LAIR1 prevents excess inflammatory tissue damage in Staphylococcus aureus skin infection and cutaneous T cell lymphoma
Hannah K. Dorando, Evan C. Mutic, Kelly L. Tomaszewski, Yulia Korshunova, Ling Tian, Mellisa K. Stefanov, Chaz C. Quinn, Deborah J. Veis, Juliane Bubeck Wardenburg, Amy C. Musiek, Neha Mehta-Shah, Jacqueline E. Payton
Hannah K. Dorando, Evan C. Mutic, Kelly L. Tomaszewski, Yulia Korshunova, Ling Tian, Mellisa K. Stefanov, Chaz C. Quinn, Deborah J. Veis, Juliane Bubeck Wardenburg, Amy C. Musiek, Neha Mehta-Shah, Jacqueline E. Payton
View: Text | PDF
Research Article Dermatology Immunology Oncology

LAIR1 prevents excess inflammatory tissue damage in Staphylococcus aureus skin infection and cutaneous T cell lymphoma

Abstract

Patients with cutaneous T cell lymphoma (CTCL) experience high morbidity and mortality due to S. aureus skin infections and sepsis, but the underlying mechanisms remain unclear. We have previously identified high levels of LAIR2, a decoy protein for the inhibitory receptor LAIR1, in advanced CTCL. Mice lack a LAIR2 homolog, so we used Lair1-KO mice to model LAIR2 overexpression. In a model of S. aureus skin infection, Lair1-KO mice had significantly larger abscesses and areas of dermonecrosis compared with WT despite similar bacterial burdens. Lair1 KO exhibited a pattern of increased inflammatory responses in infection and sterile immune stimulation, with increased production of proinflammatory cytokines and myeloid chemokines, neutrophil ROS, and collagen/extracellular matrix (ECM) pathway proteins, including collagens and complement factors. These findings support the notion that loss of LAIR1 signaling causes an excessive inflammatory response that exacerbates tissue damage and does not improve infection control. Underscoring the clinical relevance of our findings, CTCL skin lesions exhibited similarly increased expression in cytokine and collagen/ECM remodeling pathways, suggesting that high levels of LAIR2 promote excessive inflammatory tissue damage and compromise host defense against S. aureus infection. LAIR signaling represents a promising target for therapeutic development in CTCL and other inflammatory diseases.

Authors

Hannah K. Dorando, Evan C. Mutic, Kelly L. Tomaszewski, Yulia Korshunova, Ling Tian, Mellisa K. Stefanov, Chaz C. Quinn, Deborah J. Veis, Juliane Bubeck Wardenburg, Amy C. Musiek, Neha Mehta-Shah, Jacqueline E. Payton

×

Figure 4

Collagen pathway gene expression is elevated in Lair1 KO S. aureus–infected skin and macrophages.

Options: View larger image (or click on image) Download as PowerPoint
Collagen pathway gene expression is elevated in Lair1 KO S. aureus–infec...
(A and C) BMDM from WT and Lair1-KO mice were treated with PBS or PAM3CSK4 for 6 hours and were then subjected to RNA-Seq. (B and D) Skin punch biopsies from WT and Lair1-KO mouse S. aureus skin infections were taken at 2 dpi and were then subjected to RNA-Seq. GSEA was used to define the top 20 mouse Reactome pathways with enrichment scores and nominal P value in genes upregulated in Lair1 KO in BMDM treated with PAM3CSK4 (A) and 2 dpi SSTI (B); collagen-related pathways common to both analyses are bolded in teal. Genes from the 4 pathways, many of which overlapped, were classified into 3 general categories: collagen genes, collagen synthesis genes, and extracellular matrix (ECM) remodeling genes. Heatmaps show z-scored expression for these genes for BMDM (C) and S. aureus SSTI (D). (E and F) BMDM from WT and Lair1-KO mice were treated with PBS or PAM3CSK4 for 24 hours and were then fixed and stained for Serpin H1. Representative images from 3 independent experiments are shown (E). Scale bars: 50 μm. Images were analyzed in CellProfiler and mean Serpin H1 cytoplasmic fluorescence intensity per cell was calculated (F). Mean ± SEM are indicated by black bars. Statistical analysis was done by 2-way ANOVA with multiple comparisons.