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. 2012;7(11):e49408.
doi: 10.1371/journal.pone.0049408. Epub 2012 Nov 30.

Homeostatic tissue responses in skin biopsies from NOMID patients with constitutive overproduction of IL-1β

Pamela Aubert  1 , 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
Affiliations

Homeostatic tissue responses in skin biopsies from NOMID patients with constitutive overproduction of IL-1β

Pamela Aubert et al. PLoS One. 2012.

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.

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Conflict of interest statement

Competing Interests: Dr RG-M has received grant support from Regeneron and Novartis for clinical studies in patients with CAPS. This research was completed while PA was a fellow in the the Clinical Research Training Program, a public-private partnership supported jointly by the National Institutes of Health and Pfizer Inc (via a grant to the Foundation for NIH from Pfizer Inc). JE is employed by Frederick SAI. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials.

Figures

Figure 1
Figure 1. Clinical and histological features of patients with NOMID.
A. Appearance of the classical urticaria-like rash of NOMID, with scattered erythematous papules, perhaps better termed “IL-1-mediated neutrophilic dermatosis (IMEND)”. B. Representative haematoxylin and eosin (H&E) staining of a lesional skin biopsy showing prominent dermal neutrophilic urticaria. C. Comparison of representative post-NL, pre-NL, and LS biopsies by H&E (upper panel) and neutrophil elastase (lower panel) immunohistochemistry, showing the presence of neutrophils only in LS biopsies, with normal overlying epidermis. D, E. Immunoflourescence of LS biopsies showing activated caspase-1 (red) in both CD11c+ dendritic cells and CD163+ macrophages (green: double positive cells are yellow). Size bar is 100 µm.
Figure 2
Figure 2. Myeloid cells and T cells were abundant in pre-NL and LS NOMID skin.
Representative immunohistochemistry for post-NL, pre-NL, and LS skin biopsies, and cell counts/mm2 dermis. A. There were abundant CD11c+ inflammatory myeloid dendritic cells in all NOMID tissue groups. B. There were no differences in the CD1c+ resident dendritic cells across the groups. C, D, E. There were abundant CD163+ macrophages, CD3+ T cells, and HLA-DR+ activated cells in NOMID tissues. *p<0.05, **p<0.01, ***p<0.001. Size bar is 100 µm.
Figure 3
Figure 3. Gene expression of LS, pre-NL, post-NL and normal skin.
A. Principal Component Analysis (PCA) of samples used in this study, with PCA1 and PCA2 explaining together 66% of the variance. Number identifies each patient. B Venn diagram showing number of uniquely upregulated (red) or downregulated (green) genes comparing LS, pre-NL and post-NL to normal tissues (total probe-sets in lower right corner). C. Bar diagram indicating shared differentially expressed genes (DEGs) between tissue states in the same color. Most DEGs in post-NL tissue were also differentially regulated in pre-NL and LS tissue when compared with normal skin, and these are depicted as a blue block. Additional DEGs shared between LS and pre-NL (orange), shared between LS and post-NL (green), and shared between pre-NL and post-NL (purple) are shown. A large number of specifically regulated DEGs were only found in LS (red). Hence, there was a “crescendo effect” with additional numbers of up- and down-regulated DEGs recruited as the tissue became more diseased and inflamed.
Figure 4
Figure 4. Level of expression of selected genes in normal, post-NL, pre-NL and LS NOMID skin.
Gene expression for A. cytokines, B. cytokine signaling, C. JAKs and STATs, D. interferon receptors (IFNR), E. chemokines and, F. receptors that respond to mediators that induce regulatory macrophages. Asterisk indicates gene is significantly differentially regulated in LS compared to normal skin (p<0.0006) (gene expression values from Table S2, DEGs and p values from Table S1).
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