To provide an overview of filaggrin biology and the role of filaggrin variants in atopic dermatitis (AD) and allergic disease.
We performed a PubMed literature review consisting mainly of studies ...relating to filaggrin in the last 5 years.
We selected articles that were found in PubMed using the search terms filaggrin, atopic dermatitis, skin barrier, and atopy.
Filaggrin plays an important role in the development of AD and allergic disease. Novel methods in measuring filaggrin expression and identifying filaggrin mutations aid in stratifying this patient cohort. We review new insights into understanding the role of filaggrin in AD and allergic disease.
Filaggrin remains a very important player in the pathogenesis of atopic dermatitis and allergic disease. This review looks at recent studies that aid our understanding of this crucial epidermal protein.
Staphylococcus aureus is frequently isolated from the skin of atopic dermatitis (AD) patients during flares. The normal microbiota is disrupted and the diversity of the microorganisms on the skin is ...reduced. Many species that produce inhibitors of S. aureus growth decline. Strains from S. aureus clonal complex 1 are enriched among AD sufferers whereas the CC30 strains most frequently isolated from nasal carriers in the normal population are much rarer in AD. S. aureus expresses several molecules that contribute to the intensity of symptoms, including δ-toxin which stimulates mast cells, α-toxin which damages keratinocytes, phenol-soluble modulins which stimulate cytokine release by keratinocytes, protein A which triggers inflammatory responses from keratinocytes, superantigens which trigger B cell expansion and cytokine release, and proinflammatory lipoproteins. Proteases contribute to disruption of the epidermal barrier. S. aureus isolated from AD patients adheres to the deformed corneocytes from AD patients in a clumping factor B-dependent fashion. Novel targeted therapies for AD have recently been introduced to clinical practice with many more in development, including monoclonal antibodies that specifically target cytokines and their receptors, and a bacteriophage lysin that eliminates S. aureus from AD skin.
The diversity of the skin microbiome is diminished during an AD flare, with S. aureus assuming hegemony.
Proliferation of S. aureus during AD flares is encouraged by reduced competition from the microbiota and favourable growth conditions, including higher pH.
S. aureus expresses superantigens, cytolytic α- and δ-toxins, phenol-soluble modulins, protein A, and several proteases which have roles in AD pathogenesis.
Clumping factor B promotes adhesion to deformed corneocytes in AD skin, and this is likely to be an important step in colonization.
New treatments, including a lytic enzyme that is specific for S. aureus, are in development. One specific monoclonal antibody inhibitor that targets the receptor for the type 2 cytokines IL-4 and IL-13 has recently been approved for clinical use, and many others inhibitors targeting type 2 cytokines are in development.
The exposome in atopic dermatitis Stefanovic, Nicholas; Flohr, Carsten; Irvine, Alan D.
Allergy (Copenhagen),
January 2020, Volume:
75, Issue:
1
Journal Article
Peer reviewed
Open access
Atopic dermatitis (AD) is a complex inflammatory disorder with multiple interactions between genetic, immune and external factors. The sum of external factors that an individual is exposed to ...throughout their lifetime is termed the exposome. The exposome spans multiple domains from population to molecular levels and, in combination with genetic factors, holds the key to understanding the phenotypic diversity seen in AD patients. Exposomal domains are categorized into nonspecific (human and natural factors affecting populations), specific (eg humidity, ultraviolet radiation, diet, pollution, allergens, water hardness) and internal (cutaneous and gut microbiota and host cell interaction) exposures. The skin, as the organ that most directly interacts with and adapts to the external environment, is a prime target for exploration of exposomal influences on disease. Given the well‐recognized physical environmental influences on AD, this condition could be much better understood through insightful exposomal research. In this narrative review, we examine each domain in turn, highlighting current understanding of the mechanisms by which exposomal influences modulate AD pathogenesis at distinct points in time. We highlight current approaches to exposome modification in AD and other allergic disease and propose future directions for exposome characterization and modification using novel research techniques.
Atopic dermatitis Langan, Sinéad M; Irvine, Alan D; Weidinger, Stephan
The Lancet (British edition),
08/2020, Volume:
396, Issue:
10247
Journal Article
Peer reviewed
Atopic dermatitis is a common inflammatory skin disorder characterised by recurrent eczematous lesions and intense itch. The disorder affects people of all ages and ethnicities, has a substantial ...psychosocial impact on patients and relatives, and is the leading cause of the global burden from skin disease. Atopic dermatitis is associated with increased risk of multiple comorbidities, including food allergy, asthma, allergic rhinitis, and mental health disorders. The pathophysiology is complex and involves a strong genetic predisposition, epidermal dysfunction, and T-cell driven inflammation. Although type-2 mechanisms are dominant, there is increasing evidence that the disorder involves multiple immune pathways. Currently, there is no cure, but increasing numbers of innovative and targeted therapies hold promise for achieving disease control, including in patients with recalcitrant disease. We summarise and discuss advances in our understanding of the disease and their implications for prevention, management, and future research.
Filaggrin is a major structural protein in the stratum corneum of the epidermis. Mutations in the filaggrin gene are the most significant known genetic risk factor for the development of atopic ...dermatitis. Mutations in the human filaggrin gene (FLG) also confer risk for the associated allergic diseases of food allergy, asthma, and allergic rhinitis. These discoveries have highlighted the importance of skin barrier function in the pathogenesis of atopic diseases and have motivated a surge in research characterizing the filaggrin-deficient skin barrier and its consequences. In this review we discuss the mechanisms through which mutations in this protein contribute to the pathogenesis of atopic dermatitis and associated atopic conditions. We focus on recent human and murine discoveries characterizing the filaggrin-deficient epidermis with respect to biophysical, immunologic, and microbiome abnormalities.
The atopic march recognizes the increased occurrence of asthma, allergic rhinitis, or both after atopic dermatitis (AD) onset. Mechanisms for developing atopic comorbidities after AD onset are poorly ...understood but can involve the impaired cutaneous barrier, which facilitates cutaneous sensitization. The association can also be driven or amplified in susceptible subjects by a systemic TH2-dominant immune response to cutaneous inflammation. However, these associations might merely involve shared genetic loci and environmental triggers, including microbiome dysregulation, with the temporal sequence reflecting tissue-specific peak time of occurrence of each disease, suggesting more of a clustering of disorders than a march. Prospective longitudinal cohort studies provide an opportunity to explore the relationships between postdermatitis development of atopic disorders and potential predictive phenotypic, genotypic, and environmental factors. Recent investigations implicate disease severity and persistence, age of onset, parental atopic history, filaggrin (FLG) mutations, polysensitization, and the nonrural environment among risk factors for development of multiple atopic comorbidities in young children with AD. Early intervention studies to repair the epidermal barrier or alter exposure to the microbiome or allergens might elucidate the relative roles of barrier defects, genetic locus alterations, and environmental exposures in the risk and sequence of occurrence of TH2 activation disorders.
The Krebs cycle-derived metabolite itaconate is highly upregulated in inflammatory macrophages and exerts immunomodulatory effects through cysteine modifications on target proteins. The NLRP3 ...inflammasome, which cleaves IL-1β, IL-18, and gasdermin D, must be tightly regulated to avoid excessive inflammation. Here we provide evidence that itaconate modifies NLRP3 and inhibits inflammasome activation. Itaconate and its derivative, 4-octyl itaconate (4-OI), inhibited NLRP3 inflammasome activation, but not AIM2 or NLRC4. Conversely, NLRP3 activation was increased in itaconate-depleted Irg1−/− macrophages. 4-OI inhibited the interaction between NLRP3 and NEK7, a key step in the activation process, and “dicarboxypropylated” C548 on NLRP3. Furthermore, 4-OI inhibited NLRP3-dependent IL-1β release from PBMCs isolated from cryopyrin-associated periodic syndrome (CAPS) patients, and reduced inflammation in an in vivo model of urate-induced peritonitis. Our results identify itaconate as an endogenous metabolic regulator of the NLRP3 inflammasome and describe a process that may be exploited therapeutically to alleviate inflammation in NLRP3-driven disorders.
Display omitted
•Itaconate and its derivative 4-OI (which generates itaconate) block NLRP3 activation•Itaconate-depleted Irg1−/− BMDMs exhibit increased NLRP3 inflammasome activation•4-OI “dicarboxypropylates” C548 on NLRP3 and blocks the NLRP3-NEK7 interaction•4-OI reduces peritonitis in vivo and blocks IL-1β release from CAPS patient PBMCs
Hooftman et al. reveal a role for the Krebs cycle-derived metabolite itaconate in regulating the NLRP3 inflammasome. Itaconate specifically blocks NLRP3 inflammasome activation by reducing the NLRP3-NEK7 interaction, likely due to modification of C548 on NLRP3. Furthermore, itaconate inhibits IL-1β release from cells isolated from patients with the NLRP3-mediated disease CAPS.
The inhibitory effectiveness of this small molecule in vitro was also reported in a novel interferonopathy coined stimulator of interferon genes (STING)-associated vasculopathy, which is caused by a ...gain-of-function (GOF) mutation in the TMEM173 gene encoding STING, resulting in hyperactivation of the signal transducer and activator of transcription (STAT) 1/STAT2 signaling pathways.2 We now demonstrate the potential utility of this drug for AA and other symptoms occurring in the wider context of a genetic immunodeficiency syndrome associated with autoimmunity. STAT1 GOF caused by these mutations is mediated through enhanced phosphorylation caused by impaired nuclear dephosphorylation, resulting in increased expression of interferon-stimulated genes.5 Interestingly, patients with GOF STAT1 mutations have decreased expression of STAT3-stimulated genes (unpublished data), which might explain downstream reduction of IL-17 expression and consequent susceptibility to mucocutaneous Candida species infections.5 In canonical IFN-γ-JAK-STAT1 signaling, ligand engagement of the IFN-γ receptor leads to activation of receptor-associated JAK1 and JAK2. ...we hypothesized that JAK1/2 inhibition would target this pathway and could ameliorate both the CMC and the associated autoimmune AA phenotype in our patient.
Atopic dermatitis (AD) is the most common inflammatory skin disease worldwide, affecting 20% of children and 5% of adults. One critical component in the pathophysiology of AD is the epidermal skin ...barrier, with its outermost layer, the stratum corneum (SC), conferring biochemical properties that enable resilience against environmental threats and maintain homeostasis. The skin barrier may be conceptualized as a key facilitator of complex interactions between genetics, host immunity, the cutaneous microbiome, and environmental exposures. The key genetic risk factor for AD development and persistence is a loss-of-function mutation in FLG, with recent advances in genomics focusing on rare variant discovery, establishment of pathogenic mechanisms, and exploration of the role of other epidermal differentiation complex gene variants in AD. Aberrant type 2 inflammatory responses down-regulate the transcription of key epidermal barrier genes, alter the composition of SC lipids, and induce further injury through a neurocutaneous feedback loop and the itch-scratch cycle. The dysbiotic epidermis exhibits reduced bacterial diversity and enhanced colonization with Staphylococcus and Malassezia species, which contribute to both direct barrier injury through the action of bacterial toxins and perpetuation of the inflammatory cascades. Enhanced understanding of each of the pathogenic mechanisms underpinning barrier disruption has led to the development of novel topical and systemic molecules, including interleukin (IL)-4Ra, IL-13, PDE4, and Janus-associated kinase inhibitors, whose clinical effectiveness exceeds conventional treatment modalities. In this narrative review, we aim to summarize the current understanding of the above-mentioned pathophysiological and therapeutic mechanisms, with a focus on the genetic, cellular, and molecular mechanisms underpinning AD development.
Background Disease flares of established atopic dermatitis (AD) are generally associated with a low-diversity skin microbiota and Staphylococcus aureus dominance. The temporal transition of the skin ...microbiome between early infancy and the dysbiosis of established AD is unknown. Methods We randomly selected 50 children from the Cork Babies After SCOPE: Evaluating the Longitudinal Impact Using Neurological and Nutritional Endpoints (BASELINE) longitudinal birth cohort for microbiome sampling at 3 points in the first 6 months of life at 4 skin sites relevant to AD: the antecubital and popliteal fossae, nasal tip, and cheek. We identified 10 infants with AD and compared them with 10 randomly selected control infants with no AD. We performed bacterial 16S ribosomal RNA sequencing and analysis directly from clinical samples. Results Bacterial community structures and diversity shifted over time, suggesting that age strongly affects the skin microbiome in infants. Unlike established AD, these patients with infantile AD did not have noticeably dysbiotic communities before or with disease and were not colonized by S aureus . In comparing patients and control subjects, infants who had affected skin at month 12 had statistically significant differences in bacterial communities on the antecubital fossa at month 2 compared with infants who were unaffected at month 12. In particular, commensal staphylococci were significantly less abundant in infants affected at month 12, suggesting that this genus might protect against the later development of AD. Conclusions This study suggests that 12-month-old infants with AD were not colonized with S aureus before having AD. Additional studies are needed to confirm whether colonization with commensal staphylococci modulates skin immunity and attenuates development of AD.