title: Natural IgM Switches the Function of Lipopolysaccharide-Activated Murine Bone Marrow-Derived Dendritic Cells to a Regulatory Dendritic Cell That Suppresses Innate Inflammation.
abstract: We have previously shown that polyclonal natural IgM protects mice from renal ischemia/reperfusion injury (IRI) by inhibiting the reperfusion inflammatory response. We hypothesized that a potential mechanism involved IgM modulation of dendritic cells (DC), as we observed high IgM binding to splenic DC. To test this hypothesis, we pretreated bone marrow-derived DC (BMDC) with polyclonal murine or human IgM prior to LPS activation and demonstrated that 0.5 × 10(6) IgM/LPS-pretreated BMDC, when injected into wild-type C57BL/6 mice 24 h before renal ischemia, protect mice from developing renal IRI. We show that this switching of LPS-activated BMDC to a regulatory phenotype requires modulation of BMDC function that is mediated by IgM binding to nonapoptotic BMDC receptors. Regulatory BMDC require IL-10 and programmed death 1 as well as downregulation of CD40 and p65 NF-κB phosphorylation to protect in renal IRI. Blocking the programmed death ligand 1 binding site just before i.v. injection of IgM/LPS-pretreated BMDC or using IL-10 knockout BMDC fails to induce protection. Similarly, IgM/LPS-pretreated BMDC are rendered nonprotective by increasing CD40 expression and phosphorylation of p65 NF-κB. How IgM/LPS regulatory BMDC suppress in vivo ischemia-induced innate inflammation remains to be determined. However, we show that suppression is dependent on other in vivo regulatory mechanisms in the host, that is, CD25(+) T cells, B cells, IL-10, and circulating IgM. There was no increase in Foxp3(+) regulatory T cells in the spleen either before or after renal IRI. Collectively, these findings show that natural IgM anti-leukocyte Abs can switch BMDC to a regulatory phenotype despite the presence of LPS that ordinarily induces BMDC maturation.
authors.affiliation: Division of Nephrology, Center for Immunity, Inflammation and Regenerative Medicine, University of Virginia, Charlottesville, VA 22908; and pil@virginia.edu.
authors.forename: Peter I
authors.initials: PI
authors.lastname: Lobo
authors.affiliation: Division of Nephrology, Center for Immunity, Inflammation and Regenerative Medicine, University of Virginia, Charlottesville, VA 22908; and.
authors.forename: Kailo H
authors.initials: KH
authors.lastname: Schlegel
authors.affiliation: Division of Nephrology, Center for Immunity, Inflammation and Regenerative Medicine, University of Virginia, Charlottesville, VA 22908; and.
authors.forename: Amandeep
authors.initials: A
authors.lastname: Bajwa
authors.affiliation: Division of Nephrology, Center for Immunity, Inflammation and Regenerative Medicine, University of Virginia, Charlottesville, VA 22908; and.
authors.forename: Liping
authors.initials: L
authors.lastname: Huang
authors.affiliation: Division of Nephrology, Center for Immunity, Inflammation and Regenerative Medicine, University of Virginia, Charlottesville, VA 22908; and.
authors.forename: Elvira
authors.initials: E
authors.lastname: Kurmaeva
authors.affiliation: Division of Nephrology, Center for Immunity, Inflammation and Regenerative Medicine, University of Virginia, Charlottesville, VA 22908; and.
authors.forename: Binru
authors.initials: B
authors.lastname: Wang
authors.affiliation: Division of Nephrology, Center for Immunity, Inflammation and Regenerative Medicine, University of Virginia, Charlottesville, VA 22908; and.
authors.forename: Hong
authors.identifier: http://orcid.org/0000-0002-1147-2981
authors.initials: H
authors.lastname: Ye
authors.affiliation: Department of Immunology, Duke University Medical Center, Durham, NC 27710.
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Tedder
authors.affiliation: Division of Nephrology, Center for Immunity, Inflammation and Regenerative Medicine, University of Virginia, Charlottesville, VA 22908; and.
authors.forename: Gilbert R
authors.initials: GR
authors.lastname: Kinsey
authors.affiliation: Division of Nephrology, Center for Immunity, Inflammation and Regenerative Medicine, University of Virginia, Charlottesville, VA 22908; and.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Okusa
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D001854:Bone Marrow Cells / Q000276:immunology*; D019013:CD40 Antigens / Q000378:metabolism; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology*; D007075:Immunoglobulin M / Q000276:immunology*; D007249:Inflammation / Q000276:immunology*; D016753:Interleukin-10 / Q000276:immunology; D007668:Kidney / Q000098:blood supply*; D008070:Lipopolysaccharides / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation; D061026:Programmed Cell Death 1 Receptor / Q000276:immunology; D015427:Reperfusion Injury / Q000276:immunology / Q000517:prevention & control*; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D051996:Transcription Factor RelA / Q000378:metabolism
chemical_list: D019013:CD40 Antigens; C556062:IL10 protein, mouse; D007075:Immunoglobulin M; D008070:Lipopolysaccharides; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; D016753:Interleukin-10