Peptidoglycan recognition protein
[1][2][3][4] In mammals, PGRPs either kill bacteria directly by interacting with their cell wall or outer membrane, or hydrolyze peptidoglycan.
Also in 1998, Sergei Kiselev and coworkers independently discovered and cloned a protein from a mouse adenocarcinoma with the same sequence as PGRP, which they named Tag7.
[9] In 2001, Roman Dziarski and coworkers discovered and cloned three human PGRPs, named PGRP-L, PGRP-Iα, and PGRP-Iβ (for long and intermediate size transcripts).
[10] They established that human genome codes for a family of 4 PGRPs: PGRP-S (short PGRP)[6] and PGRP-L, PGRP-Iα, and PGRP-Iβ.
Toll-1 in turn triggers a signal transduction cascade that results in production of antimicrobial peptides primarily active against Gram-positive bacteria and fungi.
[1][2][3][22][23][24][25] Transmembrane PGRPs (e.g., Drosophila PGRP-LC) and intracellular PGRPs (e.g., Drosophila PGRP-LE) function as receptors – they detect m-DAP-containing peptidoglycan and activate IMD (immunodeficiency) signal transduction pathway that induces production of antimicrobial peptides active primarily against Gram-negative bacteria.
[1][2][3][26][27][28] This activation of IMD pathway also induces production of dual oxidase, which generates antimicrobial reactive oxygen species.
[1][29] Some insect PGRPs (e.g., Drosophila PGRP-SA and -LE, and B. mori PGRP-S) activate the prophenoloxidase cascade, which results in the formation of melanin, reactive oxygen species, and other antimicrobial compounds.
[3][5][30][31] Several small insect PGRPs (e.g., Drosophila PGRP-SB, -SC, and -LB) are peptidoglycan hydrolases (N-acetylmuramoyl-L-alanine amidases) that hydrolyzes the amide bond between the MurNAc and L-Ala (the first amino acid in the stem peptide).
[35][36] Some other insect PGRPs (e.g., Drosophila PGRP-LF) do not bind peptidoglycan and lack intracellular signaling domain – they complex with PGRP-LC and function to down-regulate activation of the IMD pathway.
[1][37][38] PGRPs are present and constitutively expressed or induced by bacteria in most invertebrates, including worms,[39] snails,[40] oysters,[41][42] scallops,[43][44] squid,[45] and starfish.
They likely defend the hosts against infections or regulate colonization by certain commensal bacteria, such as Vibrio fischeri in the light organ of Hawaiian bobtail squid, Euprymna scolopes.
[50] These PGRPs have both peptidoglycan-hydrolyzing amidase activity and are directly bactericidal to both Gram-positive and Gram-negative bacteria and protect eggs and developing embryos from bacterial infections.
PGLYRP1 is highly constitutively expressed in the bone marrow and in the granules of neutrophils and eosinophils, and also in activated macrophages, lactating mammary gland, and intestinal Peyer's patches' microfold (M) cells, and to a much lesser extent in epithelial cells in the eye, mouth, and respiratory and intestinal tracts.
[80] Human,[18][58] mouse,[57] and porcine[74] PGLYRP2 are enzymes, N-acetylmuramoyl-L-alanine amidases, that hydrolyze the amide bond between the MurNAc and L-alanine, the first amino acid in the stem peptide in bacterial cell wall peptidoglycan.
[98] Mouse PGRPs also play a role in maintaining anti- and pro-inflammatory homeostasis in the intestine, skin, lungs, joints, and brain.
[73] But PGLYRP2 has also pro-inflammatory effects, as it promotes the development of experimental arthritis,[105] bacterially-induced keratitis,[94] and inflammation in S. pneumoniae lung infection[95] in mice.
[107] PGLYRP1 also has anti-inflammatory effects, as it inhibits the activation of cytotoxic anti-tumor CD8+ T cells and its deletion leads to decreased tumor growth in mice.
[112] PGLYRP1-Hsp70 complexes bind to the TNFR1 (tumor necrosis factor receptor-1, which is a death receptor) and induce a cytotoxic effect via apoptosis and necroptosis.
[116] They also decrease inflammatory responses in a mouse model of acute lung injury[116] and in the complete Freund's adjuvant-induced arthritis in mice.
[153] Umbilical cord blood serum concentration of PGLYRP1 is inversely associated with pediatric asthma and pulmonary function in adolescence.
[154] Increased serum PGLYRP2 levels are present in patients with systemic lupus erythematosus and correlate with disease activity index, renal damage, and abnormal lipid profile.
[156] Decreased expression of PGLYRP2 is found in HIV-associated[157] and drug-sensitive[158] tuberculosis, Lyme disease,[159] hepatocellular carcinoma,[160] and myocardial infarction.
