title: Cutting edge: primary innate immune cells respond efficiently to polymeric peptidoglycan, but not to peptidoglycan monomers.
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.
authors.affiliation: Immunobiology and Cancer Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
authors.forename: Janaki K
authors.initials: JK
authors.lastname: Iyer
authors.forename: K Mark
authors.initials: KM
authors.lastname: Coggeshall
mesh_terms: D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000737:chemistry / Q000378:metabolism; D001408:Bacillus anthracis / Q000276:immunology; D057809:HEK293 Cells; D006801:Humans; D006868:Hydrolysis; D007113:Immunity, Innate; D007424:Intracellular Fluid / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D008247:Lysosomes / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D009000:Monocytes / Q000276:immunology* / Q000378:metabolism* / Q000382:microbiology; D009504:Neutrophils / Q000276:immunology* / Q000378:metabolism* / Q000382:microbiology; D053474:Nod1 Signaling Adaptor Protein / Q000096:biosynthesis / Q000378:metabolism; D053473:Nod2 Signaling Adaptor Protein / Q000096:biosynthesis / Q000378:metabolism; D010457:Peptidoglycan / Q000737:chemistry* / Q000276:immunology* / Q000378:metabolism; D011108:Polymers / Q000737:chemistry / Q000378:metabolism; D021381:Protein Transport / Q000276:immunology
chemical_list: C119067:NOD1 protein, human; C429018:NOD2 protein, human; D053474:Nod1 Signaling Adaptor Protein; D053473:Nod2 Signaling Adaptor Protein; D010457:Peptidoglycan; D011108:Polymers; D000119:Acetylmuramyl-Alanyl-Isoglutamine