Homeostatic Tissue Responses in Skin Biopsies from NOMID Patients with Constitutive Overproduction of IL-1β

Pamela Aubert, Mayte Suárez-Fariñas, Hiroshi Mitsui, Leanne M. Johnson-Huang, Jamie Lynn Harden, Katherine C. Pierson, Joseph G. Dolan, Inna Novitskaya, Israel Coats, Jacob Estes, Edward W. Cowen, Nicole Plass, Chyi Chia Richard Lee, Hong Wei Sun, Michelle A. Lowes, Raphaela Goldbach-Mansky

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

The autoinflammatory disorder, Neonatal-onset Multisystem Inflammatory Disease (NOMID) is the most severe phenotype of disorders caused by mutations in CIAS1 that result in increased production and secretion of active IL-1β. NOMID patients present with systemic and organ-specific inflammation of the skin, central nervous system and bone, and respond dramatically to treatment with IL-1 blocking agents. We compared the cellular infiltrates and transcriptome of skin biopsies from patients with NOMID (n = 14) before treatment (lesional (LS) and non-lesional (pre-NL) skin) and after treatment (post-NL) with the IL-1 blocker anakinra (recombinant IL-1 receptor antagonist, Kineret®, Swedish Orphan Biovitrum AB, SOBI), to normal skin (n = 5) to assess tissue responses in the context of untreated and treated disease. Abundant neutrophils distinguish LS skin from pre-NL and post-NL skin. CD11c+ dermal dendritic cells and CD163+ macrophages expressed activated caspase-1 and are a likely source of cutaneous IL-1 production. Treatment with anakinra led to the disappearance of neutrophils, but CD3+ T cells and HLA-DR+ cells remained elevated. Among the upregulated genes IL-6, IL-8, TNF, IL-17A, CCL20, and the neutrophil defensins DEFA1 and DEFA3 were differentially regulated in LS tissues (compared to normal skin). Important significantly downregulated pathways in LS skin included IL-1R/TLR signaling, type I and II cytokine receptor signaling, mitochondrial dysfunction, and antigen presentation. The differential expression and regulation of microRNAs and pathways involved in post-transcriptional modification were suggestive of epigenetic modification in the chronically inflamed tissue. Overall, the dysregulated genes and pathways suggest extensive "adaptive" mechanisms to control inflammation and maintain tissue homeostasis, likely triggered by chronic IL-1 release in the skin of patients with NOMID.

Original languageEnglish (US)
Article numbere49408
JournalPLoS One
Volume7
Issue number11
DOIs
StatePublished - Nov 30 2012
Externally publishedYes

Fingerprint

Cryopyrin-Associated Periodic Syndromes
Biopsy
interleukin-1
Interleukin-1
skin (animal)
biopsy
Skin
Tissue
Interleukin 1 Receptor Antagonist Protein
neutrophils
Neutrophils
Tissue homeostasis
inflammation
caspase-1
Genes
antigen presentation
Defensins
tissues
Caspase 1
interleukin-8

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Aubert, P., Suárez-Fariñas, M., Mitsui, H., Johnson-Huang, L. M., Harden, J. L., Pierson, K. C., ... Goldbach-Mansky, R. (2012). Homeostatic Tissue Responses in Skin Biopsies from NOMID Patients with Constitutive Overproduction of IL-1β. PLoS One, 7(11), [e49408]. https://doi.org/10.1371/journal.pone.0049408

Homeostatic Tissue Responses in Skin Biopsies from NOMID Patients with Constitutive Overproduction of IL-1β. / Aubert, Pamela; Suárez-Fariñas, Mayte; Mitsui, Hiroshi; Johnson-Huang, Leanne M.; Harden, Jamie Lynn; Pierson, Katherine C.; Dolan, Joseph G.; Novitskaya, Inna; Coats, Israel; Estes, Jacob; Cowen, Edward W.; Plass, Nicole; Lee, Chyi Chia Richard; Sun, Hong Wei; Lowes, Michelle A.; Goldbach-Mansky, Raphaela.

In: PLoS One, Vol. 7, No. 11, e49408, 30.11.2012.

Research output: Contribution to journalArticle

Aubert, P, Suárez-Fariñas, M, Mitsui, H, Johnson-Huang, LM, Harden, JL, Pierson, KC, Dolan, JG, Novitskaya, I, Coats, I, Estes, J, Cowen, EW, Plass, N, Lee, CCR, Sun, HW, Lowes, MA & Goldbach-Mansky, R 2012, 'Homeostatic Tissue Responses in Skin Biopsies from NOMID Patients with Constitutive Overproduction of IL-1β', PLoS One, vol. 7, no. 11, e49408. https://doi.org/10.1371/journal.pone.0049408
Aubert P, Suárez-Fariñas M, Mitsui H, Johnson-Huang LM, Harden JL, Pierson KC et al. Homeostatic Tissue Responses in Skin Biopsies from NOMID Patients with Constitutive Overproduction of IL-1β. PLoS One. 2012 Nov 30;7(11). e49408. https://doi.org/10.1371/journal.pone.0049408
Aubert, Pamela ; Suárez-Fariñas, Mayte ; Mitsui, Hiroshi ; Johnson-Huang, Leanne M. ; Harden, Jamie Lynn ; Pierson, Katherine C. ; Dolan, Joseph G. ; Novitskaya, Inna ; Coats, Israel ; Estes, Jacob ; Cowen, Edward W. ; Plass, Nicole ; Lee, Chyi Chia Richard ; Sun, Hong Wei ; Lowes, Michelle A. ; Goldbach-Mansky, Raphaela. / Homeostatic Tissue Responses in Skin Biopsies from NOMID Patients with Constitutive Overproduction of IL-1β. In: PLoS One. 2012 ; Vol. 7, No. 11.
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