Salient type 1 interleukin 1 receptor expression in peripheral non-immune cells

Anping Song,Stephanie A Amici,Mireia Guerau-De-Arellano,Ning Quan,Gowthami Gorantla,Ling Zhu,Xiaoyu Liu,Jessica K Lerch,Kathryn M Madalena,Olimpia Berdysz

doi:10.1038/s41598-018-19248-7

Abstract

Interleukin 1 is a pleiotropic cytokine that mediates diverse functions through its receptor, type I interleukin 1 receptor (IL-1R1). Most previous studies have focused on the expression and function of IL-1R1 in immune cells. Here we performed a comprehensive mapping of IL-1R1 distribution in multiple peripheral tissues using our IL-1R1 reporter (IL-1R1GR/GR) mice. This method yielded the highest sensitivity of in situ detection of IL-1R1 mRNA and protein. Besides validating previously reported IL-1R1 expression in the endocrine tissues including pituitary and pancreas, our results refuted previously reported exclusive IL-1R1 expression in neurons of the spinal cord dorsal horn and dorsal root ganglia (DRG). Instead, IL-1R1 expression was detected in endothelial cells within DRG, spinal cord, pancreas, colon, muscles and many immune organs. In addition, gp38+ fibroblastic reticular cells (FRCs), rather than tissue macrophages or other immune cells, were found to express high levels of IL-1R1 in colon and many immune organs. A functional test of spleen FRCs showed that they responded rapidly to systemic IL-1β stimulation in vivo. Taken together, this study provides a rigorous re-examination of IL-1R1 expression in peripheral tissues and reveals tissue FRCs as a previously unappreciated novel high IL-1R1-expressing cell type in peripheral IL-1 signaling.

Highlights

Interleukin 1 (IL-1) is a pro-inflammatory cytokine that mediates physiological and pathological responses to stress and infectious and sterile inflammatory stimuli
We have previously demonstrated that, in the IL-1R1GR/GR mice, IL-1R1 mRNA-expressing cells are faithfully tracked by co-expressed tdTomato fluorescent protein[15]
Based on our genetic design, IL-1R1 protein in the IL-1R1GR/GR mice is tagged by 3HA epitope[15]

Summary

Introduction

Interleukin 1 (IL-1) is a pro-inflammatory cytokine that mediates physiological and pathological responses to stress and infectious and sterile inflammatory stimuli. We have previously developed an IL-1R1 reporter mouse model, namely the IL-1R1 globally restored mice (IL-1R1GR/GR), to study IL-1R1 expression in the brain[15]. This mouse model allows tracking of IL-1R1 mRNA expression by the knockin tdTomato fluorescence and the IL-1R1 protein expression by the HA tag under the control of the endogenous IL-1R1 promoter. The highest IL-1R1-expressing cells in colon, muscle, and many immune organs were identified as fibroblastic reticular cells and endothelial cells, rather than leukocytes These cells rapidly responded to in vivo IL-1β stimulation with upregulation of the immediate early gene c-fos. These results reveal structural non-immune cells, rather than the mobile immune cells, as the preeminent peripheral IL-1R1 expressors and suggest these cells are the first and most critical responders to systemic or local IL-1

Methods

Results

Conclusion