Abstract
The proprotein convertase 1/3 is expressed in the regulated secretory pathway of neural and endocrine cells. Its major function is in the post-translational processing and activation of precursor proteins. The PC1/3 knock-out (KO) mouse model has allowed us to elucidate its physiological functions in studies focused primarily on neuroendocrine tissues. However, PC1/3 is also expressed in cells of the immune system, mainly in macrophages. The present study explores the effects of innate immune challenge in the PC1/3 KO mouse. PC1/3 KO mice have an enlarged spleen with marked disorganization of the marginal zone and red pulp. Immunohistochemical studies using various markers demonstrate a depletion of dendritic cells in PC1/3 KO spleens. When challenged with lipopolysaccharide, PC1/3 KO mice are more susceptible to septic shock than wild-type controls or other PC KO mice, such as PC2 and PC7 null mice. Plasma levels of proinflammatory cytokines (IL-6, IL-1β, and TNF-α) were very significantly elevated in PC1/3 KO mice, consistent with a hypercytokinemia, i.e. indicative of a major systemic uncontrolled inflammatory response or cytokine storm. Peritoneal macrophages isolated from PC1/3 KO mice also demonstrate elevated cytokine secretion when treated with LPS. Electron micrographs show morphological features indicating a prolonged activation of these cells following LPS stimulation. We also present evidence that the proinflammatory T(h)1 pathway is dominant in the PC1/3 KO mouse model. We conclude that aside from its important role in neuroendocrine functions PC1/3 also has an important role in the regulation of the innate immune system, most likely through the regulation of cytokine secretion in macrophages.
Highlights
PC1/3 is known for its role in neuroendocrine cells but not for its potential role in innate immunity
Because the spleen is an important immune organ that monitors the circulating blood for infections, especially polysaccharide-encapsulated bacteria [45], and it requires the proper function of antigenpresenting cells (APCs), such as macrophages, dendritic cells (DCs), and B cells
PC1/3 KO mouse studies have primarily focused on the study of the neuroendocrine functions of this convertase [17, 33, 34, 64]
Summary
PC1/3 is known for its role in neuroendocrine cells but not for its potential role in innate immunity. We showed that both neuroendocrine“specific” convertases, namely PC2 and PC1/3, are expressed in macrophages and lymphocytes in vivo [16] and are highly responsive to pathogen-associated molecular pattern challenge. We showed a coordinated induction of proenkephalin (a PC1/3 and PC2 substrate), PC1/3, and PC2 mRNAs as well as proenkephalin-derived peptides (i.e. enkelytin) in macrophage subpopulations [17, 18] These data support the notion of a neuroendocrine phenotypic plasticity in immune cells [19], they show that the expression of PC2 and PC1/3 is regulated by challenges (e.g. pathogen-associated molecular patterns) that activate the innate immune system, suggesting a role in innate immunity. Our data suggest that PC1/3 plays a vital role in the secretory response of macrophages to pathogen challenge
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