Background: Prion protein (PrP C ) modulates inflammation, and prion diseases affect neutrophil numbers and functions, but the regulation of PrP C in neutrophils is unknown. Results: Inflammation and stress massively up-regulated PrP C in neutrophils via glucocorticoids and TGF-.
Conclusion:We show a novel pathway of regulation of PrP C , with functional consequences for neutrophils. Significance: Systemic control of the expression and function of PrP C broadly modulates cellular physiology and pathology.The prion protein (PrP C ) is a cell surface protein expressed mainly in the nervous system. In addition to the role of its abnormal conformer in transmissible spongiform encephalopathies, normal PrP C may be implicated in other degenerative conditions often associated with inflammation. PrP C is also present in cells of hematopoietic origin, including T cells, dendritic cells, and macrophages, and it has been shown to modulate their functions. Here, we investigated the impact of inflammation and stress on the expression and function of PrP C in neutrophils, a cell type critically involved in both acute and chronic inflammation. We found that systemic injection of LPS induced transcription and translation of PrP C in mouse neutrophils. Up-regulation of PrP C was dependent on the serum content of TGF- and glucocorticoids (GC), which, in turn, are contingent on the activation of the hypothalamic-pituitary-adrenal axis in response to systemic inflammation. GC and TGF-, either alone or in combination, directly up-regulated PrP C in neutrophils, and accordingly, the blockade of GC receptors in vivo curtailed the LPS-induced increase in the content of PrP C . Moreover, GC also mediated up-regulation of PrP C in neutrophils following noninflammatory restraint stress. Finally, neutrophils with upregulated PrP C presented enhanced peroxide-dependent cytotoxicity to endothelial cells. The data demonstrate a novel interplay of the nervous, endocrine, and immune systems upon both the expression and function of PrP C in neutrophils, which may have a broad impact upon the physiology and pathology of various organs and systems.