Neuroimmunoendocrine Regulation of the Prion Protein in Neutrophils

Abstract

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.

Activation and function of murine primary microglia in the absence of the prion protein

“…The CD47-Sirpa signaling system, however, also regulates properties of polymorphonuclear cells, such as adhesion, migration and phagocytosis, as well as macrophage-mediated clearance of apoptotic neutrophils, with robust functional consequences (Parkos et al, 1996;Liu et al, 2001;Lawrence et al, 2009;Myers et al, 2011;Zen et al, 2013;Stenberg et al, 2013Stenberg et al, , 2014Greenlee-Wacker et al, 2014). Interestingly, we have found no difference between Prnp-null and wild type neutrophils taken from B10.129Ola mice in their sensitivity to spontaneous or peroxideinduced apoptosis in vitro (Mariante et al, 2012), nor in their recruitment to the peritoneal cavity following in vivo injections of zymosan (R.M. Mariante et al, unpublished results).…”

“…Among the immune cells, PrP C has been implicated in the physiology of lymphocytes, macrophages, dendritic cells, neutrophils and others (Isaacs et al, 2006;Mariante et al, 2012), and a role of PrP C was reported in the activation of microglia (Brown et al, 1998). The latter are mononuclear phagocytes resident in the brain parenchyma, and constitute about 5 to 20% of the total number of glial cells, depending on the specific region of the brain (Lawson et al, 1990;Perry and Gordon, 1991).…”

Prion Protein Modulates Monoaminergic Systems and Depressive-like Behavior in Mice

“…Indeed, the scaffold hypothesis is consistent with the often controversial functional properties assigned to the prion protein, which extend far beyond the nervous system, including immune responses (11,12), cancer biology (6,13), heart oxidative stress (14), glucose homeostasis (15), and stem cell regulation (16,17). Such widespread influence probably depends on the ability of PrP C to bind several partners, varied combinations of which populate the cell surface of distinct cell types (5,10).…”

LPS-induced systemic inflammation reveals an immunomodulatory role for the prion protein at the blood-brain interface

“…Similarly, systemic LPS upregulated PrP C in circulating neutrophils [60], whereas LPS incubation increased PRNP expression in neuronal cell cultures [61]. As expected, PRNP expression was low in PrP C -deficient goats, regardless of treatment, which probably reflects nonsense-mediated mRNA decay [62].…”