Academic Journal
View in EDS

MyD88 restricts dysbiosis-mediated inflammation in filaggrin deficient skin.

Bibliographic Details
Title: MyD88 restricts dysbiosis-mediated inflammation in filaggrin deficient skin.
Authors: Wu MJ; Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America., Ravipati A; Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America., Wang Y; Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America., Feller LE; Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America., Chu A; Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America., Damarla R; Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America., Li Z; Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America., Tsoi LC; Department of Dermatology, University of Michigan, Ann Arbor, Michigan, United States of America., Griffin R; Dermatology Branch, NIAMS, NIH, Bethesda, Maryland, United States of America., Hou P; Dermatology Branch, NIAMS, NIH, Bethesda, Maryland, United States of America., Liang H; Dermatology Branch, NIAMS, NIH, Bethesda, Maryland, United States of America., Geha R; Division of Immunology, Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, United States of America., Segre JA; Translational and Functional Genomics Branch, NHGRI, NIH, Bethesda, Maryland, United States of America., Kong HH; Dermatology Branch, NIAMS, NIH, Bethesda, Maryland, United States of America., Gudjonsson JE; Department of Dermatology, University of Michigan, Ann Arbor, Michigan, United States of America., Archer NK; Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
Source: PloS one [PLoS One] 2026 Aug 14; Vol. 21 (8), pp. e0353968. Date of Electronic Publication: 2026 Aug 14 (Print Publication: 2026).
Publication Type: Journal Article
Language: English
Journal Info: Publisher: Public Library of Science Country of Publication: United States NLM ID: 101285081 Publication Model: eCollection Cited Medium: Internet ISSN: 1932-6203 (Electronic) Linking ISSN: 19326203 NLM ISO Abbreviation: PLoS One Subsets: MEDLINE
Imprint Name(s): Original Publication: San Francisco, CA : Public Library of Science
MeSH Terms: Myeloid Differentiation Factor 88*/genetics , Myeloid Differentiation Factor 88*/metabolism , Dysbiosis*/genetics , Dysbiosis*/immunology , Skin*/pathology , Skin*/microbiology , Skin*/metabolism , Skin*/immunology , Intermediate Filament Proteins*/deficiency , Intermediate Filament Proteins*/genetics , Inflammation*/pathology , Inflammation*/genetics , Inflammation*/metabolism , Dermatitis, Atopic*/genetics , Dermatitis, Atopic*/pathology , Dermatitis, Atopic*/immunology , Dermatitis, Atopic*/microbiology , Dermatitis, Atopic*/metabolism, Interleukin-17/metabolism ; Animals ; Filaggrin Proteins ; Mice ; Mice, Knockout ; Skin Microbiome ; Signal Transduction
Abstract: Atopic dermatitis (AD) is a common inflammatory skin disease associated with epidermal barrier dysfunction, immune dysregulation, and microbial dysbiosis. Loss-of-function mutations in filaggrin, a critical epidermal protein, represent the strongest genetic risk factor for AD and result in compromised skin barrier integrity and altered immune responses. MyD88 is an adaptor protein essential for TLR and IL-1 receptor signaling, with dual roles in promoting inflammation and regulating immune tolerance. However, the function of MyD88 in maintaining skin homeostasis in the context of filaggrin deficiency remains unclear. Here, we used filaggrin-deficient (ft/ft) mice crossed with MyD88 knockout mice (ft/ftMyD88-/-) to investigate the immunological and microbial consequences of MyD88 signaling. In wildtype and ft/ft mice, MyD88 was predominantly expressed in skin epithelia during homeostasis, whereas ft/ftMyD88-/- mice developed spontaneous periocular skin inflammation. RNA-seq revealed upregulation of the IL-17 pathway in ft/ftMyD88-/- inflamed skin. Flow cytometry identified Vγ4 ⁺ γδ T cells as the major source of IL-17A in ft/ftMyD88-/- inflamed skin. We also discovered that ft/ftMyD88-/- skin inflammation was associated with markedly downregulated lipid metabolism genes as well as sebaceous gland abnormalities histologically. Moreover, 16S rRNA gene sequencing demonstrated microbial dysbiosis in ft/ft MyD88-/- periocular skin, which drove skin inflammation as well as IL-17-producing γδ T cell infiltration. Our findings indicate a role for MyD88 in homeostatic control of sebaceous glands and suppression of dysbiosis-driven IL-17A-mediated inflammation in filaggrin-deficient skin. These insights advance our understanding of AD pathogenesis and may offer novel therapeutic strategies for patients with filaggrin mutations.
(Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)
Competing Interests: N.K.A. has received previous grant support from Pfizer, Boehringer Ingelheim, and Verdant Scientific and was a paid consultant for Janssen Pharmaceuticals and Alphyn Biologics. This does not alter our adherence to PLOS ONE policies on sharing data and materials. The remaining authors declare no competing interests.
References: Br J Dermatol. 2017 Nov;177(5):1394-1400. (PMID: 28317091)
Immunity. 2006 Jan;24(1):79-91. (PMID: 16413925)
Allergy. 2023 Jun;78(6):1524-1537. (PMID: 36308463)
Proc Natl Acad Sci U S A. 2019 May 28;116(22):10917-10926. (PMID: 31088972)
J Cell Mol Med. 2019 Feb;23(2):1288-1299. (PMID: 30515983)
J Steroid Biochem Mol Biol. 2013 Sep;137:107-23. (PMID: 23435015)
Int J Biol Macromol. 2024 Jun;271(Pt 1):132666. (PMID: 38806081)
Nat Med. 2019 Jul;25(7):1164-1174. (PMID: 31235962)
J Infect Dis. 2021 May 28;223(10):1753-1765. (PMID: 33837391)
Nat Rev Microbiol. 2018 Mar;16(3):143-155. (PMID: 29332945)
Pediatr Dermatol. 2011 May-Jun;28(3):230-4. (PMID: 21517950)
JAMA Dermatol. 2018 Mar 1;154(3):293-300. (PMID: 29344612)
J Invest Dermatol. 2023 May;143(5):790-800.e12. (PMID: 36496196)
Nat Commun. 2019 Oct 16;10(1):4703. (PMID: 31619666)
Cell Host Microbe. 2017 Nov 8;22(5):653-666.e5. (PMID: 29120743)
One Health. 2016 Mar 04;2:33-41. (PMID: 28616476)
Nat Methods. 2016 Jul;13(7):581-3. (PMID: 27214047)
J Invest Dermatol. 2025 Jul;145(7):1622-1632. (PMID: 39927906)
PLoS One. 2013 Apr 22;8(4):e61217. (PMID: 23630581)
Clin Exp Dermatol. 2009 Jul;34(5):e63-5. (PMID: 19438578)
J Biol Chem. 2024 Jul;300(7):107442. (PMID: 38838779)
Clin Immunol. 2018 Oct;195:88-92. (PMID: 30099194)
Genome Biol. 2014;15(12):550. (PMID: 25516281)
Cell Rep. 2023 Sep 26;42(9):113121. (PMID: 37715952)
Acta Derm Venereol. 1995 Nov;75(6):429-33. (PMID: 8651017)
Immunity. 2009 Aug 21;31(2):331-41. (PMID: 19682929)
Cell Rep. 2019 Jun 11;27(11):3401-3412.e3. (PMID: 31189120)
J Cell Sci. 2009 May 1;122(Pt 9):1285-94. (PMID: 19386895)
BMJ. 2009 Jul 09;339:b2433. (PMID: 19589816)
J Dermatol Sci. 2015 Nov;80(2):158-60. (PMID: 26381575)
Proc Natl Acad Sci U S A. 2015 Jun 30;112(26):8046-51. (PMID: 26080440)
J Allergy Clin Immunol. 2012 Apr;129(4):1031-9.e1. (PMID: 22322004)
J Invest Dermatol. 2004 Sep;123(3):417-25. (PMID: 15304077)
Lancet. 2020 Aug 1;396(10247):345-360. (PMID: 32738956)
N Engl J Med. 2011 Oct 6;365(14):1315-27. (PMID: 21991953)
Sci Rep. 2022 Mar 23;12(1):4943. (PMID: 35322811)
Nature. 2008 Oct 9;455(7214):808-12. (PMID: 18716618)
J Allergy Clin Immunol. 2017 Apr;139(4):1368-1371. (PMID: 27725187)
Cell. 2019 Feb 21;176(5):982-997.e16. (PMID: 30712873)
Allergy. 2019 Oct;74(10):1920-1933. (PMID: 30937919)
Int J Dermatol. 1996 Nov;35(11):791-3. (PMID: 8915731)
Ann Allergy Asthma Immunol. 2021 Jan;126(1):3-12. (PMID: 32771354)
Cells. 2025 May 20;14(10):. (PMID: 40422250)
J Invest Dermatol. 2017 Mar;137(3):696-705. (PMID: 27984037)
Immunity. 2015 Nov 17;43(5):1011-21. (PMID: 26588783)
Cell Host Microbe. 2010 Feb 18;7(2):140-50. (PMID: 20159619)
Front Immunol. 2024 Feb 16;15:1334844. (PMID: 38433843)
Cell Mol Immunol. 2023 May;20(5):448-474. (PMID: 36928371)
Genome Res. 2012 May;22(5):850-9. (PMID: 22310478)
Proc Natl Acad Sci U S A. 2020 Aug 4;117(31):18649-18660. (PMID: 32690687)
iScience. 2023 Apr 10;26(5):106630. (PMID: 37192973)
Front Immunol. 2018 Jan 29;9:80. (PMID: 29434599)
J Invest Dermatol. 2010 Jan;130(1):184-91. (PMID: 19657352)
Immunity. 2015 Aug 18;43(2):289-303. (PMID: 26231118)
Allergol Int. 2013 Jun;62(2):151-61. (PMID: 23712284)
J Allergy Clin Immunol. 2018 May;141(5):1668-1676.e16. (PMID: 29421277)
Eye (Lond). 2025 May;39(7):1276-1285. (PMID: 39833573)
F1000Prime Rep. 2014 Nov 04;6:97. (PMID: 25580251)
J Leukoc Biol. 2017 Sep;102(3):791-803. (PMID: 28642279)
Am J Pathol. 2010 Feb;176(2):754-63. (PMID: 20019195)
Nat Immunol. 2013 Jun;14(6):584-92. (PMID: 23624556)
J Allergy Clin Immunol. 2019 Apr;143(4):1426-1443.e6. (PMID: 30240702)
J Allergy Clin Immunol. 2009 Sep;124(3 Suppl 2):R7-R12. (PMID: 19720210)
Grant Information: K01 AR073924 United States AR NIAMS NIH HHS; P30 AR075043 United States AR NIAMS NIH HHS; R01 AR073665 United States AR NIAMS NIH HHS
Substance Nomenclature: 0 (Myeloid Differentiation Factor 88)
0 (Filaggrin Proteins)
0 (Myd88 protein, mouse)
0 (Intermediate Filament Proteins)
0 (Interleukin-17)
Entry Date(s): Date Created: 20260814 Date Completed: 20260814 Latest Revision: 20260817
Update Code: 20260817
PubMed Central ID: PMC13475889
DOI: 10.1371/journal.pone.0353968
PMID: 42599875
Database: MEDLINE
Description
ISSN:1932-6203
DOI:10.1371/journal.pone.0353968