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’, whereas in NOD1/2 double knockout mice, which cannot recognize peptidoglycan, programmed death-ligand 1 was undetected. Our results explain a role for constitutively formed calcium phosphate nanoparticles in the gut lumen and show how this helps to shape intestinal immune homeostasis.
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The authors thank the UK Medical Research Council (grant no. U105960399) for their continued support and the UK Engineering and Physical Sciences Research Council for support of the Ion Beam Centre as a UK National Facility (GR/R50097). The authors acknowledge the Dairy Council and the Sir Halley Stewart Trust for support. Work in the laboratory of J.D.L is supported by the Dutch MS Research Foundation. The authors thank M-J. Melief for help in modifying in situ techniques for the detection of peptidoglycan and I. Stroo for providing snap-frozen NOD1/2−/− samples from mice originally from S.E.G.'s laboratory. The authors thank J. Kaufman, A. Wyllie and P. Mastroeni (all University of Cambridge) for brainstorming and advice. J.C.H-G. and P.A.M. acknowledge financial support from the European Union's Seventh Framework Programme under a contract for an Integrated Infrastructure Initiative (reference no. 312483-ESTEEM2). P.A.M. also acknowledges financial support from the European Research Council (reference 291,522 3DIMAGE). N.A.M. and D.S.D. were supported by projects BB/J014762/1 and BB/K021257/1 and institute strategic programme grant funding from the Biological and Biotechnological Research Council. I.R.W. and D.R. were supported by grants from the National Institutes of Health (DK064730 and AI111388).
The authors declare no competing financial interests.
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Powell, J., Thomas-McKay, E., Thoree, V. et al. An endogenous nanomineral chaperones luminal antigen and peptidoglycan to intestinal immune cells. Nature Nanotech 10, 361–369 (2015). https://doi.org/10.1038/nnano.2015.19
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