Atopic dermatitis, allergic contact dermatitis and chronic spontaneous urticaria are common inflammatory conditions involving the skin. This inflammation may result from unique and, yet, shared pathogenic mechanisms, which may account for their coexistence and association in atopic patients.

Atopic dermatitis (AD) is the most common inflammatory skin disorder in the developed world, with a lifetime prevalence of 15–20% [1]. It is often associated with other atopic conditions, such as asthma, allergic rhinitis and chronic rhinosinusitis with nasal polyps [2]. AD is a chronic, relapsing and inflammatory skin disease characterized by intense itching and excoriations with erythematous, xerotic, fissured and lichenificated skin, as well as an increased risk of skin infections [3,4]. The pathogenesis of AD has not been completely elucidated. Genetic heritage and its interactions with the environment contribute to epidermal skin barrier disruption, altered inflammatory response and skin microbiome dysbiosis [5,6], and oxidative stress also plays an important pathogenetic role [7]. Recent studies have pointed to the key role of epigenetic changes in AD development, mainly mediated by DNA methylation, histone acetylation and the action of specific non-coding RNAs, including micro-RNAs (miRNAs), small interfering RNAs, long non-coding RNAs and Pivi-interacting RNAs [8]. Skin barrier abnormalities include decreased filaggrin, loricrin, involucrin, ceramides, antimicrobial peptides and disorders of tight junctions [9,10]. In particular, filaggrin, a structural protein responsible for keratinization, moisturization and antimicrobial peptide functions, is mutated in 15–50% of patients with AD [11,12]. Skin barrier disruption stimulates keratinocytes and dendritic cells to produce activation-regulated chemokine (TARC), thymic stromal lymphopoietin (TSLP) and cytokines, including IL-1β, IL-25 and IL-33, which trigger type-2 inflammation, activating both innate and adaptative immunity [13,14]. Type-2 innate lymphoid cells and Th2 cells produce IL-4, IL-5 and IL-13 [13], key mediators of type-2 response. They promote Th-naïve lymphocytes developing Th2 phenotypes, B lymphocyte isotypes switching from IgM to IgE [15], eosinophil recruitment and activation [16], itch exacerbation [17] and skin remodeling toward fibrosis in the chronic disease phase [1].

Allergic contact dermatitis (ACD) is a common inflammatory skin disorder characterized by pruritus, erythema, vesicles and scaling of the skin [18]. ACD is common, with some studies demonstrating prevalence rates as high as 20% in the general population, and it accounts for the vast majority of occupational skin disorders in the Western world [18,19]. ACD involves type IV-mediated hypersensitivity to a specific allergen, resulting in an inflammatory response with exposure. The first phase is sensitization, when a person is first exposed to a hapten, which is defined as a low-molecular-weight antigen that, when bound to a larger carrier, can elicit an immune response.

After hapten has been recognized and phagocytized by dermal dendritic cells and Langerhans cells, the hapten–peptide complexes migrate to regional lymph nodes and induce the proliferation and circulation of hapten-specific T cells (Th1, Th2, Th17 and T regulatory cells) and the creation of effector and memory T cells. Clinical symptoms of ACD are produced in the elicitation phase, when re-exposure to the allergen, recognized by the sensitized hapten-specific T cells, causes an inflammatory cascade of cytokines and cellular infiltrates [20]. Since the reaction to the allergen is not always immediate, with a possible delay of up to 72 h, it may be difficult to identify the culprit agents. Thorough questioning of the patient’s occupation, hobbies and any changes in personal products or clothing is helpful [21], and certain distributions, such as on the eyelid, lateral face, central face, neck or hands suggest the consideration of ACD. Patch testing is the only practical, scientific and objective method to confirm the diagnosis of ACD.

Chronic spontaneous urticaria (CSU) is defined as the spontaneous appearance of itchy red wheals and/or angioedema for more than six weeks without any apparent cause [22,23], and it affects about 1.8% of the adult population [24]. CSU is mainly caused by the activation of cutaneous mast cells (MCs), leading to the release of histamine and other mediators, such as platelet-activating factor (PAF) and cytokines, which results in vasodilatation, plasma extravasation and sensory nerve activation, as well as cell recruitment in the urticarial lesions (mainly T cells, eosinophils and basophils). Wheals are characterized by edema of the upper and mid-dermis, whereas similar changes may occur in the lower dermis, resulting in angioedema [22]. The pathophysiology of CSU is not well understood, but there are two main pathogenetic mechanisms underlying the disease: dysregulation of intracellular signaling pathways within mast cells and basophils, which leads to defects in the trafficking or function of these cells, and development of autoantibodies to FcεRIα or IgE on both mast cells and basophils [25]. Basophil numbers appear to be reduced in at least 50% of patients [26], and they seem to be hyporeactive [27]. Furthermore, their development is dependent on the interaction of stem cell factor (SCF) with the c-kit, as well as TGF-β produced by Tregs. In CSU, circulating Tregs (CD4 + CD25 + FOXP3+) are reduced and/or defective compared with normal cells [28], and the reduced frequency of Tregs is consistent with an autoimmune hypothesis for CSU [29,30]. These events lead to mast cell degranulation and the predisposition to pathological mast cell activation if inappropriately upregulated. However, autoimmune theory is the most widely accepted hypothesis for explaining the pathogenesis of CSU, as it is thought that up to 45% of cases of CSU have autoimmune etiology [25]. Specifically, CSU is associated with the development of circulating IgG antibodies against IgE and the high-affinity IgE receptor FcεR1; approximately 40% of these patients have circulating antibodies against one of the two targets [31], with a higher frequency of positivity in CSU patients with a positive autologous serum skin test (ASST) [32]. It seems likely that different pathomechanisms are interlinked in CSU rather than independent cascades [33].

miRNAs represent an abundant class of small non-coding RNAs which regulate gene expression post-transcriptionally [34]. miRNAs are short (20–22 nucleotides long), endogenous and single-stranded RNAs, whose genes [35], highly conserved throughout evolution across species [36], are located within the introns and exons of protein-coding genes [37].

The first miRNAs were found in Caenorhabditis elegans in early 1990s [34]; afterward, the first human miRNA was discovered in the 2000s [38]. Currently, 2588 mature miRNAs have been identified for humans in miRbase [39], and it is estimated that they modulate more than 60% of all human protein-coding genes by sequence-specific base pairing [35]. In fact, it is widely recognized that one miRNA may regulate many genes as its targets, while one gene may be targeted by many miRNAs. [40]

Primary transcripts of miRNAs are generated by RNA polymerase II and sequentially processed by ribonuclease III class enzymes [37] (Drosha) to produce an miRNA precursor of 70 nucleotides (the pre-miRNA) [41]. After nuclear processing, the pre-miRNA is transferred to the cytosol, where Dicer, another ribonuclease III class enzyme, cleaves it into mature double-stranded miRNA with 19–24 nucleotides. One strand of this mature miRNA duplex is then incorporated into the RNA-induced silencing complex (RISC) [42] and serves as a guide for the recognition of target mRNAs [43]. The other strand is unrolled from the guide strand and degraded, but, in some cases, both strands of the miRNA duplex are functional [44]. The miRNA–RNA-induced silencing complexes interact with mRNA targets by sequence-specific base pairing, generally within the 3′-untranslated region of the target mRNAs [45]. Two different mechanisms of RISC-mediated gene regulation exist, and they depend on the level of miRNA–mRNA complementarity: at sites with extensive complementarity, the miRNA can mediate mRNA cleavage; however, sites with a lower degree of complementarity may lead to translational repression or mRNA destabilization [46].

Circular RNAs (CircRNAs) are single-stranded, covalently closed RNA molecules that are ubiquitous across species ranging from viruses to mammals [47]. One of the most commonly reported mechanisms of action of circRNAs is the “sponging” of miRNAs by binding to the miRNA response element (MRE), thereby indirectly increasing the transcription of their target mRNAs [48].

MiRNAs play an important role in biological processes such as cellular proliferation, differentiation and apoptosis. Further, they are implicated in inflammatory diseases, cancer [49], immune response, neural development, DNA repair and oxidative stress response [50].

In addition, miRNAs are stable in body fluids, so they are more available for assays and less invasive than biopsies [51]. Thus, the interest in miRNAs as both biomarkers and possible therapeutic targets is increasing [52].

2. miRNA in AD, ACD and CSU: Pathogenetic Role and Therapeutic Strategies