An endogenous nanomineral chaperones luminal antigen and peptidoglycan to intestinal immune cells

Abstract

In humans and other mammals, it is known that calcium and phosphate ions are secreted from the distal small intestine into the lumen. However, why this secretion occurs is unclear. Here, we show that the process leads to the formation of amorphous magnesium-substituted calcium phosphate nanoparticles that trap soluble macromolecules, such as bacterial peptidoglycan and orally-fed protein antigens, in the lumen and transport them to immune cells of the intestinal tissue. The macromolecule-containing nanoparticles utilize epithelial M cells to enter Peyer’s patches - small areas of the intestine concentrated with particle-scavenging immune cells. In wild type mice, intestinal immune cells containing these naturally-formed nanoparticles expressed the immune tolerance-associated molecule ‘programmed death-ligand 1 (PD-L1)’, whereas in NOD1/2 double knock-out mice, which cannot recognize peptidoglycan, PD-L1 was undetected. Our results explain a role for constitutively formed calcium phosphate nanoparticles in the gut lumen and how this helps to shape intestinal immune homeostasis.

Increased Abundance of M Cells in the Gut Epithelium Dramatically Enhances Oral Prion Disease Susceptibility

“…Therefore, systemic RANKL neutralization by treatment with anti-RANKL antibody could have affected other important cellular processes involved in prion pathogenesis. To exclude these, we used a more refined model of M cell-deficiency, RANK ΔIEC mice [23, 38], to further elucidate the role of M cells in the transport of prions from the intestinal lumen into GALT. These mice are specifically deficient in Tnfrsf11a (which encodes RANK) only in Vil1 -expressing intestinal epithelial cells.…”

“…However, since RANKL-RANK signalling has multiple roles in the immune system, a more refined model is required to specifically determine the role of M cells in oral prion disease pathogenesis. In the current study a unique conditional knockout mouse model was used in which RANK expression was specifically deleted only in the intestinal epithelium (RANK ΔIEC mice) [23, 38]. In these mice the complete loss of M cells prevents M cell-mediated antigen uptake from the gut lumen, without altering other RANKL-RANK signalling events required for normal immune development and function [23, 38].…”

“…In the current study a unique conditional knockout mouse model was used in which RANK expression was specifically deleted only in the intestinal epithelium (RANK ΔIEC mice) [23, 38]. In these mice the complete loss of M cells prevents M cell-mediated antigen uptake from the gut lumen, without altering other RANKL-RANK signalling events required for normal immune development and function [23, 38]. Using these mice our data clearly show that M cells are critically required for the initial trans-epithelial transfer of prions across the gut epithelium into Peyer’s patches in order to establish host infection.…”

Brain microbiota disruption within inflammatory demyelinating lesions in multiple sclerosis

“…The bacterial sequences detected in the present studies of human brain resemble those of environmental (soil-derived) bacteria28, largely without human disease associations. Phagocytes including macrophages, neutrophils and dendritic cells can engulf live microbes or microbial compounds at different mucosal sites29. Polymicrobial species have been detected in human blood, particularly in leucocytes including neutrophils and macrophages30.…”

Materials design at the interface of nanoparticles and innate immunity

“…However, amorphous nanoparticles made of calcium phosphate have recently been posited to have a critical, endogenous role in generating tolerance to gut microbial products 73 . In this study, the authors investigated amorphous calcium phosphate particles and their interactions with Peyer's patches, lymphoid tissue structures found in the gut.…”