for S. aureus resistance
to RELM bactericidal activity. This sug-
gests that RELMs may disrupt mem-
branes similarly to the majority of pore-
forming amphipathic AMPs. Liposome
disruption assays showed that mRELMa
and hRETN can permeabilize artificial
membranes. Since these assays used
liposomes with a lipid composition similar
to that of bacterial membranes, the au-
thors suggest cellular lysis as a possible
mechanism for the observed bactericidal
activity. Similar findings were obtained
with mRELMb (Propheter et al., 2017),
suggesting that membrane lysis could
be a common mechanism of RELM mem-
ber’s bactericidal properties. Interest-
ingly, however, ultrastructural analyses
of P. aeruginosa treated with mRELMb
(Propheter et al., 2017) do not show the
typical morphological signs of lytic
AMPs with membrane disruption and
bleb formation. Instead, intracytoplasmic
protein aggregates are observed, simi-
larly to P. aeruginosa treated with peptide
fragments of hornerin, an abundant pre-
cursor of highly hydrophilic, cationic,
intrinsically disordered antimicrobial pep-
tides (CIDAMPs) found in the stratum cor-
neum of healthy skin (Gerstel et al., 2018;
Latendorf et al., 2019). CIDAMPs are ribo-
some-targeting AMPs that have the
in vitro propensity to form microbicidal
amyloid-like nanostructures (Gerstel
et al., 2018). Thus, it would be of interest
to explore whether members of the
RELM family have additional intracellular
targets possibly also targeting the bacte-
rial ribosome.

The skin surface has unique physical
and chemical properties relative to other
body sites, including an acidic pH (Zloto-
gorski, 1987), suggesting that an innate
skin defense system should have adapted
to these conditions. Indeed, Harris et al.
(2019) found that the sensitivity of the
acid-resilient bacterial species Listeria
monocytogenes toward mRELMa was
highest at pH 5 and diminished at pH 7.
This could indicate that skin pathogens
like P. aeruginosa or Cutibacterium
(formerly Propionibacterium) acnes may
also be more sensitive at acidic pH to-
ward RELMs—as seen for skin horny-
layer-derived and histidine-rich CIDAMPs
(Latendorf et al., 2019).
To interrogate the in vivo relevance of
RELMs in skin innate immunity, Harris
et al. (2019) studied the skin microbiota
composition of RELMa-knockout mice
and found that wild-type and knockout
mice have distinct skin microbiotas.
Consistent with their in vitro findings, the
relative abundance of coagulase-nega-
tive Staphylococci and Streptococcus is
increased in the knockout mice. Since
other known mouse skin AMPs seem to
be unaltered, RELM may contribute to
shaping the composition of mouse skin
microbiota by its direct bactericidal prop-
erties and thus protect the skin from bac-
terial infection.
Dietary vitamin A deficiency causes a
marked susceptibility to infection and
inflammation; as such, synthetic retinoids
are widely used for treatment of inflam-
matory skin diseases. To delineate
whether RELM family members are regu-
lated by vitamin A, Harris et al. (2019)
analyzed the human resistin promoter for
retinoic acid response elements (RARE)
and found binding to several predicted
RAREs. Consistently, the authors show
that retinol, a pro-form of vitamin A,
induces the resistin gene in human
sebocytes synergistically with IL1b, which
suggests that resistin protein may be
generated in sebaceous glands upon
inflammation.
Harris et al. (2019) then explored
whether mouse RELMa expression is
similarly dependent on vitamin A. Mice
fed with a vitamin-A-deficient diet have
less abundant RELMa transcripts and
RELMa protein levels in the skin —in
770 Cell Host & Microbe 25, June 12, 2019
contrast to several known mouse skin
antimicrobial proteins, which are not
markedly affected. Thus, RELMa is
unique among known skin antimicrobial
proteins in that its expression requires
vitamin A in the diet. This led to the ques-
tion of whether administration of exoge-
nous therapeutic retinoids can stimulate
RELMa expression in vivo. Harris et al.
(2019) now present experimental evi-
dence that a synthetic retinoid rescues
the increased susceptibility toward
S. pyogenes infection of mice fed with
a vitamin-A-deficient diet. Conversely,
treatment of RELMa-knockout mice with
therapeutic retinoids does not alter
susceptibility to infection.
The study by Harris et al. (2019) provides
convincing evidence of a role for RELMa,
possibly generated by sebocytes, in
vitamin-A-dependent antibacterial skin
defense in mice. Curiously, in adipocytes,
retinoids inhibit the expression of resistin
(Felipe et al., 2004), and in human epithelial
cells, this adipokine inhibits beta-defensin
production (Harder et al., 2004). Thus, the
question of whether vitamin-A-dependent
regulation of RELMs differs in sebocytes,
adipocytes, and epithelial cells merits
future studies.
Further, additional investigations will
be required for a more comprehensive
understanding of the range of microor-
ganisms that are targeted by mouse
RELMa and human resistin and to identify
which bacterial species (in addition to
S. aureus) can trigger RELMa and RETN
expression.
An important remaining question is
how skin bacteria trigger RELM expres-
sion in skin. The finding that the vitamin
A derivative retinol drives resistin expres-
sion through RAR(s) suggests that skin
bacteria could similarly regulate retinol
or retinoic acid levels in keratinocytes
and sebocytes and thus promote RAR-
dependent transcription of RELM-encod-
ing genes.
This study suggests that fat-soluble
vitamins appear to be of particular impor-
tance for the expression of lipophilic skin
antimicrobial proteins, which is possibly
of relevance to defend bacteria, like
C. acnes, residing in a lipid-rich environ-
ment. While RELMa is a unique example
of an antimicrobial protein regulated by
Cell Host & Microbe
Previews
vitamin A, prior work identified a role for
vitamin D in the expression of cathelicidin
(Schauber et al., 2006). Collectively, the
findings of Harris et al. (2019) and previ-
ous reports linking changes in the skin mi-
crobiome to skin conditions such as acne
vulgaris and hidradenitis suppurativa sug-
gest that diet plays an important role in
skin microflora and defense O’Neill and
Gallo, (2018).
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