Natural IgM switches the function of LPS activated murine bone marrow dendritic cells (BMDC) to a 'regulatory' DC that suppresses innate inflammation1
| Autor: | Lobo, Peter I, Schlegel, Kailo H., Bajwa, Amandeep, Huang, Liping, Kurmaeva, Elvira, Wang, Binru, Ye, Hong, Tedder, Thomas F., Kinsey, Gilbert R., Okusa, Mark D. |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Inflammation
Lipopolysaccharides Mice Knockout B-Lymphocytes Mice Inbred BALB C T-Lymphocytes Programmed Cell Death 1 Receptor Transcription Factor RelA Bone Marrow Cells Dendritic Cells Kidney Lymphocyte Activation Article Interleukin-10 Mice Inbred C57BL Mice Immunoglobulin M Reperfusion Injury Animals CD40 Antigens Phosphorylation Cells Cultured Signal Transduction |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|