Control of intestinal Nod2-mediated peptidoglycan recognition by epithelium-associated lymphocytes.
Innate immune recognition of the bacterial cell wall constituent peptidoglycan by the cytosolic nucleotide-binding oligomerization domain 2 (Nod2) receptor has a pivotal role in the maintenance of intestinal mucosal homeostasis. Whereas peptidoglycan cleavage by gut-derived lysozyme preserves the recognition motif, the N-acetylmuramoyl-L-alanine amidase activity of the peptidoglycan recognition protein 2 (PGLYRP-2) destroys the Nod2-detected muramyl dipeptide structure. PGLYRP-2 green fluorescent protein (GFP) reporter and wild-type mice were studied by flow cytometry and quantitative RT-PCR to identify Pglyrp-2 expression in cells of the intestinal mucosa and reveal a potential regulatory function on epithelial peptidoglycan recognition. CD3(+)/CD11c(+) T lymphocytes revealed significant Pglyrp-2 expression, whereas epithelial cells and intestinal myeloid cells were negative. The mucosal Pglyrp-2-expressing lymphocyte population demonstrated a mixed T-cell receptor (TCR) αβ or γδ phenotype with predominant CD8α and less so CD8β expression, as well as significant staining for the activation markers B220 and CD69, presenting a typical intraepithelial lymphocyte phenotype. Importantly, exposure of peptidoglycan to PGLYRP-2 significantly reduced Nod2/Rip2-mediated epithelial activation. Also, moderate but significant alterations of the intestinal microbiota composition were noted in Pglyrp-2-deficient animals. PGLYRP-2 might thus have a significant role in regulation of the enteric host-microbe homeostasis.
Duerr
C U
CU
Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany.
Salzman
N H
NH
Dupont
A
A
Szabo
A
A
Normark
B H
BH
Normark
S
S
Locksley
R M
RM
Mellroth
P
P
Hornef
M W
MW
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D002478:Cells, Cultured; D005818:Genetic Engineering; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D054884:Host-Pathogen Interactions; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D008213:Lymphocyte Activation; D054892:Metagenome; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009238:N-Acetylmuramoyl-L-alanine Amidase / Q000378:metabolism*; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D010457:Peptidoglycan / Q000276:immunology; D011506:Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology
D015703:Antigens, CD; D053473:Nod2 Signaling Adaptor Protein; C495945:Nod2 protein, mouse; D010457:Peptidoglycan; D011506:Proteins; D011948:Receptors, Antigen, T-Cell; D049452:Green Fluorescent Proteins; D009238:N-Acetylmuramoyl-L-alanine Amidase; C416533:Pglyrp2 protein, mouse