4. Basic mechanisms and potential targets
4.1 Disturbed skin barrier (FLG, pH, microbiome)
The skin barrier in AE is disturbed on multiple levels, including
physical, chemical, immunological, neurologic, and microbial components
[1].
Martin et al recently summarized genetic risk factors for AE, many of
them belonging to extracellular matrix components and its modulators
(e.g. FLG, COL5A3, COL6A6, and MMP9, TMEM79) [50, 51]. A variety of
AE mice models are used to investigate skin barrier defects, among them
FLG ft/ft mice [52], Hrnr-/- mice [53], and TMEM79-/- mice
[51]. One major genetic predisposition for the development of AE are
loss-of-function mutations in the skin barrier gene filaggrin [54].
Degradation products of histidine-rich filaggrin support the healthy
skin barrier as natural moisturizing factors (NMF) and simultaneously
maintain an acidic skin pH [55]. The skin pH in AE and especially AE
lesions was reported to be increased [56]. In line, an acidic skin
pH is associated with low scaling and high hydration, whereas alkaline
skin pH is associated with skin barrier dysfunction and decreased
stratum corneum integrity [57, 58]. Alkalization of the skin pH
directly modulates the activity of the stratum corneum located serine
protease kallikrein 5 (KLK5) which has the ability to degrade cell
junction proteins, leading to barrier dysfunction and itch [59].
Recently, exogenic mutations in the KLK5 inhibitor Lympho-epithelial
Kazal-type-related inhibitor (LEKTI) were associated with AE, supporting
the importance of protease activity in the disease [60].
Furthermore, the lipid composition of the skin is abnormal in AE.
Changes in ceramides and free fatty acids were reported, the latter
correlating with the skin microbiome composition [61, 62].
A skin microbiome dysbiosis towards Staphylococcus aureus and
decreased microbial diversity is another hallmark of AE [63]. The
intrinsic and extrinsic factors shaping the skin microbiome are complex
and yet poorly understood [35]. However, several factors relevant in
AE are known to influence the microbiome. The acidic skin pH of healthy
skin for example limits the growth of harmful skin bacteria as S.
aureus and enhances the growth of the commensal S. epidermidis[64, 65]. Genetics also shape the skin microbiome as recently shown
in a mouse model: wild-type and Flgft/ft mice significantly differed in
the skin microbiome composition, revealing less diversity with an
increased staphylococci colonization [52]. In this study, AE did not
develop under germ free conditions but was dependent on microbial
colonization and subsequent IL-1beta induction [52]. Both
alpha-diversity and S. aureus abundance correlate with disease
severity. However, this association seems to depend on the skin site and
could be shown for the thigh but not the back of AE patients in a recent
study [66]. Not only the presence of S. aureus but also
capability of S. aureus strains to produce biofilm and toxins is
associated with AE severity [63, 67] [67, 68]. S. aureusactivates the immune system in AE amongst others by the expression of
proteases, toxins, superantigens and other virulence factors [63,
69] (Fig. 2). Interestingly, cigarette smoke redirects S.
aureus towards virulence factor associated with persisting infection
and could therefore explain the avoidable risk factor of tobacco smoke
for AE [25, 70]. The virulence factors trigger a vicious cycle in
AE. The stimulation of the immune system shapes the inflammatory
environment, the expression of IL-31 causes itch and the resulting
scratching further damages the skin barrier. The complex interaction
between S. aureus and the innate and adaptive immune system has
been nicely summarized by Yoshikawa et al 2019 [63].
In the context of itch and scratch-response, sensory neurons are
important [71]. However, the nervous system is not only responsible
for pruritus, but also modulates the immune response in AE [72].