Regulation of cytokine expression by Schwann cells in response to α2-macroglobulin binding to LRP1

Abstract

Binding of activated α(2)-macroglobulin (α(2)M) to LDL receptor-related protein-1 (LRP1) in Schwann cells activates ERK/MAP kinase and Akt and thereby promotes cell survival and migration. The goal of this study was to determine whether α(2)M binding to LRP1 regulates expression of cytokines and chemokines. To assess the LRP1 response selectively, we studied primary cultures of rat Schwann cells. In a screening assay that detects 84 gene products, monocyte chemoattractant protein-1 (MCP-1/CCL2) mRNA expression was increased more than 13-fold in Schwann cells treated with activated α(2)M. The effects of α(2)M on MCP-1 expression were selective, because expression of the general proinflammatory cytokine tumor necrosis factor-α (TNF-α) was not induced. We confirmed that α(2)M selectively induces expression of MCP-1 and not TNF-α in single-target qPCR assays. MCP-1 protein accumulated at increased levels in conditioned medium of α(2)M-treated cells. LRP1 was necessary for induction of MCP-1 expression, as determined in experiments with the LRP1 antagonist receptor-associated protein, a mutated form of full-length α(2)M that does not bind LRP1, and in studies with Schwann cells in which LRP1 was silenced. Inhibiting ERK/MAP kinase activation blocked expression of MCP-1. These studies support a model in which LRP1 regulates multiple aspects of Schwann cell physiology in the response to PNS injury.