CERS1 is a biomarker of Staphylococcus aureus abundance and atopic dermatitis severity

被引：1

作者：

Kenney, H. Mark ^{[1
]}

Yoshida, Takeshi ^{[2
]}

Berdyshev, Evgeny ^{[3
,4
]}

Calatroni, Agustin ^{[5
]}

Gill, Steven R. ^{[6
]}

Simpson, Eric L. ^{[7
]}

Lussier, Stephanie ^{[5
]}

Boguniewicz, Mark ^{[8
,9
]}

Hata, Tissa ^{[10
]}

Fuxench, Zelma C. Chiesa ^{[11
]}

De Benedetto, Anna ^{[2
]}

Ong, Peck Y. ^{[12
]}

Ko, Justin ^{[13
]}

Davidson, Wendy ^{[14
]}

David, Gloria ^{[5
]}

Schlievert, Patrick M. ^{[15
]}

Leung, Donald Y. M. ^{[8
,9
]}

Beck, Lisa A. ^{[1
,2
]}

机构：

[1] Univ Rochester, Dept Pathol & Lab Med, Med Ctr, Rochester, NY USA

[2] Univ Rochester, Med Ctr, Dept Dermatol, Rochester, NY USA

[3] Natl Jewish Hlth, Sch Med, Denver, CO 80206 USA

[4] Univ Colorado, Sch Med, Denver, CO USA

[5] Univ Durham, Durham, England

[6] Univ Rochester, Med Ctr, Dept Obstet & Gynecol, Rochester, NY 14642 USA

[7] Oregon Hlth & Sci Univ, Dept Dermatol, Portland, OR USA

[8] Natl Jewish Hlth, Dept Pediat, Div Allergy Immunol, Denver, CO USA

[9] Univ Colorado, Sch Med, Denver, CO USA

[10] Univ Calif San Diego, Cardiothorac Surg, San Diego, CA USA

[11] Univ Penn, Dept Dermatol, Philadelphia, PA USA

[12] Univ Southern Calif, Childrens Hosp Los Angeles, Dept Pediat, Childrens Hosp Los Angeles, Los Angeles, CA 90007 USA

[13] Stanford Univ, Dept Dermatol, Stanford, CA USA

[14] NIAID, Div Allergy Immunol & Transplantat, NIH, Bethesda, MD USA

[15] Univ Iowa, Dept Microbiol & Immunol, Iowa City, IA USA

来源：

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY | 2025年 / 155卷 / 02期

基金：

美国国家卫生研究院;

关键词：

Atopic dermatitis; type; 2; immunity; transcriptomics; microbiome; Staphylococcus aureus; dupilumab; skin barrier; sphingolipids; ceramide synthase; CERS1; CERAMIDE SYNTHASE 1; ACID CHAIN-LENGTH; BARRIER FUNCTION; STRATUM-CORNEUM; SKIN; EXPRESSION; DUPILUMAB; PLACEBO;

D O I：

10.1016/j.jaci.2024.09.017

中图分类号：

R392 [医学免疫学];

学科分类号：

100102 ;

摘要：

Background: Atopic dermatitis (AD) is an inflammatory skin condition characterized by widely variable cutaneous Staphylococcus aureus abundance that contributes to disease severity and rapidly responds to type 2 immune blockade (ie, dupilumab). The molecular mechanisms regulating S aureus levels between AD subjects remain poorly understood. Objective: We investigated host genes that may be predictive of S aureus abundance and correspond with AD severity. Methods: We studied data derived from the National Institutes of Health/National Institute of Allergy and Infectious Diseases- funded (NCT03389893 [ADRN-09]) randomized, double-blind, placebo-controlled multicenter study of dupilumab in adults (n = 71 subjects) with moderate-to-severe AD. Bulk RNA sequencing of skin biopsy samples (n = 57 lesional, 55 nonlesional) was compared to epidermal S aureus abundance, lipidomic, and AD clinical measures. Results: S aureus abundance and ceramide synthase 1 (CERS1) expression positively correlated at baseline across both nonlesional (r = 0.29, P = .030) and lesional (r = 0.41, P = .0015) skin. Lesional CERS1 expression also positively correlated with AD severity (ie, SCORAD r = 0.44, P = .0006) and skin barrier dysfunction (transepidermal water loss area under the curve r = 0.31, P = .025) at baseline. CERS1 expression (forms C C18:0 sphingolipids) was negatively associated with elongation of very long-chain fatty acids (ELOVL6; C C16:0 C16:0/ C16:0/C C16:0/C18:0 C16:0/C18:0) expression and corresponded with a shorter chain length sphingolipid composition. Dupilumab rapidly reduced CERS1 expression (day 7) and ablated the relationship with S aureus abundance and ELOVL6 expression by day 21. Conclusion: CERS1 is a unique molecular biomarker of S aureus abundance and AD severity that may contribute to dysfunctional skin barrier and shorter-chain sphingolipid composition through fatty acid sequestration as a maladaptive compensatory response to reduced ELOVL6. (J Allergy Clin Immunol 2025;155:479-90.)

引用

页码：479 / 490

页数：12

共 54 条

[1]

Nutten S., Atopic dermatitis: global epidemiology and risk factors, Ann Nutr Metab, 66, pp. 8-16, (2015)

[2]

Chiesa Fuxench Z.C., Block J.K., Boguniewicz M., Boyle J., Fonacier L., Gelfand J.M., Et al., Atopic Dermatitis in America study: a cross-sectional study examining the prevalence and disease burden of atopic dermatitis in the US adult population, J Invest Dermatol, 139, pp. 583-590, (2019)

[3]

Czarnowicki T., He H., Krueger J.G., Guttman-Yassky E., Atopic dermatitis endotypes and implications for targeted therapeutics, J Allergy Clin Immunol, 143, pp. 1-11, (2019)

[4]

Hill D.A., Spergel J.M., The atopic march: critical evidence and clinical relevance, Ann Allergy Asthma Immunol, 120, pp. 131-137, (2018)

[5]

Schuler C.F., Billi A.C., Maverakis E., Tsoi L.C., Gudjonsson J.E., Novel insights into atopic dermatitis, J Allergy Clin Immunol, 151, pp. 1145-1154, (2023)

[6]

Leung D.Y., Pathogenesis of atopic dermatitis, J Allergy Clin Immunol, 104, 3, pp. S99-S108, (1999)

[7]

Palmer C.N., Irvine A.D., Terron-Kwiatkowski A., Zhao Y., Liao H., Lee S.P., Et al., Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis, Nat Genet, 38, pp. 441-446, (2006)

[8]

Swartzendruber D.C., Wertz P.W., Madison K.C., Downing D.T., Evidence that the corneocyte has a chemically bound lipid envelope, J Invest Dermatol, 88, pp. 709-713, (1987)

[9]

Farwanah H., Pierstorff B., Schmelzer C.E., Raith K., Neubert R.H., Kolter T., Et al., Separation and mass spectrometric characterization of covalently bound skin ceramides using LC/APCI-MS and nano-ESI-MS/MS, J Chromatogr B Analyt Technol Biomed Life Sci, 852, pp. 562-570, (2007)

[10]

Hill J., Paslin D., Wertz P.W., A new covalently bound ceramide from human stratum corneum –ω-hydroxyacylphytosphingosine, Int J Cosmet Sci, 28, pp. 225-230, (2006)

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