Unknown,Transcriptomics,Genomics,Proteomics

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Neutrophil-derived IL-1β is sufficient for abscess formation in immunity against Staphylococcus aureus in mice

ABSTRACT: Neutrophil abscess formation is critical in innate immunity against many pathogens. Here, the mechanism of neutrophil abscess formation was investigated using a mouse model of Staphylococcus aureus cutaneous infection. Gene expression analysis of S. aureus-infected skin revealed that induction of neutrophil recruitment genes was largely dependent upon IL-1beta/IL-1R activation. Unexpectedly, using IL 1beta reporter mice, neutrophils were identified as the primary source of IL-1beta at the site of infection. Furthermore, IL-1beta-producing neutrophils were necessary and sufficient for abscess formation and bacterial clearance. S. aureus-induced IL 1beta production by neutrophils required TLR2, NOD2, FPRs and the ASC/NLRP3 inflammasome. Taken together, IL-1beta and neutrophil abscess formation during an infection are functionally, spatially and temporally linked as a consequence of direct IL-1beta production by neutrophils. Lesional skin biopsies obtained from C57BL/6J WT mice or IL-1R-deficient mice at 4 hours post-infection with Staphylococcus aureus. Uninfected skin biopsies were also collected from WT and IL-1R-deficient mice.

ORGANISM(S): Mus musculus

SUBMITTER: Lloyd Miller

PROVIDER: E-GEOD-36826 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Neutrophil-derived IL-1β is sufficient for abscess formation in immunity against Staphylococcus aureus in mice.

Cho John S JS Guo Yi Y Ramos Romela Irene RI Hebroni Frank F Plaisier Seema B SB Xuan Caiyun C Granick Jennifer L JL Matsushima Hironori H Takashima Akira A Iwakura Yoichiro Y Cheung Ambrose L AL Cheng Genhong G Lee Delphine J DJ Simon Scott I SI Miller Lloyd S LS

PLoS pathogens 20121129 11

Neutrophil abscess formation is critical in innate immunity against many pathogens. Here, the mechanism of neutrophil abscess formation was investigated using a mouse model of Staphylococcus aureus cutaneous infection. Gene expression analysis and in vivo multispectral noninvasive imaging during the S. aureus infection revealed a strong functional and temporal association between neutrophil recruitment and IL-1β/IL-1R activation. Unexpectedly, neutrophils but not monocytes/macrophages or other M ...[more]

PMID: 23209417

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Project description:The autoinflammatory disorder, Neonatal-onset Multisystem Inflammatory Disease (NOMID) is the most severe phenotype of disorders caused by mutations in the CIAS1 gene that result in increased production and secretion of active IL-1≤. NOMID patients present with systemic and organ-specific inflammation of the skin, central nervous system and bony growth plates, 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®), to normal skin (n=5). 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 the likely sources 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 included IL-1R/TLR signaling, type I and II cytokine receptor signaling, mitochondrial dysfunction, and antigen presentation. Differential expression and regulation of microRNAs and pathways involved in post-transcriptional modification are indicative of epigenetic modification in the various tissue states. Overall, the dysregulated genes and pathways suggest extensive “adaptive” mechanisms to control inflammation, and maintain tissue homeostasis in the skin of patients with NOMID. To determine the transcsriptome of skin samples in Neonatal-onset Multisystem Inflammatory Disease (NOMID), using pre-treatment non-lesional (pre-NL, n=4); lesional (LS, n=6); post-treatment non-lesional (post-NL, n=8), and normal skin (n=5). Comparison of mean gene expression of each group at baseline, and considering treatment effect

Dataset Information

Neutrophil-derived IL-1β is sufficient for abscess formation in immunity against Staphylococcus aureus in mice

Publications

Neutrophil-derived IL-1β is sufficient for abscess formation in immunity against Staphylococcus aureus in mice.

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