Natural IgM Switches the Function of Lipopolysaccharide-Activated XXXX Bone Marrow-Derived Dendritic Cells to a Regulatory Dendritic Cell That Suppresses Innate Inflammation.

@entity1 @entity32 @entity8 @entity558 @entity1992 @entity63 @entity19 @entity1618 @entity14636 @entity3783 @entity3744
UNASSIGNED: We have previously shown that polyclonal natural IgM protects @entity19 from @entity8 /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 @entity1 IgM prior to @entity558 activation and demonstrated that 0.5 * 10(6) IgM/ @entity558 -pretreated BMDC, when injected into wild-type C57BL/6 @entity19 24 h before @entity8 , protect @entity19 from developing renal IRI. We show that this switching of @entity558 -activated BMDC to a regulatory phenotype requires modulation of BMDC function that is mediated by IgM binding to nonapoptotic BMDC receptors. Regulatory BMDC require @entity1618 and programmed death 1 as well as downregulation of @entity14636 and @entity1992 NF-kB phosphorylation to protect in renal IRI. Blocking the programmed death ligand 1 binding site just before i.v. injection of IgM/ @entity558 -pretreated BMDC or using @entity1618 knockout BMDC fails to induce protection. Similarly, IgM/ @entity558 -pretreated BMDC are rendered nonprotective by increasing @entity14636 expression and phosphorylation of @entity1992 NF-kB. How IgM/ @entity558 regulatory BMDC suppress in vivo @entity63 -induced @entity32 remains to be determined. However, we show that suppression is dependent on other in vivo regulatory mechanisms in the host, that is, @entity3783 (+) T cells, B cells, @entity1618 , and circulating IgM. There was no increase in @entity3744 (+) 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 @entity558 that ordinarily induces BMDC maturation.
