Cutting Edge: Primary Innate Immune Cells Respond Efficiently to Polymeric Peptidoglycan, but Not to Peptidoglycan Monomers

Overview

Journal J Immunol

Specialty Allergy & Immunology

Date 2011 Mar 2

PMID 21357534

Citations 25

Authors

Janaki K Iyer

K Mark Coggeshall

Affiliations

Soon will be listed here.

Abstract

The cell wall of bacteria induces proinflammatory cytokines in monocytes and neutrophils in human blood. The nature of the stimulating component of bacterial cell walls is not well understood. We have previously shown polymeric peptidoglycan (PGN) has this activity, and the cytokine response requires PGN internalization and trafficking to lysosomes. In this study, we demonstrate that peptidoglycan monomers such as muramyl dipeptide and soluble peptidoglycan fail to induce robust cytokine production in immune cells, although they activate the nucleotide-binding oligomerization domain proteins in transfected cell models. We further show that lysosomal extracts from immune cells degrade intact peptidoglycan into simpler products and that the lysosomal digestion products activate the nucleotide-binding oligomerization domain proteins. We conclude that naive innate immune cells recognize PGN in its polymeric form rather than monomers such as muramyl dipeptide and require PGN lysosomal hydrolysis to respond. These findings offer new opportunities in the treatment of sepsis, especially sepsis arising from Gram-positive organisms.

Citing Articles

Monocyte uptake of polymeric peptidoglycan is bimodal and governed by complement C3 and C4 opsonins.

Popescu N, Kluza J, Reidy M, Duggan E, Lambris J, Thompson L JCI Insight. 2024; 10(2).

PMID: 39656526 PMC: 11790019. DOI: 10.1172/jci.insight.186346.

Gram-Positive Bacteria Cell Wall Peptidoglycan Polymers Activate Human Dendritic Cells to Produce IL-23 and IL-1β and Promote T17 Cell Differentiation.

Turner S, Raisley B, Roach K, Bajana S, Munroe M, James J Microorganisms. 2023; 11(1).

PMID: 36677464 PMC: 9867153. DOI: 10.3390/microorganisms11010173.

Chemically Modified Bacterial Sacculi as a Vaccine Microparticle Scaffold.

Weidenbacher P, Rodriguez-Rivera F, Sanyal M, Visser J, Do J, Bertozzi C ACS Chem Biol. 2022; 17(5):1184-1196.

PMID: 35412807 PMC: 9127789. DOI: 10.1021/acschembio.2c00140.

Internalization of Polymeric Bacterial Peptidoglycan Occurs through Either Actin or Dynamin Dependent Pathways.

Popescu N, Cochran J, Duggan E, Kluza J, Silasi R, Coggeshall K Microorganisms. 2022; 10(3).

PMID: 35336127 PMC: 8951193. DOI: 10.3390/microorganisms10030552.

Complement C5 inhibition protects against hemolytic anemia and acute kidney injury in anthrax peptidoglycan-induced sepsis in baboons.

Keshari R, Popescu N, Silasi R, Regmi G, Lupu C, Simmons J Proc Natl Acad Sci U S A. 2021; 118(37).

PMID: 34507997 PMC: 8449412. DOI: 10.1073/pnas.2104347118.

References

Rockel C, Hartung T, Hermann C . Different Staphylococcus aureus whole bacteria mutated in putative pro-inflammatory membrane components have similar cytokine inducing activity. Immunobiology. 2010; 216(3):316-21. DOI: 10.1016/j.imbio.2010.08.001. View

Schleifer K, Kandler O . Peptidoglycan types of bacterial cell walls and their taxonomic implications. Bacteriol Rev. 1972; 36(4):407-77. PMC: 408328. DOI: 10.1128/br.36.4.407-477.1972. View

Girardin S, Boneca I, Carneiro L, Antignac A, Jehanno M, Viala J . Nod1 detects a unique muropeptide from gram-negative bacterial peptidoglycan. Science. 2003; 300(5625):1584-7. DOI: 10.1126/science.1084677. View

Lee J, Tattoli I, Wojtal K, Vavricka S, Philpott D, Girardin S . pH-dependent internalization of muramyl peptides from early endosomes enables Nod1 and Nod2 signaling. J Biol Chem. 2009; 284(35):23818-29. PMC: 2749154. DOI: 10.1074/jbc.M109.033670. View

Coulombe F, Divangahi M, Veyrier F, de Leseleuc L, Gleason J, Yang Y . Increased NOD2-mediated recognition of N-glycolyl muramyl dipeptide. J Exp Med. 2009; 206(8):1709-16. PMC: 2722178. DOI: 10.1084/jem.20081779. View

Volz T, Nega M, Buschmann J, Kaesler S, Guenova E, Peschel A . Natural Staphylococcus aureus-derived peptidoglycan fragments activate NOD2 and act as potent costimulators of the innate immune system exclusively in the presence of TLR signals. FASEB J. 2010; 24(10):4089-102. DOI: 10.1096/fj.09-151001. View

Shimada T, Park B, Wolf A, Brikos C, Goodridge H, Becker C . Staphylococcus aureus evades lysozyme-based peptidoglycan digestion that links phagocytosis, inflammasome activation, and IL-1beta secretion. Cell Host Microbe. 2010; 7(1):38-49. PMC: 2818986. DOI: 10.1016/j.chom.2009.12.008. View

Clark N, Marinis J, Cobb B, Abbott D . MEKK4 sequesters RIP2 to dictate NOD2 signal specificity. Curr Biol. 2008; 18(18):1402-8. PMC: 2581469. DOI: 10.1016/j.cub.2008.07.084. View

Girardin S, Boneca I, Viala J, Chamaillard M, Labigne A, Thomas G . Nod2 is a general sensor of peptidoglycan through muramyl dipeptide (MDP) detection. J Biol Chem. 2003; 278(11):8869-72. DOI: 10.1074/jbc.C200651200. View

10.

Melmed G, Thomas L, Lee N, Tesfay S, Lukasek K, Michelsen K . Human intestinal epithelial cells are broadly unresponsive to Toll-like receptor 2-dependent bacterial ligands: implications for host-microbial interactions in the gut. J Immunol. 2003; 170(3):1406-15. DOI: 10.4049/jimmunol.170.3.1406. View

11.

Langer M, Malykhin A, Maeda K, Chakrabarty K, Williamson K, Feasley C . Bacillus anthracis peptidoglycan stimulates an inflammatory response in monocytes through the p38 mitogen-activated protein kinase pathway. PLoS One. 2008; 3(11):e3706. PMC: 2577892. DOI: 10.1371/journal.pone.0003706. View

12.

Hitotsumatsu O, Ahmad R, Tavares R, Wang M, Philpott D, Turer E . The ubiquitin-editing enzyme A20 restricts nucleotide-binding oligomerization domain containing 2-triggered signals. Immunity. 2008; 28(3):381-90. PMC: 3606373. DOI: 10.1016/j.immuni.2008.02.002. View

13.

Bertrand M, Doiron K, Labbe K, Korneluk R, Barker P, Saleh M . Cellular inhibitors of apoptosis cIAP1 and cIAP2 are required for innate immunity signaling by the pattern recognition receptors NOD1 and NOD2. Immunity. 2009; 30(6):789-801. DOI: 10.1016/j.immuni.2009.04.011. View

14.

Girardin S, Travassos L, Herve M, Blanot D, Boneca I, Philpott D . Peptidoglycan molecular requirements allowing detection by Nod1 and Nod2. J Biol Chem. 2003; 278(43):41702-8. DOI: 10.1074/jbc.M307198200. View

15.

Chamaillard M, Hashimoto M, Horie Y, Masumoto J, Qiu S, Saab L . An essential role for NOD1 in host recognition of bacterial peptidoglycan containing diaminopimelic acid. Nat Immunol. 2003; 4(7):702-7. DOI: 10.1038/ni945. View

16.

Pryzwansky K, Martin L, Spitznagel J . Immunocytochemical localization of myeloperoxidase, lactoferrin, lysozyme and neutral proteases in human monocytes and neutrophilic granulocytes. J Reticuloendothel Soc. 1978; 24(3):295-310. View

17.

Wolfert M, Murray T, Boons G, Moore J . The origin of the synergistic effect of muramyl dipeptide with endotoxin and peptidoglycan. J Biol Chem. 2002; 277(42):39179-86. DOI: 10.1074/jbc.M204885200. View

18.

Mogensen T . Pathogen recognition and inflammatory signaling in innate immune defenses. Clin Microbiol Rev. 2009; 22(2):240-73, Table of Contents. PMC: 2668232. DOI: 10.1128/CMR.00046-08. View

19.

Travassos L, Girardin S, Philpott D, Blanot D, Nahori M, Werts C . Toll-like receptor 2-dependent bacterial sensing does not occur via peptidoglycan recognition. EMBO Rep. 2004; 5(10):1000-6. PMC: 1299148. DOI: 10.1038/sj.embor.7400248. View

20.

Marina-Garcia N, Franchi L, Kim Y, Hu Y, Smith D, Boons G . Clathrin- and dynamin-dependent endocytic pathway regulates muramyl dipeptide internalization and NOD2 activation. J Immunol. 2009; 182(7):4321-7. PMC: 2753867. DOI: 10.4049/jimmunol.0802197. View