Guardians of the barrier: Microbiota engage AHR in keratinocytes to maintain skin homeostasis
2021; Cell Press; Volume: 29; Issue: 8 Linguagem: Inglês
10.1016/j.chom.2021.07.007
ISSN1934-6069
Autores Tópico(s)Pharmacological Effects of Natural Compounds
ResumoThe skin barrier is critical in ensuring homeostasis, yet factors influencing its development, repair, and maintenance are ill-defined. In this issue of Cell Host & Microbe, Uberoi et al. demonstrate the skin microbiota's role in maintaining barrier integrity via AHR signaling in keratinocytes, which has implications for skin disease management. The skin barrier is critical in ensuring homeostasis, yet factors influencing its development, repair, and maintenance are ill-defined. In this issue of Cell Host & Microbe, Uberoi et al. demonstrate the skin microbiota's role in maintaining barrier integrity via AHR signaling in keratinocytes, which has implications for skin disease management. Main textThe skin serves as the primary interface between humans and the environment. The skin barrier refers to the semi-permeable membrane, which exists in the keratinized squamous epithelial layer of the skin termed the epidermis. This barrier protects against the myriad mechanical, chemical, allergic, and microbial insults that our skin is exposed to on a daily basis. One key barrier function is to regulate the diffusion of vital molecules across the barrier and to prevent transepidermal water loss (TEWL). Loss of skin barrier integrity is observed in several inflammatory skin diseases and is particularly well described in atopic dermatitis (AD).AD is a chronic inflammatory skin condition affecting an estimated 3% of the global population, with higher rates in children (Laughter et al., 2021Laughter M.R. Maymone M.B.C. Mashayekhi S. Arents B.W.M. Karimkhani C. Langan S.M. Dellavalle R.P. Flohr C. The global burden of atopic dermatitis: lessons from the Global Burden of Disease Study 1990-2017.Br. J. Dermatol. 2021; 184: 304-309https://doi.org/10.1111/bjd.19580Crossref PubMed Scopus (59) Google Scholar). Affected individuals have red, dry, itchy skin lesions often involving the skin folds, face and hands, and these are highly susceptible to bacterial and viral skin infections. The cental role of the skin barrier to AD is underlined by the fact that the most important genetic contributor to disease is loss of function mutations in the Filaggrin (FLG) gene, which encodes a protein with a vital structural role in the epidermis (Sandilands et al., 2007Sandilands A. Terron-Kwiatkowski A. Hull P.R. O'Regan G.M. Clayton T.H. Watson R.M. Carrick T. Evans A.T. Liao H. Zhao Y. et al.Comprehensive analysis of the gene encoding filaggrin uncovers prevalent and rare mutations in ichthyosis vulgaris and atopic eczema.Nat. Genet. 2007; 39: 650-654https://doi.org/10.1038/ng2020Crossref PubMed Scopus (505) Google Scholar). Skin barrier disturbance is often also associated with an altered cutaneous microbiome, and there is a dominance of Staphylococcus aureus seen alongside reduced expression of crucial barrier genes such as CLDN8 (encoding Claudin 8) in lesional AD skin (Fyhrquist et al., 2019Fyhrquist N. Muirhead G. Prast-Nielsen S. Jeanmougin M. Olah P. Skoog T. Jules-Clement G. Feld M. Barrientos-Somarribas M. Sinkko H. et al.Microbe-host interplay in atopic dermatitis and psoriasis.Nat. Commun. 2019; 10: 4703https://doi.org/10.1038/s41467-019-12253-yCrossref PubMed Scopus (112) Google Scholar). Additionally, both in AD and psoriasis, another immune-mediated skin condition associated with a disrupted skin barrier, there was a loss of commensal bacteria including Lactobacilli, Burkholderia spp., and C. acnes.Deciphering the mechanisms by which the cutaneous microbiota interact with epithelial barrier sites is of great importance. The aryl-hydrocarbon receptor (AHR) is a ligand-activated transcription factor present at barrier sites including the gut, lungs, and skin. In the skin it is most abundant in epidermal keratinocytes where it has an environment-sensing role. AHR responds to xenobiotic substances by inducing their metabolism through expression of the AHR gene battery including CYP1A1, a member of cytochrome p450 family of enzymes. Increasingly, however, AHR is becoming recognized as one mechanism by which the microbiota interacts with the host to maintain homeostasis. In the skin, AHR activation by tryptophan-derived physiological ligands generated by host or microbial metabolism have been shown to be beneficial in murine models of psoriasis (Di Meglio et al., 2014Di Meglio P. Duarte J.H. Ahlfors H. Owens N.D. Li Y. Villanova F. Tosi I. Hirota K. Nestle F.O. Mrowietz U. et al.Activation of the aryl hydrocarbon receptor dampens the severity of inflammatory skin conditions.Immunity. 2014; 40: 989-1001https://doi.org/10.1016/j.immuni.2014.04.019Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholar) and AD (Yu et al., 2019Yu J. Luo Y. Zhu Z. Zhou Y. Sun L. Gao J. Sun J. Wang G. Yao X. Li W. A tryptophan metabolite of the skin microbiota attenuates inflammation in patients with atopic dermatitis through the aryl hydrocarbon receptor.J Allergy Clin Immunol. 2019; 143: 2108-2119https://doi.org/10.1016/j.jaci.2018.11.036Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar). AHR has also been shown to regulate skin barrier repair through activation of this pathway by coal tar, one of the most long-standing topical treatments for AD and psoriasis (van den Bogaard et al., 2013van den Bogaard E.H. Bergboer J.G. Vonk-Bergers M. van Vlijmen-Willems I.M. Hato S.V. van der Valk P.G. Schröder J.M. Joosten I. Zeeuwen P.L. Schalkwijk J. Coal tar induces AHR-dependent skin barrier repair in atopic dermatitis.J. Clin. Invest. 2013; 123: 917-927https://doi.org/10.1172/JCI65642Crossref PubMed Scopus (240) Google Scholar).Although the existing knowledge suggests that AHR and the microbiome are relevant in skin diseases in which the skin barrier is disturbed, the mechanisms by which the microbiome influences the development, maintenance and repair of skin barrier is an area yet to be fully understood.In this issue of Cell Host & Microbe, Uberoi et al., 2021Uberoi A. Bartow-McKenney C. Zheng Q. Flowers L. Campbell A. Knight S.A.B. Chan N. Wei M. Lovins V. Bugayev J. et al.Commensal microbiota regulates skin barrier function and repair via signaling through the aryl hydrocarbon receptor.Cell Host Microbe. 2021; 29: 1235-1248https://doi.org/10.1016/j.chom.2021.05.011Abstract Full Text Full Text PDF Scopus (27) Google Scholar outline the essential contribution of the cutaneous microbiome to skin barrier function through activation of AHR in keratinocytes (Figure 1). First, they identified differentially regulated epidermal gene pathways between mice raised with specific-pathogen-free (SPF) microbiota and gnotobiotic mice raised in sterile, or germ free (GF), conditions. Importantly, these pathways were significantly enriched for skin, epidermal, and keratinocyte development genes, including downregulation of genes involved in cornified envelope formation (e.g., involucrin and envoplakin) and desquamation (e.g., kallikrein-related peptidases 5 and 7) in GF mice, suggesting a role for microbial regulation of epithelial barrier development. This was associated with ultrastructural differences in GF epidermal skin and a reduction of key barrier proteins including cytokeratin-10, tight junction protein-3, and desmoglein-1. Additionally, primary keratinocytes from GF mice had reduced expression of the genes involved in keratinocyte terminal differentiation and transmembrane junction formation, both crucial to the development of an effective skin barrier, after exposure to high-calcium conditions compared with those of SPF mice.Next, the authors utilized a murine model in which the epidermis was artificially disrupted using tape stripping to induce skin barrier disruption and then compared the rate of barrier repair in the SPF and GF mice. SPF mice were found to have a significantly more rapid restoration of the skin barrier over 24 h than did GF mice. Mice in which the cutaneous microbiota had been depleted through antibiotics also demonstrated delayed barrier repair, providing further evidence of the vital role of cutaneous microbes for skin barrier function and repair. To elucidate the host mechanism of microbial sensing, a comparative analysis of the murine epidermal transcriptome of SPF and GF mice brought AHR into focus.Interestingly, the presence of microbes appears to be essential for Ahr expression in itself; downregulation of Ahr expression, and not only of its downstream target genes, was observed in GF mice compared with in SPF mice. The regulation of Ahr expression is a poorly investigated area and further studies are needed, for example addressing whether other environmental stimuli (e.g., non-microbial ligands and cytokines) exert the same effect. This is of particular importance given the tight control of AHR activity in part provided by multiple negative feedback loops. Importantly, failure of these feedback loops results in barrier disruption and exacerbated psoriasiform inflammation as seen in mice lacking Ahr (Kyoreva et al., 2021Kyoreva M. Li Y. Hoosenally M. Hardman-Smart J. Morrison K. Tosi I. Tolaini M. Barinaga G. Stockinger B. Mrowietz U. Nestle F.O. Smith C.O. Barker J.N. Di Meglio P. CYP1A1 Enzymatic Activity Influences Skin Inflammation Via Regulation of the AHR Pathway.J Invest Dermatol. 2021; 141: 1553-1563https://doi.org/10.1016/j.jid.2020.11.024Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar).In line with the increasingly reported beneficial role for AHR activation by physiological ligands, topical treatment with the AHR ligand 6-formylindolo[3,2-b]carbazole (FICZ) accelerated barrier recovery in GF mice after tape stripping and induced significantly greater expression of genes involved in epidermal differentiation and gap junction formation than in mice treated with vehicle control.Exacerbated skin inflammation had been previously shown in Ahr-knockout mice treated with topical imiquimod, and Ahr deficiency in non-hematopoietic cells of the skin had been identified as responsible for the hyperinflammatory phenotype (Di Meglio et al., 2014Di Meglio P. Duarte J.H. Ahlfors H. Owens N.D. Li Y. Villanova F. Tosi I. Hirota K. Nestle F.O. Mrowietz U. et al.Activation of the aryl hydrocarbon receptor dampens the severity of inflammatory skin conditions.Immunity. 2014; 40: 989-1001https://doi.org/10.1016/j.immuni.2014.04.019Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholar). Uberoi et al., 2021Uberoi A. Bartow-McKenney C. Zheng Q. Flowers L. Campbell A. Knight S.A.B. Chan N. Wei M. Lovins V. Bugayev J. et al.Commensal microbiota regulates skin barrier function and repair via signaling through the aryl hydrocarbon receptor.Cell Host Microbe. 2021; 29: 1235-1248https://doi.org/10.1016/j.chom.2021.05.011Abstract Full Text Full Text PDF Scopus (27) Google Scholar here conclusively identify AHR in keratinocytes as responsible for skin homeostasis and maintenance of the skin barrier by employing a mouse selectively lacking Ahr in keratinocytes (K14CreAhrf/f). After tape-strip injury these mice demonstrated significantly delayed barrier recovery compared with that in mice in which the keratinocytes were Ahr sufficient (Ahrf/f). In a mouse model of AD-like dermatitis, in which ovalbumin (OVA) is applied epicutaneously on tape-stripped skin, mice lacking keratinocyte Ahr developed increased Staphylococcus aureus infection and exacerbated disease severity.Finally, the authors sought to assess whether the defective skin barrier phenotype in GF mice could be rescued through the use of human skin commensals in an AHR-dependent mechanism. They utilized a cocktail of commensals cultured from human skin (Flowers' flora) that was able to activate AHR when topically applied to GF mice and resulted in accelerated skin barrier repair after tape-stripping compared with in non-treated GF mice. SPF mice pre-treated with Flowers' flora demonstrated improved barrier recovery in the OVA model compared with in non-pre-treated mice.The work by Uberoi et al., 2021Uberoi A. Bartow-McKenney C. Zheng Q. Flowers L. Campbell A. Knight S.A.B. Chan N. Wei M. Lovins V. Bugayev J. et al.Commensal microbiota regulates skin barrier function and repair via signaling through the aryl hydrocarbon receptor.Cell Host Microbe. 2021; 29: 1235-1248https://doi.org/10.1016/j.chom.2021.05.011Abstract Full Text Full Text PDF Scopus (27) Google Scholar adds important knowledge to this emerging field of cutaneous host-microbe interactions and demonstrates microbiota-mediated regulation of epidermal differentiation and barrier function via AHR signaling in keratinocytes. Additionally, impaired AHR signaling results in increased susceptibility to Staphylococcus aureus infection and atopic-dermatitis-like disease.There are, however, several questions in the field that are yet to be determined. The exact mechanisms by which AhR expression is related to the presence of a competent skin microbiome is unclear, as are the wider determinants of Ahr expression at barrier sites. Retention of the effects of microbial colonization (or absence of it) on the genes driving epidermal keratinocyte differentiation could be due to epigenetic mechanisms, as hypothesized by the authors, but this is far from certain. Furthermore, many of the microbes in SPF murine skin and Flowers flora can act as pathogens in certain settings; thus, identification of specific commensal species that have potent AHR activating activity with little risk of pathogenicity is highly desirable when considering probiotic therapeutic candidates. Similarly, further profiling of the AHR ligands produced by microbial species would also be of interest therapeutically to add to existing knowledge in this domain, where microbial metabolites of tryptophan, termed indoles, are widely recognized to have AHR-activating potential in the gut and now also in the skin (Yu et al., 2019Yu J. Luo Y. Zhu Z. Zhou Y. Sun L. Gao J. Sun J. Wang G. Yao X. Li W. A tryptophan metabolite of the skin microbiota attenuates inflammation in patients with atopic dermatitis through the aryl hydrocarbon receptor.J Allergy Clin Immunol. 2019; 143: 2108-2119https://doi.org/10.1016/j.jaci.2018.11.036Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar).Most importantly, what are the implications for diseases associated with impaired skin barrier function such as AD, psoriasis, and chronic wounds? Biologic therapies such as dupliumab, which targets interleukin-4 (IL-4) and IL-13 signaling, are effective for moderate to severe AD, but its use is limited by cost and side effect profile in some patients. Topical modulators of AHR have been demonstrated to be effective in both AD (Paller et al., 2021Paller A.S. Stein Gold L. Soung J. Tallman A.M. Rubenstein D.S. Gooderham M. Efficacy and patient-reported outcomes from a phase 2b, randomized clinical trial of tapinarof cream for the treatment of adolescents and adults with atopic dermatitis.J. Am. Acad. Dermatol. 2021; 84: 632-638https://doi.org/10.1016/j.jaad.2020.05.135Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar) and psoriasis (Stein Gold et al., 2021Stein Gold L. Bhatia N. Tallman A.M. Rubenstein D.S. A phase 2b, randomized clinical trial of tapinarof cream for the treatment of plaque psoriasis: Secondary efficacy and patient-reported outcomes.J. Am. Acad. Dermatol. 2021; 84: 624-631https://doi.org/10.1016/j.jaad.2020.04.181Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar). The lack of novel topical treatments for these conditions makes them of particular therapeutic interest, especially for patients with mild to moderate disease who do not qualify for biological drugs. Ultimately, greater understanding of the interaction between the microbiota and AHR could be transformative for the management of these skin diseases in the future. Main textThe skin serves as the primary interface between humans and the environment. The skin barrier refers to the semi-permeable membrane, which exists in the keratinized squamous epithelial layer of the skin termed the epidermis. This barrier protects against the myriad mechanical, chemical, allergic, and microbial insults that our skin is exposed to on a daily basis. One key barrier function is to regulate the diffusion of vital molecules across the barrier and to prevent transepidermal water loss (TEWL). Loss of skin barrier integrity is observed in several inflammatory skin diseases and is particularly well described in atopic dermatitis (AD).AD is a chronic inflammatory skin condition affecting an estimated 3% of the global population, with higher rates in children (Laughter et al., 2021Laughter M.R. Maymone M.B.C. Mashayekhi S. Arents B.W.M. Karimkhani C. Langan S.M. Dellavalle R.P. Flohr C. The global burden of atopic dermatitis: lessons from the Global Burden of Disease Study 1990-2017.Br. J. Dermatol. 2021; 184: 304-309https://doi.org/10.1111/bjd.19580Crossref PubMed Scopus (59) Google Scholar). Affected individuals have red, dry, itchy skin lesions often involving the skin folds, face and hands, and these are highly susceptible to bacterial and viral skin infections. The cental role of the skin barrier to AD is underlined by the fact that the most important genetic contributor to disease is loss of function mutations in the Filaggrin (FLG) gene, which encodes a protein with a vital structural role in the epidermis (Sandilands et al., 2007Sandilands A. Terron-Kwiatkowski A. Hull P.R. O'Regan G.M. Clayton T.H. Watson R.M. Carrick T. Evans A.T. Liao H. Zhao Y. et al.Comprehensive analysis of the gene encoding filaggrin uncovers prevalent and rare mutations in ichthyosis vulgaris and atopic eczema.Nat. Genet. 2007; 39: 650-654https://doi.org/10.1038/ng2020Crossref PubMed Scopus (505) Google Scholar). Skin barrier disturbance is often also associated with an altered cutaneous microbiome, and there is a dominance of Staphylococcus aureus seen alongside reduced expression of crucial barrier genes such as CLDN8 (encoding Claudin 8) in lesional AD skin (Fyhrquist et al., 2019Fyhrquist N. Muirhead G. Prast-Nielsen S. Jeanmougin M. Olah P. Skoog T. Jules-Clement G. Feld M. Barrientos-Somarribas M. Sinkko H. et al.Microbe-host interplay in atopic dermatitis and psoriasis.Nat. Commun. 2019; 10: 4703https://doi.org/10.1038/s41467-019-12253-yCrossref PubMed Scopus (112) Google Scholar). Additionally, both in AD and psoriasis, another immune-mediated skin condition associated with a disrupted skin barrier, there was a loss of commensal bacteria including Lactobacilli, Burkholderia spp., and C. acnes.Deciphering the mechanisms by which the cutaneous microbiota interact with epithelial barrier sites is of great importance. The aryl-hydrocarbon receptor (AHR) is a ligand-activated transcription factor present at barrier sites including the gut, lungs, and skin. In the skin it is most abundant in epidermal keratinocytes where it has an environment-sensing role. AHR responds to xenobiotic substances by inducing their metabolism through expression of the AHR gene battery including CYP1A1, a member of cytochrome p450 family of enzymes. Increasingly, however, AHR is becoming recognized as one mechanism by which the microbiota interacts with the host to maintain homeostasis. In the skin, AHR activation by tryptophan-derived physiological ligands generated by host or microbial metabolism have been shown to be beneficial in murine models of psoriasis (Di Meglio et al., 2014Di Meglio P. Duarte J.H. Ahlfors H. Owens N.D. Li Y. Villanova F. Tosi I. Hirota K. Nestle F.O. Mrowietz U. et al.Activation of the aryl hydrocarbon receptor dampens the severity of inflammatory skin conditions.Immunity. 2014; 40: 989-1001https://doi.org/10.1016/j.immuni.2014.04.019Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholar) and AD (Yu et al., 2019Yu J. Luo Y. Zhu Z. Zhou Y. Sun L. Gao J. Sun J. Wang G. Yao X. Li W. A tryptophan metabolite of the skin microbiota attenuates inflammation in patients with atopic dermatitis through the aryl hydrocarbon receptor.J Allergy Clin Immunol. 2019; 143: 2108-2119https://doi.org/10.1016/j.jaci.2018.11.036Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar). AHR has also been shown to regulate skin barrier repair through activation of this pathway by coal tar, one of the most long-standing topical treatments for AD and psoriasis (van den Bogaard et al., 2013van den Bogaard E.H. Bergboer J.G. Vonk-Bergers M. van Vlijmen-Willems I.M. Hato S.V. van der Valk P.G. Schröder J.M. Joosten I. Zeeuwen P.L. Schalkwijk J. Coal tar induces AHR-dependent skin barrier repair in atopic dermatitis.J. Clin. Invest. 2013; 123: 917-927https://doi.org/10.1172/JCI65642Crossref PubMed Scopus (240) Google Scholar).Although the existing knowledge suggests that AHR and the microbiome are relevant in skin diseases in which the skin barrier is disturbed, the mechanisms by which the microbiome influences the development, maintenance and repair of skin barrier is an area yet to be fully understood.In this issue of Cell Host & Microbe, Uberoi et al., 2021Uberoi A. Bartow-McKenney C. Zheng Q. Flowers L. Campbell A. Knight S.A.B. Chan N. Wei M. Lovins V. Bugayev J. et al.Commensal microbiota regulates skin barrier function and repair via signaling through the aryl hydrocarbon receptor.Cell Host Microbe. 2021; 29: 1235-1248https://doi.org/10.1016/j.chom.2021.05.011Abstract Full Text Full Text PDF Scopus (27) Google Scholar outline the essential contribution of the cutaneous microbiome to skin barrier function through activation of AHR in keratinocytes (Figure 1). First, they identified differentially regulated epidermal gene pathways between mice raised with specific-pathogen-free (SPF) microbiota and gnotobiotic mice raised in sterile, or germ free (GF), conditions. Importantly, these pathways were significantly enriched for skin, epidermal, and keratinocyte development genes, including downregulation of genes involved in cornified envelope formation (e.g., involucrin and envoplakin) and desquamation (e.g., kallikrein-related peptidases 5 and 7) in GF mice, suggesting a role for microbial regulation of epithelial barrier development. This was associated with ultrastructural differences in GF epidermal skin and a reduction of key barrier proteins including cytokeratin-10, tight junction protein-3, and desmoglein-1. Additionally, primary keratinocytes from GF mice had reduced expression of the genes involved in keratinocyte terminal differentiation and transmembrane junction formation, both crucial to the development of an effective skin barrier, after exposure to high-calcium conditions compared with those of SPF mice.Next, the authors utilized a murine model in which the epidermis was artificially disrupted using tape stripping to induce skin barrier disruption and then compared the rate of barrier repair in the SPF and GF mice. SPF mice were found to have a significantly more rapid restoration of the skin barrier over 24 h than did GF mice. Mice in which the cutaneous microbiota had been depleted through antibiotics also demonstrated delayed barrier repair, providing further evidence of the vital role of cutaneous microbes for skin barrier function and repair. To elucidate the host mechanism of microbial sensing, a comparative analysis of the murine epidermal transcriptome of SPF and GF mice brought AHR into focus.Interestingly, the presence of microbes appears to be essential for Ahr expression in itself; downregulation of Ahr expression, and not only of its downstream target genes, was observed in GF mice compared with in SPF mice. The regulation of Ahr expression is a poorly investigated area and further studies are needed, for example addressing whether other environmental stimuli (e.g., non-microbial ligands and cytokines) exert the same effect. This is of particular importance given the tight control of AHR activity in part provided by multiple negative feedback loops. Importantly, failure of these feedback loops results in barrier disruption and exacerbated psoriasiform inflammation as seen in mice lacking Ahr (Kyoreva et al., 2021Kyoreva M. Li Y. Hoosenally M. Hardman-Smart J. Morrison K. Tosi I. Tolaini M. Barinaga G. Stockinger B. Mrowietz U. Nestle F.O. Smith C.O. Barker J.N. Di Meglio P. CYP1A1 Enzymatic Activity Influences Skin Inflammation Via Regulation of the AHR Pathway.J Invest Dermatol. 2021; 141: 1553-1563https://doi.org/10.1016/j.jid.2020.11.024Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar).In line with the increasingly reported beneficial role for AHR activation by physiological ligands, topical treatment with the AHR ligand 6-formylindolo[3,2-b]carbazole (FICZ) accelerated barrier recovery in GF mice after tape stripping and induced significantly greater expression of genes involved in epidermal differentiation and gap junction formation than in mice treated with vehicle control.Exacerbated skin inflammation had been previously shown in Ahr-knockout mice treated with topical imiquimod, and Ahr deficiency in non-hematopoietic cells of the skin had been identified as responsible for the hyperinflammatory phenotype (Di Meglio et al., 2014Di Meglio P. Duarte J.H. Ahlfors H. Owens N.D. Li Y. Villanova F. Tosi I. Hirota K. Nestle F.O. Mrowietz U. et al.Activation of the aryl hydrocarbon receptor dampens the severity of inflammatory skin conditions.Immunity. 2014; 40: 989-1001https://doi.org/10.1016/j.immuni.2014.04.019Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholar). Uberoi et al., 2021Uberoi A. Bartow-McKenney C. Zheng Q. Flowers L. Campbell A. Knight S.A.B. Chan N. Wei M. Lovins V. Bugayev J. et al.Commensal microbiota regulates skin barrier function and repair via signaling through the aryl hydrocarbon receptor.Cell Host Microbe. 2021; 29: 1235-1248https://doi.org/10.1016/j.chom.2021.05.011Abstract Full Text Full Text PDF Scopus (27) Google Scholar here conclusively identify AHR in keratinocytes as responsible for skin homeostasis and maintenance of the skin barrier by employing a mouse selectively lacking Ahr in keratinocytes (K14CreAhrf/f). After tape-strip injury these mice demonstrated significantly delayed barrier recovery compared with that in mice in which the keratinocytes were Ahr sufficient (Ahrf/f). In a mouse model of AD-like dermatitis, in which ovalbumin (OVA) is applied epicutaneously on tape-stripped skin, mice lacking keratinocyte Ahr developed increased Staphylococcus aureus infection and exacerbated disease severity.Finally, the authors sought to assess whether the defective skin barrier phenotype in GF mice could be rescued through the use of human skin commensals in an AHR-dependent mechanism. They utilized a cocktail of commensals cultured from human skin (Flowers' flora) that was able to activate AHR when topically applied to GF mice and resulted in accelerated skin barrier repair after tape-stripping compared with in non-treated GF mice. SPF mice pre-treated with Flowers' flora demonstrated improved barrier recovery in the OVA model compared with in non-pre-treated mice.The work by Uberoi et al., 2021Uberoi A. Bartow-McKenney C. Zheng Q. Flowers L. Campbell A. Knight S.A.B. Chan N. Wei M. Lovins V. Bugayev J. et al.Commensal microbiota regulates skin barrier function and repair via signaling through the aryl hydrocarbon receptor.Cell Host Microbe. 2021; 29: 1235-1248https://doi.org/10.1016/j.chom.2021.05.011Abstract Full Text Full Text PDF Scopus (27) Google Scholar adds important knowledge to this emerging field of cutaneous host-microbe interactions and demonstrates microbiota-mediated regulation of epidermal differentiation and barrier function via AHR signaling in keratinocytes. Additionally, impaired AHR signaling results in increased susceptibility to Staphylococcus aureus infection and atopic-dermatitis-like disease.There are, however, several questions in the field that are yet to be determined. The exact mechanisms by which AhR expression is related to the presence of a competent skin microbiome is unclear, as are the wider determinants of Ahr expression at barrier sites. Retention of the effects of microbial colonization (or absence of it) on the genes driving epidermal keratinocyte differentiation could be due to epigenetic mechanisms, as hypothesized by the authors, but this is far from certain. Furthermore, many of the microbes in SPF murine skin and Flowers flora can act as pathogens in certain settings; thus, identification of specific commensal species that have potent AHR activating activity with little risk of pathogenicity is highly desirable when considering probiotic therapeutic candidates. Similarly, further profiling of the AHR ligands produced by microbial species would also be of interest therapeutically to add to existing knowledge in this domain, where microbial metabolites of tryptophan, termed indoles, are widely recognized to have AHR-activating potential in the gut and now also in the skin (Yu et al., 2019Yu J. Luo Y. Zhu Z. Zhou Y. Sun L. Gao J. Sun J. Wang G. Yao X. Li W. A tryptophan metabolite of the skin microbiota attenuates inflammation in patients with atopic dermatitis through the aryl hydrocarbon receptor.J Allergy Clin Immunol. 2019; 143: 2108-2119https://doi.org/10.1016/j.jaci.2018.11.036Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar).Most importantly, what are the implications for diseases associated with impaired skin barrier function such as AD, psoriasis, and chronic wounds? Biologic therapies such as dupliumab, which targets interleukin-4 (IL-4) and IL-13 signaling, are effective for moderate to severe AD, but its use is limited by cost and side effect profile in some patients. Topical modulators of AHR have been demonstrated to be effective in both AD (Paller et al., 2021Paller A.S. Stein Gold L. Soung J. Tallman A.M. Rubenstein D.S. Gooderham M. Efficacy and patient-reported outcomes from a phase 2b, randomized clinical trial of tapinarof cream for the treatment of adolescents and adults with atopic dermatitis.J. Am. Acad. Dermatol. 2021; 84: 632-638https://doi.org/10.1016/j.jaad.2020.05.135Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar) and psoriasis (Stein Gold et al., 2021Stein Gold L. Bhatia N. Tallman A.M. Rubenstein D.S. A phase 2b, randomized clinical trial of tapinarof cream for the treatment of plaque psoriasis: Secondary efficacy and patient-reported outcomes.J. Am. Acad. Dermatol. 2021; 84: 624-631https://doi.org/10.1016/j.jaad.2020.04.181Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar). The lack of novel topical treatments for these conditions makes them of particular therapeutic interest, especially for patients with mild to moderate disease who do not qualify for biological drugs. Ultimately, greater understanding of the interaction between the microbiota and AHR could be transformative for the management of these skin diseases in the future. The skin serves as the primary interface between humans and the environment. The skin barrier refers to the semi-permeable membrane, which exists in the keratinized squamous epithelial layer of the skin termed the epidermis. This barrier protects against the myriad mechanical, chemical, allergic, and microbial insults that our skin is exposed to on a daily basis. One key barrier function is to regulate the diffusion of vital molecules across the barrier and to prevent transepidermal water loss (TEWL). Loss of skin barrier integrity is observed in several inflammatory skin diseases and is particularly well described in atopic dermatitis (AD). AD is a chronic inflammatory skin condition affecting an estimated 3% of the global population, with higher rates in children (Laughter et al., 2021Laughter M.R. Maymone M.B.C. Mashayekhi S. Arents B.W.M. Karimkhani C. Langan S.M. Dellavalle R.P. Flohr C. The global burden of atopic dermatitis: lessons from the Global Burden of Disease Study 1990-2017.Br. J. Dermatol. 2021; 184: 304-309https://doi.org/10.1111/bjd.19580Crossref PubMed Scopus (59) Google Scholar). Affected individuals have red, dry, itchy skin lesions often involving the skin folds, face and hands, and these are highly susceptible to bacterial and viral skin infections. The cental role of the skin barrier to AD is underlined by the fact that the most important genetic contributor to disease is loss of function mutations in the Filaggrin (FLG) gene, which encodes a protein with a vital structural role in the epidermis (Sandilands et al., 2007Sandilands A. Terron-Kwiatkowski A. Hull P.R. O'Regan G.M. Clayton T.H. Watson R.M. Carrick T. Evans A.T. Liao H. Zhao Y. et al.Comprehensive analysis of the gene encoding filaggrin uncovers prevalent and rare mutations in ichthyosis vulgaris and atopic eczema.Nat. Genet. 2007; 39: 650-654https://doi.org/10.1038/ng2020Crossref PubMed Scopus (505) Google Scholar). Skin barrier disturbance is often also associated with an altered cutaneous microbiome, and there is a dominance of Staphylococcus aureus seen alongside reduced expression of crucial barrier genes such as CLDN8 (encoding Claudin 8) in lesional AD skin (Fyhrquist et al., 2019Fyhrquist N. Muirhead G. Prast-Nielsen S. Jeanmougin M. Olah P. Skoog T. Jules-Clement G. Feld M. Barrientos-Somarribas M. Sinkko H. et al.Microbe-host interplay in atopic dermatitis and psoriasis.Nat. Commun. 2019; 10: 4703https://doi.org/10.1038/s41467-019-12253-yCrossref PubMed Scopus (112) Google Scholar). Additionally, both in AD and psoriasis, another immune-mediated skin condition associated with a disrupted skin barrier, there was a loss of commensal bacteria including Lactobacilli, Burkholderia spp., and C. acnes. Deciphering the mechanisms by which the cutaneous microbiota interact with epithelial barrier sites is of great importance. The aryl-hydrocarbon receptor (AHR) is a ligand-activated transcription factor present at barrier sites including the gut, lungs, and skin. In the skin it is most abundant in epidermal keratinocytes where it has an environment-sensing role. AHR responds to xenobiotic substances by inducing their metabolism through expression of the AHR gene battery including CYP1A1, a member of cytochrome p450 family of enzymes. Increasingly, however, AHR is becoming recognized as one mechanism by which the microbiota interacts with the host to maintain homeostasis. In the skin, AHR activation by tryptophan-derived physiological ligands generated by host or microbial metabolism have been shown to be beneficial in murine models of psoriasis (Di Meglio et al., 2014Di Meglio P. Duarte J.H. Ahlfors H. Owens N.D. Li Y. Villanova F. Tosi I. Hirota K. Nestle F.O. Mrowietz U. et al.Activation of the aryl hydrocarbon receptor dampens the severity of inflammatory skin conditions.Immunity. 2014; 40: 989-1001https://doi.org/10.1016/j.immuni.2014.04.019Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholar) and AD (Yu et al., 2019Yu J. Luo Y. Zhu Z. Zhou Y. Sun L. Gao J. Sun J. Wang G. Yao X. Li W. A tryptophan metabolite of the skin microbiota attenuates inflammation in patients with atopic dermatitis through the aryl hydrocarbon receptor.J Allergy Clin Immunol. 2019; 143: 2108-2119https://doi.org/10.1016/j.jaci.2018.11.036Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar). AHR has also been shown to regulate skin barrier repair through activation of this pathway by coal tar, one of the most long-standing topical treatments for AD and psoriasis (van den Bogaard et al., 2013van den Bogaard E.H. Bergboer J.G. Vonk-Bergers M. van Vlijmen-Willems I.M. Hato S.V. van der Valk P.G. Schröder J.M. Joosten I. Zeeuwen P.L. Schalkwijk J. Coal tar induces AHR-dependent skin barrier repair in atopic dermatitis.J. Clin. Invest. 2013; 123: 917-927https://doi.org/10.1172/JCI65642Crossref PubMed Scopus (240) Google Scholar). Although the existing knowledge suggests that AHR and the microbiome are relevant in skin diseases in which the skin barrier is disturbed, the mechanisms by which the microbiome influences the development, maintenance and repair of skin barrier is an area yet to be fully understood. In this issue of Cell Host & Microbe, Uberoi et al., 2021Uberoi A. Bartow-McKenney C. Zheng Q. Flowers L. Campbell A. Knight S.A.B. Chan N. Wei M. Lovins V. Bugayev J. et al.Commensal microbiota regulates skin barrier function and repair via signaling through the aryl hydrocarbon receptor.Cell Host Microbe. 2021; 29: 1235-1248https://doi.org/10.1016/j.chom.2021.05.011Abstract Full Text Full Text PDF Scopus (27) Google Scholar outline the essential contribution of the cutaneous microbiome to skin barrier function through activation of AHR in keratinocytes (Figure 1). First, they identified differentially regulated epidermal gene pathways between mice raised with specific-pathogen-free (SPF) microbiota and gnotobiotic mice raised in sterile, or germ free (GF), conditions. Importantly, these pathways were significantly enriched for skin, epidermal, and keratinocyte development genes, including downregulation of genes involved in cornified envelope formation (e.g., involucrin and envoplakin) and desquamation (e.g., kallikrein-related peptidases 5 and 7) in GF mice, suggesting a role for microbial regulation of epithelial barrier development. This was associated with ultrastructural differences in GF epidermal skin and a reduction of key barrier proteins including cytokeratin-10, tight junction protein-3, and desmoglein-1. Additionally, primary keratinocytes from GF mice had reduced expression of the genes involved in keratinocyte terminal differentiation and transmembrane junction formation, both crucial to the development of an effective skin barrier, after exposure to high-calcium conditions compared with those of SPF mice. Next, the authors utilized a murine model in which the epidermis was artificially disrupted using tape stripping to induce skin barrier disruption and then compared the rate of barrier repair in the SPF and GF mice. SPF mice were found to have a significantly more rapid restoration of the skin barrier over 24 h than did GF mice. Mice in which the cutaneous microbiota had been depleted through antibiotics also demonstrated delayed barrier repair, providing further evidence of the vital role of cutaneous microbes for skin barrier function and repair. To elucidate the host mechanism of microbial sensing, a comparative analysis of the murine epidermal transcriptome of SPF and GF mice brought AHR into focus. Interestingly, the presence of microbes appears to be essential for Ahr expression in itself; downregulation of Ahr expression, and not only of its downstream target genes, was observed in GF mice compared with in SPF mice. The regulation of Ahr expression is a poorly investigated area and further studies are needed, for example addressing whether other environmental stimuli (e.g., non-microbial ligands and cytokines) exert the same effect. This is of particular importance given the tight control of AHR activity in part provided by multiple negative feedback loops. Importantly, failure of these feedback loops results in barrier disruption and exacerbated psoriasiform inflammation as seen in mice lacking Ahr (Kyoreva et al., 2021Kyoreva M. Li Y. Hoosenally M. Hardman-Smart J. Morrison K. Tosi I. Tolaini M. Barinaga G. Stockinger B. Mrowietz U. Nestle F.O. Smith C.O. Barker J.N. Di Meglio P. CYP1A1 Enzymatic Activity Influences Skin Inflammation Via Regulation of the AHR Pathway.J Invest Dermatol. 2021; 141: 1553-1563https://doi.org/10.1016/j.jid.2020.11.024Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar). In line with the increasingly reported beneficial role for AHR activation by physiological ligands, topical treatment with the AHR ligand 6-formylindolo[3,2-b]carbazole (FICZ) accelerated barrier recovery in GF mice after tape stripping and induced significantly greater expression of genes involved in epidermal differentiation and gap junction formation than in mice treated with vehicle control. Exacerbated skin inflammation had been previously shown in Ahr-knockout mice treated with topical imiquimod, and Ahr deficiency in non-hematopoietic cells of the skin had been identified as responsible for the hyperinflammatory phenotype (Di Meglio et al., 2014Di Meglio P. Duarte J.H. Ahlfors H. Owens N.D. Li Y. Villanova F. Tosi I. Hirota K. Nestle F.O. Mrowietz U. et al.Activation of the aryl hydrocarbon receptor dampens the severity of inflammatory skin conditions.Immunity. 2014; 40: 989-1001https://doi.org/10.1016/j.immuni.2014.04.019Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholar). Uberoi et al., 2021Uberoi A. Bartow-McKenney C. Zheng Q. Flowers L. Campbell A. Knight S.A.B. Chan N. Wei M. Lovins V. Bugayev J. et al.Commensal microbiota regulates skin barrier function and repair via signaling through the aryl hydrocarbon receptor.Cell Host Microbe. 2021; 29: 1235-1248https://doi.org/10.1016/j.chom.2021.05.011Abstract Full Text Full Text PDF Scopus (27) Google Scholar here conclusively identify AHR in keratinocytes as responsible for skin homeostasis and maintenance of the skin barrier by employing a mouse selectively lacking Ahr in keratinocytes (K14CreAhrf/f). After tape-strip injury these mice demonstrated significantly delayed barrier recovery compared with that in mice in which the keratinocytes were Ahr sufficient (Ahrf/f). In a mouse model of AD-like dermatitis, in which ovalbumin (OVA) is applied epicutaneously on tape-stripped skin, mice lacking keratinocyte Ahr developed increased Staphylococcus aureus infection and exacerbated disease severity. Finally, the authors sought to assess whether the defective skin barrier phenotype in GF mice could be rescued through the use of human skin commensals in an AHR-dependent mechanism. They utilized a cocktail of commensals cultured from human skin (Flowers' flora) that was able to activate AHR when topically applied to GF mice and resulted in accelerated skin barrier repair after tape-stripping compared with in non-treated GF mice. SPF mice pre-treated with Flowers' flora demonstrated improved barrier recovery in the OVA model compared with in non-pre-treated mice. The work by Uberoi et al., 2021Uberoi A. Bartow-McKenney C. Zheng Q. Flowers L. Campbell A. Knight S.A.B. Chan N. Wei M. Lovins V. Bugayev J. et al.Commensal microbiota regulates skin barrier function and repair via signaling through the aryl hydrocarbon receptor.Cell Host Microbe. 2021; 29: 1235-1248https://doi.org/10.1016/j.chom.2021.05.011Abstract Full Text Full Text PDF Scopus (27) Google Scholar adds important knowledge to this emerging field of cutaneous host-microbe interactions and demonstrates microbiota-mediated regulation of epidermal differentiation and barrier function via AHR signaling in keratinocytes. Additionally, impaired AHR signaling results in increased susceptibility to Staphylococcus aureus infection and atopic-dermatitis-like disease. There are, however, several questions in the field that are yet to be determined. The exact mechanisms by which AhR expression is related to the presence of a competent skin microbiome is unclear, as are the wider determinants of Ahr expression at barrier sites. Retention of the effects of microbial colonization (or absence of it) on the genes driving epidermal keratinocyte differentiation could be due to epigenetic mechanisms, as hypothesized by the authors, but this is far from certain. Furthermore, many of the microbes in SPF murine skin and Flowers flora can act as pathogens in certain settings; thus, identification of specific commensal species that have potent AHR activating activity with little risk of pathogenicity is highly desirable when considering probiotic therapeutic candidates. Similarly, further profiling of the AHR ligands produced by microbial species would also be of interest therapeutically to add to existing knowledge in this domain, where microbial metabolites of tryptophan, termed indoles, are widely recognized to have AHR-activating potential in the gut and now also in the skin (Yu et al., 2019Yu J. Luo Y. Zhu Z. Zhou Y. Sun L. Gao J. Sun J. Wang G. Yao X. Li W. A tryptophan metabolite of the skin microbiota attenuates inflammation in patients with atopic dermatitis through the aryl hydrocarbon receptor.J Allergy Clin Immunol. 2019; 143: 2108-2119https://doi.org/10.1016/j.jaci.2018.11.036Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar). Most importantly, what are the implications for diseases associated with impaired skin barrier function such as AD, psoriasis, and chronic wounds? Biologic therapies such as dupliumab, which targets interleukin-4 (IL-4) and IL-13 signaling, are effective for moderate to severe AD, but its use is limited by cost and side effect profile in some patients. Topical modulators of AHR have been demonstrated to be effective in both AD (Paller et al., 2021Paller A.S. Stein Gold L. Soung J. Tallman A.M. Rubenstein D.S. Gooderham M. Efficacy and patient-reported outcomes from a phase 2b, randomized clinical trial of tapinarof cream for the treatment of adolescents and adults with atopic dermatitis.J. Am. Acad. Dermatol. 2021; 84: 632-638https://doi.org/10.1016/j.jaad.2020.05.135Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar) and psoriasis (Stein Gold et al., 2021Stein Gold L. Bhatia N. Tallman A.M. Rubenstein D.S. A phase 2b, randomized clinical trial of tapinarof cream for the treatment of plaque psoriasis: Secondary efficacy and patient-reported outcomes.J. Am. Acad. Dermatol. 2021; 84: 624-631https://doi.org/10.1016/j.jaad.2020.04.181Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar). The lack of novel topical treatments for these conditions makes them of particular therapeutic interest, especially for patients with mild to moderate disease who do not qualify for biological drugs. Ultimately, greater understanding of the interaction between the microbiota and AHR could be transformative for the management of these skin diseases in the future. W.A. is co-funded by the Medical Research Council/British Skin Foundation/British Association of Dermatologists ( MR/P001394/1 ). Research in the Di Meglio laboratory is supported by the National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College London. Figure created with BioRender.com. Commensal microbiota regulates skin barrier function and repair via signaling through the aryl hydrocarbon receptorUberoi et al.Cell Host & MicrobeJune 30, 2021In BriefA self-renewing skin barrier is needed for terrestrial life. Uberoi et al. demonstrate that the skin microbiota regulates barrier repair and integrity by activating keratinocyte aryl hydrocarbon receptor (AHR). This microbiota-AHR axis was targeted with a defined consortium of human skin commensals to improve barrier repair in disease models. Full-Text PDF Open Archive
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