title: Signaling through CD14 attenuates the inflammatory response to Borrelia burgdorferi, the agent of Lyme disease.
abstract: Lyme disease is a chronic inflammatory disorder caused by the spirochetal bacterium, Borrelia burgdorferi. In vitro evidence suggests that binding of spirochetal lipoproteins to CD14, a pattern recognition receptor expressed on monocytes/macrophages and polymorphonuclear cells, is a critical requirement for cellular activation and the subsequent release of proinflammatory cytokines that most likely contribute to symptomatology and clinical manifestations. To test the validity of this notion, we assessed the impact of CD14 deficiency on Lyme disease in C3H/HeN mice. Contrary to an anticipated diminution in pathology, CD14(-/-) mice exhibited more severe and persistent inflammation than did CD14(+/+) mice. This disparity reflects altered gene regulation within immune cells that may engender the higher bacterial burden and serum cytokine levels observed in CD14(-/-) mice. Comparing their in vitro stimulatory activity, live spirochetes, but not lysed organisms, were a potent CD14-independent stimulus of cytokine production, triggering an exaggerated response by CD14(-/-) macrophages. Collectively, our in vivo and in vitro findings support the provocative notion that: 1) pattern recognition by CD14 is entirely dispensable for elaboration of an inflammatory response to B. burgdorferi, and 2) CD14-independent signaling pathways are inherently more destructive than CD14-dependent pathways. Continued study of CD14-independent signaling pathways may provide mechanistic insight into the inflammatory processes that underlie development of chronic inflammation.
authors.affiliation: Center for Immunology and Microbial Disease, Albany Medical College, Albany, NY12208, USA.
authors.forename: Mohammed Rafii-El-Idrissi
authors.initials: MR
authors.lastname: Benhnia
authors.forename: Danielle
authors.initials: D
authors.lastname: Wroblewski
authors.forename: Muhammad Naveed
authors.initials: MN
authors.lastname: Akhtar
authors.forename: Raina A
authors.initials: RA
authors.lastname: Patel
authors.forename: Wendy
authors.initials: W
authors.lastname: Lavezzi
authors.forename: Sophie C
authors.initials: SC
authors.lastname: Gangloff
authors.forename: Sanna M
authors.initials: SM
authors.lastname: Goyert
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: Caimano
authors.forename: Justin D
authors.initials: JD
authors.lastname: Radolf
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Sellati
mesh_terms: D000818:Animals; D025065:Borrelia burgdorferi / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis / Q000097:blood / Q000235:genetics; D007113:Immunity, Innate / Q000235:genetics; D018836:Inflammation Mediators / Q000097:blood / Q000502:physiology*; D018950:Lipopolysaccharide Receptors / Q000235:genetics / Q000502:physiology*; D008193:Lyme Disease / Q000235:genetics / Q000276:immunology* / Q000382:microbiology / Q000473:pathology*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D051379:Mice; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000096:biosynthesis; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D013583:Synovial Membrane / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D051193:Toll-Like Receptors; D014158:Transcription, Genetic / Q000276:immunology
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D018950:Lipopolysaccharide Receptors; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D051193:Toll-Like Receptors