# LRP1 Shedding in Ricin-Induced Lung Injury: A Cell-Specific Response to Toxin Exposure

## TL;DR

This study shows that ricin causes cell-specific LRP1 shedding in the lungs, with fibroblasts and macrophages showing significant changes, while other cell types remain unaffected.

## Contribution

The study reveals a cell-specific pattern of LRP1 shedding in response to ricin, highlighting its role in modulating cellular resistance or susceptibility.

## Key findings

- Soluble LRP1 levels increase in bronchoalveolar lavage fluid but not in serum after ricin exposure.
- Fibroblasts and macrophages show increased LRP1 shedding, while AT-II cells and neutrophils do not.
- LRP1 shedding in fibroblasts is mediated by metalloproteinases and correlates with reduced membrane-bound LRP1.

## Abstract

Ricin is a highly potent toxin that causes severe lung injury upon inhalation by initiating a complex cascade of cellular responses that ultimately leads to cell death. The low-density lipoprotein receptor-related protein 1 (LRP1) is a multifunctional receptor involved in various physiological processes, including ricin-mediated toxicity. This study explores the role of LRP1 shedding in the development of ricin-induced lung injury. Analysis of bronchoalveolar lavage fluid (BALF) from ricin-intoxicated mice and swine showed a significant increase in soluble LRP1 (sLRP1) levels, whereas serum LRP1 levels remained largely unchanged, suggesting the lungs are the primary source of sLRP1 release. In vitro assays demonstrated the formation of ricin-sLRP1 complexes, indicating that sLRP1 in BALF retained ricin-binding capability. Flow cytometric analysis of lung cells revealed a reduction in both the percentage and total number of LRP1-expressing cells following ricin exposure. Further investigation of specific lung cell populations showed that alveolar epithelial type II (AT-II) cells, despite experiencing significant injury, exhibited minimal LRP1 shedding. No shedding of LRP1 occurred in neutrophils. In contrast, fibroblasts, which were resistant to ricin-induced cell death, exhibited increased shedding of LRP1 and a corresponding decrease in membrane-bound LRP1 expression. This shedding of the LRP1 ectodomain was mediated by metalloproteinases. Immunohistochemical staining further confirmed decreased LRP1 expression in fibroblasts from ricin-exposed mice. Macrophages also showed substantial LRP1 shedding, despite undergoing significant depletion. These findings highlight the complex cell-specific nature of LRP1 shedding in response to ricin intoxication and suggests the potential role of LRP1 in modulation of cellular susceptibility and resistance to ricin-induced lung injury.