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Bhardwaj MicroRNAs in atopic dermatitis
[7]
cells and Th1 cells predominate . The Th2 cytokines and microbe invasion, release AMPs which in turn limit
interleukin (IL)-4, IL-5 and IL-13 predominate in acute penetration of microbes and allergens. Keratinocytes
lesions, and in chronic lesions, there is increase of from skin of patients with AD may not produce
[7]
interferon-γ (IFN-γ) and IL-12 . There is a complex enough AMPs to control Staphylococcus aureus and
interaction between the keratinocytes and T cell viral replication, predisposing these patients to S.
subpopulations, and their respective cytokine milieu. aureus and viral infections. The Th2, Th22 and TH17
There are numerous T cells in the skin, approximately cytokine pathways are associated with the acute
6
[6]
10 memory T cells per square cm of body surface lesions of AD . In patients with chronic disease,
area. Keratinocytes in eczema skin produce high there is intensification of these pathways along with
[6]
levels of thymic stromal lymphopoietin (TSLP) that appearance of a significant Th1 component .
signals dendritic cells to drive Th2 polarization .
[7]
+
Th17 T cells are a subset of memory CD4 T cells A recently described class of gene expression
[8]
that produce IL-17A and IL-17F . Higher Th17 cell regulators in inflammatory conditions is short single-
count has been shown to be crucial to development stranded RNA molecules termed microRNAs
of initial Th2-related phase, while reduced levels (miRNAs) [20] . MiRNAs, which are 19-25 nucleotides
[9]
are seen in the chronic Th-1 mediated phase . IL- in length, cause gene silencing through degradation
17 is a proinflammatory cytokine highly expressed of target RNAs or inhibition of translation. Since
in acute AD, but barely detectable in chronic AD. each miRNA can have hundreds of target genes,
It has been described as a master regulator of together miRNAs can affect expression of numerous
antimicrobial peptides (AMPs) [10] . Low levels of IL-17 proteins [20] . It is estimated that miRNAs collectively
in the chronic phase of AD correlate with higher risk of influence approximately 30% of genes [21] . The
cutaneous super infections [11] . Th22 cells have been importance of miRNAs is evidenced by the fact that
characterized recently as IL-22-producung T cells [12] . deletion of Dicer enzyme, required for maturation of
IL-22 which is the prototypical Th22 cytokine is highly precursor miRNA is lethal in mice [22] . They have been
expressed in AD. High levels of chemokine ligand shown to be key regulators in early development,
(CCL) 27 can be found in chronic AD lesions [13] . This proliferation, stress response and apoptosis [23] . They
chemokine has been shown to induce homing of Th22 have been implicated in the pathogenesis of cancer,
cells in lesional AD skin. IL-22 is a member of the IL- developmental abnormalities and cardiovascular
10 cytokine family. It also induces AMP production, diseases [24] . Not only does each miRNA target
although less efficiently that IL-17. It is responsible for hundreds of genes, the individual genes are targeted
epidermal hyperplasia and downregulates filaggrin by several miRNAs adding to the complexity of these
expression [14] . interactions. MiRNAs are, therefore, well positioned to
affect allergic inflammatory pathways. Their role has
The “outside-in” hypothesis proposes that the defective been investigated in asthma, eosinophilic esophagitis,
barrier allows penetration of allergens and microbes allergic rhinitis as well as atopic dermatitis. They have
[5]
into the skin of patients with AD . At the opposite been implicated in the morphogenesis of murine
end of the debate, the inside-out hypothesis proposes skin [25] . Murine disease models have shown the
a polarized immune response being the cause of a therapeutic effects of inhibition or overexpression of
[5]
defective skin barrier . A strong association has been miRNAs, thus making them potential therapeutic and
established between loss-of-function mutations in skin diagnostic candidates.
barrier gene encoding filaggrin (FLG) and AD [15,16] . Up
to a 40% of patients with AD have FLG mutations [17] . The importance of miRNAs in skin development is
The barrier defect in AD patients with FLG mutations underscored by the fact that their global ablation
promotes enhanced allergen penetration leading to by targeting Dicer 1 prevents hair follicles from
increased production of TSLP by keratinocytes. This invaginating, disrupting the epidermal morphology [25,26] .
in turn leads to a Th2-type milieu. In fact, TSLP has MiR-203 has been identified as a skin and
been called a “master switch for allergic inflammation”. keratinocyte specific miRNA. Its expression is higher
Aside from FLG, loss-of-function mutations in serine in the suprabasal layers compared to the basal
protease inhibitors (e.g. SPINK5) are associated layer [26] . It can induce keratinocyte differentiation. Its
with epidermal barrier dysfunction through increased critical role in epidermal morphogenesis is supported
Th1 responses [18] . Innate pattern recognition by the observation that overexpression in mice results
receptors such as Toll-like receptors are expressed in a thinner epidermis and decreased proliferation [27] .
on keratinocytes and antigen-presenting cells in the MiR-203 directly targets p63 which is critical to the
skin [19] . The TLRs, when stimulated by tissue injury development of epidermis [28] . p63 is an essential

16 Journal of Translational Genetics and Genomics ¦ Volume 1 ¦ November 17, 2017