IL-24 promotes atopic dermatitis-like inflammation through driving MRSA-induced allergic responses

Abstract

Atopic dermatitis (AD) is a prevalent inflammatory skin disorder in which patients experience recurrent eczematous lesions and intense itching. The colonization of Staphylococcus aureus (S. aureus) is correlated with the severity of the disease, but its role in AD development remains elusive. Using single-cell RNA sequencing, we uncovered that keratinocytes activate a distinct immune response characterized by induction of Il24 when exposed to methicillin-resistant S. aureus (MRSA). Further experiments using animal models showed that the administration of recombinant IL-24 protein worsened AD-like pathology. Genetic ablation of Il24 or the receptor Il20rb in keratinocytes alleviated allergic inflammation and atopic march. Mechanistically, IL-24 acted through its heterodimeric receptors on keratinocytes and augmented the production of IL-33, which in turn aggravated type 2 immunity and AD-like skin conditions. Overall, these findings establish IL-24 as a critical factor for onset and progression of AD and a compelling therapeutic target.

Keywords

IL-24 / atopic dermatitis / MRSA / keratinocytes / allergic inflammation

References

[1] Bieber T. Atopic dermatitis: an expanding therapeutic pipeline for a complex disease. Nat Rev Drug Discov 2022;21:21–40.

[2] Bromberg JF, Wrzeszczynska MH, Devgan G et al. Stat3 as an oncogene. Cell 1999;98:295–303.

[3] Brunner PM, Suarez-Farinas M, He H et al. The atopic dermatitis blood signature is characterized by increases in inflammatory and cardiovascular risk proteins. Sci Rep 2017;7:8707.

[4] Byrd AL, Deming C, Cassidy SKB et al. Staphylococcus aureus and Staphylococcus epidermidis strain diversity underlying pediatric atopic dermatitis. Sci Transl Med 2017;9:1.

[5] Byrd AL, Belkaid Y, Segre JA. The human skin microbiome. Nat Rev Microbiol 2018;16:143–155.

[6] Carmi-Levy I, Homey B, Soumelis V. A modular view of cytokine networks in atopic dermatitis. Clin Rev Allergy Immunol 2011;41:245–253.

[7] Chen YE, Fischbach MA, Belkaid Y. Skin microbiota-host interactions. Nature 2018;553:427–436.

[8] Choi HMT, Schwarzkopf M, Fornace ME et al. Third-generation in situ hybridization chain reaction: multiplexed, quantitative, sensitive, versatile, robust. Development 2018;145:1.

[9] Chong WP, Mattapallil MJ, Raychaudhuri K et al. The cytokine IL-17A Limits Th17 pathogenicity via a negative feedback loop driven by autocrine induction of IL-24. Immunity 2020;53:384–397.e5.

[10] Davidson S, Coles M, Thomas T et al. Fibroblasts as immune regulators in infection, inflammation and cancer. Nat Rev Immunol 2021;21:704–717.

[11] Deng L, Costa F, Blake KJ et al. S. aureus drives itch and scratch-induced skin damage through a V8 protease-PAR1 axis. Cell 2023;186:5375–5393.e25.

[12] Dobin A, Davis CA, Schlesinger F et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics 2013;29:15–21.

[13] Dumoutier L, Leemans C, Lejeune D et al. Cutting edge: STAT activation by IL-19, IL-20 and mda-7 through IL-20 receptor complexes of two types. J Immunol 2001;167:3545–3549.

[14] Freitas E, Gooderham M, Torres T. New topical therapies in development for atopic dermatitis. Drugs 2022;82:843–853.

[15] Geoghegan JA, Irvine AD, Foster TJ. Staphylococcus aureus and atopic dermatitis: a complex and evolving relationship. Trends Microbiol 2018;26:484–497.

[16] Hamelmann E, Schwarze J, Takeda K et al. Noninvasive measurement of airway responsiveness in allergic mice using barometric plethysmography. Am J Respir Crit Care Med 1997;156:766–775.

[17] Harris-Tryon TA, Grice EA. Microbiota and maintenance of skin barrier function. Science 2022;376:940–945.

[18] Hasegawa T, Oka T, Demehri S. Alarmin cytokines as central regulators of cutaneous immunity. Front Immunol 2022;13:876515.

[19] He M, Liang P. IL-24 transgenic mice: in vivo evidence of overlapping functions for IL-20, IL-22, and IL-24 in the epidermis. J Immunol 2010;184:1793–1798.

[20] Heinz S, Benner C, Spann N et al. Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities. Mol Cell 2010;38:576–589.

[21] Higaki S, Morohashi M, Yamagishi T et al. Comparative study of staphylococci from the skin of atopic dermatitis patients and from healthy subjects. Int J Dermatol 1999;38:265–269.

[22] Hulpusch C, Weins AB, Traidl-Hoffmann C et al. A new era of atopic eczema research: Advances and highlights. Allergy 2021;76:3408–3421.

[23] Imai Y, Yasuda K, Sakaguchi Y et al. Skin-specific expression of IL-33 activates group 2 innate lymphoid cells and elicits atopic dermatitis-like inflammation in mice. Proc Natl Acad Sci U S A 2013;110:13921–13926.

[24] Inaba K, Inaba M, Romani N et al. Generation of large numbers of dendritic cells from mouse bone marrow cultures supplemented with granulocyte/macrophage colony-stimulating factor. J Exp Med 1992;176:1693–1702.

[25] Jin SH, Choi D, Chun YJ et al. Keratinocyte-derived IL-24 plays a role in the positive feedback regulation of epidermal inflammation in response to environmental and endogenous toxic stressors. Toxicol Appl Pharmacol 2014;280:199–206.

[26] Kaymak T, Kaya B, Wuggenig P et al. IL-20 subfamily cytokines impair the oesophageal epithelial barrier by diminishing filaggrin in eosinophilic oesophagitis. Gut 2023;72:821–833.

[27] Kolumam G, Wu XM, Lee WP et al. IL-22R Ligands IL-20, IL-22, and IL-24 Promote Wound Healing in Diabetic db/db Mice. PLoS One 2017;12:e0170639.

[28] Kong HH, Oh J, Deming C et al; NISC Comparative Sequence Program. Temporal shifts in the skin microbiome associated with disease flares and treatment in children with atopic dermatitis. Genome Res 2012;22:850–859.

[29] Kuleshov MV, Jones MR, Rouillard AD et al. Enrichr: a comprehensive gene set enrichment analysis web server 2016 update. Nucleic Acids Res 2016;44:W90–W97.

[30] Langan SM, Irvine AD, Weidinger S. Atopic dermatitis. Lancet (London, England) 2020;396:345–360.

[31] Langmead B, Salzberg SL. Fast gapped-read alignment with Bowtie 2. Nat Methods 2012;9:357–359.

[32] Lee AS, de Lencastre H, Garau J et al. Methicillin-resistant Staphylococcus aureus. Nat Rev Dis Primers 2018;4:18033.

[33] Leyden JJ, Marples RR, Kligman AM. Staphylococcus aureus in the lesions of atopic dermatitis. Br J Dermatol 1974;90:525–530.

[34] Leyva-Castillo JM, Galand C, Kam C et al. Mechanical skin injury promotes food anaphylaxis by driving intestinal mast cell expansion. Immunity 2019;50:1262–1275.e4 e1264.

[35] Leyva-Castillo JM, McGurk A, Geha MDR. Allergic skin inflammation and S. aureus skin colonization are mutually reinforcing. Clin Immunol 2020;218:108511.

[36] Li F, Adase CA, Zhang LJ. Isolation and culture of primary mouse keratinocytes from neonatal and adult mouse skin. J Vis Exp 2017;125:e56027.

[37] Li H, Dai T, Liu C et al. Phenotypes of atopic dermatitis and the risk for subsequent asthma: a systematic review and meta-analysis. J Am Acad Dermatol 2022;86:365–372.

[38] Liberzon A, Birger C, Thorvaldsdottir H et al. The molecular signatures database (MSigDB) hallmark gene set collection. Cell Syst 2015;1:417–425.

[39] Liu YJ. Thymic stromal lymphopoietin: master switch for allergic inflammation. J Exp Med 2006;203:269–273.

[40] Liu H, Archer NK, Dillen CA et al. Staphylococcus aureus epicutaneous exposure drives skin inflammation via IL-36-Mediated T cell responses. Cell Host Microbe 2017;22:653653–666.e5 e655.

[41] Liu S, Hur YH, Cai X et al. A tissue injury sensing and repair pathway distinct from host pathogen defense. Cell 2023;186:2127–2143.e22.

[42] May-Zhang AA, Benthal JT, Southard-Smith EM. Hybridization chain reaction for mRNA localization in single cells from mouse and human Cryosections. Curr Protoc 2022;2:e439.

[43] Meylan P, Lang C, Mermoud S et al. Skin colonization by Staphylococcus aureus Precedes the clinical diagnosis of atopic dermatitis in infancy. J Invest Dermatol 2017;137:2497–2504.

[44] Myles IA, Fontecilla NM, Valdez PA et al. Signaling via the IL-20 receptor inhibits cutaneous production of IL-1βand IL-17A to promote infection with methicillin-resistant Staphylococcus aureus. Nat Immunol 2013;14:804–811.

[45] Ogonowska P, Gilaberte Y, Baranska-Rybak W et al. Colonization With Staphylococcus aureus in Atopic Dermatitis Patients: Attempts to Reveal the Unknown. Front Microbiol 2020;11:567090.

[46] Paller AS, Spergel JM, Mina-Osorio P et al. The atopic march and atopic multimorbidity: Many trajectories, many pathways. J Allergy Clin Immunol 2019;143:46–55.

[47] Patrick GJ, Liu H, Alphonse MP et al. Epicutaneous Staphylococcus aureus induces IL-36 to enhance IgE production and ensuing allergic disease. J Clin Invest 2021;131:1.

[48] Rutz S, Wang X, Ouyang W. The IL-20 subfamily of cytokines —from host defence to tissue homeostasis. Nat Rev Immunol 2014;14:783–795.

[49] Satija R, Farrell JA, Gennert D et al. Spatial reconstruction of single-cell gene expression data. Nat Biotechnol 2015;33:495–502.

[50] Sauane M, Lebedeva IV, Su ZZ et al. Melanoma differentiation associated gene-7/interleukin-24 promotes tumor cell-specific apoptosis through both secretory and nonsecretory pathways. Cancer Res 2004;64:2988–2993.

[51] Schmetzer O, Lakin E, Topal FA et al. IL-24 is a common and specific autoantigen of IgE in patients with chronic spontaneous urticaria. J Allergy Clin Immunol 2018;142:876–882.

[52] Schmitz J, Owyang A, Oldham E et al. IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. Immunity 2005;23:479–490.

[53] Segaud J, Yao W, Marschall P et al. Context-dependent function of TSLP and IL-1beta in skin allergic sensitization and atopic march. Nat Commun 2022;13:4703.

[54] Sideris N, Paschou E, Bakirtzi K et al. New and upcoming topical treatments for atopic dermatitis: a review of the literature. J Clin Med 2022;11:4974.

[55] Sie C, Kant R, Peter C et al. IL-24 intrinsically regulates TH17 cell pathogenicity in mice. J Exp Med 2022;219:1.

[56] Simpson EL, Villarreal M, Jepson B et al. Patients with atopic dermatitis colonized with Staphylococcus aureus have a distinct phenotype and endotype. J Invest Dermatol 2018;138:2224–2233.

[57] Smith Begolka W, Chovatiya R, Thibau IJ et al. Financial burden of atopic dermatitis out-of-pocket health care expenses in the United States. Dermatitis 2021;32:S62–S70.

[58] Son YI, Egawa S, Tatsumi T, Redlinger RE Jr, Kalinski P, and Kanto T (2002). A novel bulk-culture method for generating mature dendritic cells from mouse bone marrow cells. J Immunol Methods 262, 145–157.

[59] Soumelis V, Reche PA, Kanzler H et al. Human epithelial cells trigger dendritic cell mediated allergic inflammation by producing TSLP. Nat Immunol 2002;3:673–680.

[60] Spergel JM, Mizoguchi E, Brewer JP et al. Epicutaneous sensitization with protein antigen induces localized allergic dermatitis and hyperresponsiveness to methacholine after single exposure to aerosolized antigen in mice. J Clin Invest 1998;101:1614–1622.

[61] Stander S. Atopic Dermatitis. N Engl J Med 2021;384:1136–1143.

[62] Tam K, Torres VJ. Staphylococcus aureus Secreted Toxins and Extracellular Enzymes. Microbiol Spectr 2019;7:1–34.

[63] Tauber M, Balica S, Hsu CY et al. Staphylococcus aureus density on lesional and nonlesional skin is strongly associated with disease severity in atopic dermatitis. J Allergy Clin Immunol 2016;137:1272–1274.e3.

[64] Thammavongsa V, Kim HK, Missiakas D et al. Staphylococcal manipulation of host immune responses. Nat Rev Microbiol 2015;13:529–543.

[65] Tomczak H, Wrobel J, Jenerowicz D et al. The role of Staphylococcus aureus in atopic dermatitis: microbiological and immunological implications. Postepy Dermatol Alergol 2019;36:485–491.

[66] Wang M, Tan Z, Zhang R et al. Interleukin 24 (MDA-7/MOB-5) signals through two heterodimeric receptors, IL-22R1/IL-20R2 and IL-20R1/IL-20R2. J Biol Chem 2002;277:7341–7347.

[67] Wang YH, Angkasekwinai P, Lu N et al. IL-25 augments type 2 immune responses by enhancing the expansion and functions of TSLP-DC-activated Th2 memory cells. J Exp Med 2007;204:1837–1847.

[68] Wang J, Hu B, Zhao Z et al. Intracellular XBP1-IL-24 axis dismantles cytotoxic unfolded protein response in the liver. Cell Death Dis 2020;11:17.

[69] Wang F, Trier AM, Li F et al. A basophil-neuronal axis promotes itch. Cell 2021;184:422422–440.e17 e417.

[70] Weidinger S, Beck LA, Bieber T et al. Atopic dermatitis. Nat Rev Dis Primers 2018;4:1.

[71] Wu J, Xu J, Liu B et al. Chromatin analysis in human early development reveals epigenetic transition during ZGA. Nature 2018;557:256–260.

[72] Yoo J, Omori M, Gyarmati D et al. Spontaneous atopic dermatitis in mice expressing an inducible thymic stromal lymphopoietin transgene specifically in the skin. J Exp Med 2005;202:541–549.

[73] Zhang Y, Liu T, Meyer CA et al. Model-based analysis of ChIP-Seq (MACS). Genome Biol 2008;9:R137.

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