Regulation of intestinal microbiota by the NLR protein family

Abstract

The human intestine harbors a diverse microbial community consisting of a large number of bacteria and other micro-organisms that have co-evolved with the host intestinal immune system. During this process, microbiota and the host immune system shape one another by various mechanisms to achieve a successful symbiotic relationship. An increasing amount of evidence suggests that dysbiosis--the breakdown of such harmonized colonization--may result in infectious and inflammatory disorders, and recent advances in our studies indicate that receptors such as Toll-like receptors and NLR (nucleotide-binding oligomerization domain-like receptor; or nucleotide-binding domain- and leucine-rich repeat-containing receptor) proteins that detect micro-organisms and their products play a critical role in maintaining intestinal homeostasis. In this review, we summarize the role of NLR proteins in the regulation of intestinal microbiota. NLR proteins belong to a diverse family of cytoplasmic microbial sensors, mutations of which are involved in various disorders, including inflammatory bowel diseases. Understanding of the different roles of NLR family proteins in the intestine is, therefore, an important step towards the development of therapeutics against digestive diseases.

Fig. 1.

Epithelial barriers of the intestine. The human intestine has developed multiple strategies to protect the intestinal epithelial cells from invasion by resident and pathogenic bacteria. Enterocytes, the most abundant cell type in the intestinal epithelium, secrete anti-microbial proteins such as RegIIIγ. Paneth cells, which are specialized epithelial cells in the ileal crypts, produce abundant anti-microbial compounds such as α-defensins to regulate bacterial populations. Goblet cells produce mucin glycoproteins, constituents of the mucus layer, where anti-microbial proteins are enriched and resistance against bacteria is enforced. Sampling of bacterial products by dendritic cells (DCs) through their dendrites or by M cells via transcytosis leads to antigen presentation to the lymphocytes in Peyer’s patches. This results in the development of plasma cells, which produce and secrete IgA into the luminal surface of the intestine.

Fig. 2.

Structures of NLR protein family. NLR proteins are classified into subfamilies by protein-interaction domains such as CARD or PYRIN. NBDs [NACHT (NAIP CIITA HET-E TP1) domains or NODs] and LRRs are domains common to all NLRs. Two major subfamilies are the CARD- and PYRIN-containing subfamilies. (A) Schema of basic structure of NLR proteins. (B) Representatives of the of the NLRC (NLR family, CARD containing) subfamily proteins. (C) Representatives of the NLRP (NLR family, PYRIN containing) subfamily proteins. (D) An example from the other NLR subfamily, NAIP5. Birc1e, baculovirus inhibitor of apoptosis protein repeat c1e.

Fig. 3.

NOD2-mediated regulation of bacteria by Paneth cells. (A) With functional NOD2, Paneth cells sense bacteria or bacterial antigens and release anti-microbial peptides, which keep the intestinal flora under control. (B) Deletion of NOD2 or the presence of a NOD2 ‘loss of function’ mutation renders Paneth cells non-functional. Lack of Paneth cell-derived antibacterial compounds leads to dysregulated bacterial colonization of the intestinal mucosa and breakdown of homeostasis.