scholarly journals Human peptidoglycan recognition protein S is an effector of neutrophil-mediated innate immunity

Blood ◽  
2005 ◽  
Vol 106 (7) ◽  
pp. 2551-2558 ◽  
Author(s):  
Ju Hyun Cho ◽  
Iain P. Fraser ◽  
Koichi Fukase ◽  
Shoichi Kusumoto ◽  
Yukari Fujimoto ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Antimicrobial Effect ◽  
Protein S ◽  
Host Recognition ◽  
Human Neutrophils ◽  
Peptidoglycan Recognition Protein ◽  
Acid Type ◽  
Potential Synergy ◽  
Recognition Protein ◽  
Bacterial Peptidoglycan

AbstractInnate immune responses to bacteria require cooperative interactions between host recognition molecules and phagocytes. The peptidoglycan recognition proteins (PGRPs) are a large group of proteins found in insects and mammals that bind to bacterial peptidoglycan (PGN). PGRP-S is located with other antimicrobial proteins, such as lysozyme, in the granules of human neutrophils. Whereas both PGRP-S and lysozyme recognize PGN, the exact binding specificity of human PGRP-S, its functional activity, and its potential synergy with other neutrophil-derived bactericidal proteins such as lysozyme have not been determined. Here we show that human PGRP-S binds to and inhibits the growth of Staphylococcus aureus (containing lysine-type PGN) and Escherichia coli (containing mesodiaminopimelic acid-type PGN). The binding affinity and thus antimicrobial activity of PGRP-S is determined by the third amino acid in the PGN stem peptide. Furthermore, the antimicrobial effect of PGRP-S against E coli is synergistic with lysozyme, and lysozyme and PGRP-S colocalize in neutrophil extracellular traps (NETs), suggesting that these granule-derived proteins act together to kill bacteria trapped in the NETs. Taken together, these results indicate that human PGRP-S plays a role in innate immunity in the context of neutrophils by contributing to the killing of intracellular and extracellular bacteria. (Blood. 2005;106:2551-2558)

scholarly journals The Frameshift Mutation in Nod2 Results in Unresponsiveness Not Only to Nod2- but Also Nod1-activating Peptidoglycan Agonists

2005 ◽  
Vol 280 (43) ◽  
pp. 35859-35867 ◽  
Author(s):  
Mihai G. Netea ◽  
Gerben Ferwerda ◽  
Dirk J. de Jong ◽  
Catherine Werts ◽  
Ivo G. Boneca ◽  
...  
Keyword(s):  
Crohn Disease ◽  
Frameshift Mutation ◽  
Susceptibility Gene ◽  
Muramyl Dipeptide ◽  
Protein S ◽  
Diaminopimelic Acid ◽  
Gram Negative ◽  
Peptidoglycan Recognition Protein ◽  
Recognition Protein ◽  
Bacterial Peptidoglycan

NOD2/CARD15 is the first characterized susceptibility gene in Crohn disease. The Nod2 1007fs (Nod2fs) frameshift mutation is the most prevalent in Crohn disease patients. Muramyl dipeptide from bacterial peptidoglycan is the minimal motif detected by Nod2 but not by Nod2fs. Here we investigated the response of human peripheral blood mononuclear cells (PBMCs) from Crohn disease patients not only to muramyl dipeptide but also to several other muramyl peptides. Most unexpectedly, we observed that patients homozygous for the Nod2fs mutation were totally unresponsive to MurNAc-l-Ala-d-Glu-meso-diaminopimelic acid (DAP) (M-TriDAP), the specific agonist of Nod1, and to Gram-negative bacterial peptidoglycan. In contrast, PBMCs from a patient homozygous for the Nod2 R702W mutation, also associated with Crohn disease, displayed normal response to Gram-negative bacterial peptidoglycan. In addition, the blockage of the Nod1/M-TriDAP pathway could be partially overcome by co-stimulation with the Toll-like receptors agonists lipoteichoic acid or lipopolysaccharide. Investigation into the mechanism of this finding revealed that Nod2fs did not act as a dominant-negative molecule for the Nod1/M-TriDAP pathway, implying that the blockage is dependent upon the expression or activity of other factors. We demonstrated that PBMCs from Nod2fs patients express high levels of the peptidoglycan recognition protein S, a secreted protein known to interact with muramyl peptides. We proposed that through a scavenger function, peptidoglycan recognition protein S may dampen M-TriDAP-dependent responses in Nod2fs patients. Together, our results identified a cross-talk between the Nod1 and Nod2 pathways and suggested that down-regulation of Nod1/M-TriDAP pathway may be associated with Crohn disease.

Defect in neutrophil killing and increased susceptibility to infection with nonpathogenic gram-positive bacteria in peptidoglycan recognition protein-S (PGRP-S)–deficient mice

Blood ◽  
2003 ◽  
Vol 102 (2) ◽  
pp. 689-697 ◽  
Author(s):  
Roman Dziarski ◽  
Kenneth A. Platt ◽  
Eva Gelius ◽  
Håkan Steiner ◽  
Dipika Gupta
Keyword(s):  
Inflammatory Responses ◽  
Protein S ◽  
Intracellular Killing ◽  
Gram Positive ◽  
Peptidoglycan Recognition Protein ◽  
Susceptibility To Infection ◽  
Gram Positive Bacteria ◽  
Recognition Protein ◽  
Factor Α ◽  
Increased Susceptibility

AbstractInsect peptidoglycan recognition protein-S (PGRP-S), a member of a family of innate immunity pattern recognition molecules conserved from insects to mammals, recognizes bacterial cell wall peptidoglycan and activates 2 antimicrobial defense systems, prophenoloxidase cascade and antimicrobial peptides through Toll receptor. We show that mouse PGRP-S is present in neutrophil tertiary granules and that PGRP-S–deficient (PGRP-S-/-) mice have increased susceptibility to intraperitoneal infection with gram-positive bacteria of low pathogenicity but not with more pathogenic gram-positive or gram-negative bacteria. PGRP-S-/- mice have normal inflammatory responses and production of tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6). Neutrophils from PGRP-S-/- mice have normal phagocytic uptake of bacteria but are defective in intracellular killing and digestion of relatively nonpathogenic gram-positive bacteria. Therefore, mammalian PGRP-S functions in intracellular killing of bacteria. Thus, only bacterial recognition by PGRP-S, but not its effector function, is conserved from insects to mammals.

Crystal Structure of Human Peptidoglycan Recognition Protein S (PGRP-S) at 1.70Å Resolution

2005 ◽  
Vol 347 (4) ◽  
pp. 683-691 ◽  
Author(s):  
Rongjin Guan ◽  
Qian Wang ◽  
Eric J. Sundberg ◽  
Roy A. Mariuzza
Keyword(s):  
Crystal Structure ◽  
Protein S ◽  
Peptidoglycan Recognition Protein ◽  
Recognition Protein

Peptidoglycan recognition protein-S (PGRP-S) is upregulated by NF-κB

2008 ◽  
Vol 430 (2) ◽  
pp. 138-141 ◽  
Author(s):  
Ming-Fei Lang ◽  
Armin Schneider ◽  
Carola Krüger ◽  
Roland Schmid ◽  
Roman Dziarski ◽  
...  
Keyword(s):  
Protein S ◽  
Peptidoglycan Recognition Protein ◽  
Recognition Protein

scholarly journals A peptidoglycan recognition protein in innate immunity conserved from insects to humans

1998 ◽  
Vol 95 (17) ◽  
pp. 10078-10082 ◽  
Author(s):  
D. Kang ◽  
G. Liu ◽  
A. Lundstrom ◽  
E. Gelius ◽  
H. Steiner
Keyword(s):  
Innate Immunity ◽  
Peptidoglycan Recognition Protein ◽  
Recognition Protein

scholarly journals Peptidoglycan Recognition Protein 2 (N-Acetylmuramoyl-l-Ala Amidase) Is Induced in Keratinocytes by Bacteria through the p38 Kinase Pathway

2005 ◽  
Vol 73 (11) ◽  
pp. 7216-7225 ◽  
Author(s):  
Haitao Wang ◽  
Dipika Gupta ◽  
Xinna Li ◽  
Roman Dziarski
Keyword(s):  
Specific Inhibitor ◽  
Dominant Negative ◽  
Mitogen Activated Protein Kinase ◽  
Keratinocyte Differentiation ◽  
Differentiation Markers ◽  
Healthy Human ◽  
Peptidoglycan Recognition Protein ◽  
Mitogen Activated Protein ◽  
Recognition Protein ◽  
Bacterial Peptidoglycan

ABSTRACT Human peptidoglycan recognition protein 2 (PGLYRP2) is an N-acetylmuramoyl-l-alanine amidase that hydrolyzes bacterial peptidoglycan and is constitutively produced in the liver and secreted into the blood. Here we demonstrate that PGLYRP2 was not expressed in healthy human skin and had low expression in the eye. However, upon exposure to gram-positive and gram-negative bacteria or cytokines, PGLYRP2 expression was highly induced in keratinocytes and to a lower level in corneal epithelial cells. Expression of PGLYRP2 was not induced in nonepithelial cells. Exposure of keratinocytes to bacteria induced keratinocyte differentiation and stress response and inhibited activation of signal transduction molecules involved in cell proliferation. Induction of PGLYRP2 expression correlated with expression of differentiation markers (cytokeratins and transglutaminase). Bacteria induced activation of p38 mitogen-activated protein kinase (MAPK) in keratinocytes, which was required for the induction of PGLYRP2 expression, because induction of PGLYRP2 transcription by bacteria was inhibited by SB203580 (a specific inhibitor of p38 MAPK) and by a dominant-negative p38 construct. Induction of PGLYRP2 expression by bacteria (in contrast to expression of human β-defensin-2) was not mediated by Toll-like receptor 2 or 4. PGLYRP2 may function in the skin and the eyes as an inducible scavenger of proinflammatory peptidoglycan.

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