Natural IgM switches the function of lipopolysaccharide-activated murine bone marrow-derived dendritic cells to a regulatory dendritic cell that suppresses innate inflammation

Peter I. Lobo, Kailo H. Schlegel, Amandeep Bajwa, Liping Huang, Elvira Kurmaeva, Binru Wang, Hong Ye, Thomas F. Tedder, Gilbert R. Kinsey, Mark D. Okusa

Research output: Contribution to journalArticle

13 Citations (Scopus)

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 3 106 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.

Original languageEnglish (US)
Pages (from-to)5215-5226
Number of pages12
JournalJournal of Immunology
Volume195
Issue number11
DOIs
StatePublished - Dec 1 2015

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Dendritic Cells
Immunoglobulin M
Lipopolysaccharides
Bone Marrow
Inflammation
Reperfusion Injury
Kidney
Interleukin-10
Ischemia
Phosphorylation
Phenotype
Regulatory T-Lymphocytes
Inbred C57BL Mouse
Reperfusion
Leukocytes
B-Lymphocytes
Down-Regulation
Spleen
Binding Sites
Ligands

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

Cite this

Natural IgM switches the function of lipopolysaccharide-activated murine bone marrow-derived dendritic cells to a regulatory dendritic cell that suppresses innate inflammation. / 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.

In: Journal of Immunology, Vol. 195, No. 11, 01.12.2015, p. 5215-5226.

Research output: Contribution to journalArticle

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. / Natural IgM switches the function of lipopolysaccharide-activated murine bone marrow-derived dendritic cells to a regulatory dendritic cell that suppresses innate inflammation. In: Journal of Immunology. 2015 ; Vol. 195, No. 11. pp. 5215-5226.
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T1 - Natural IgM switches the function of lipopolysaccharide-activated murine bone marrow-derived dendritic cells to a regulatory dendritic cell that suppresses innate inflammation

AU - Lobo, Peter I.

AU - Schlegel, Kailo H.

AU - Bajwa, Amandeep

AU - Huang, Liping

AU - Kurmaeva, Elvira

AU - Wang, Binru

AU - Ye, Hong

AU - Tedder, Thomas F.

AU - Kinsey, Gilbert R.

AU - Okusa, Mark D.

PY - 2015/12/1

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N2 - 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 3 106 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.

AB - 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 3 106 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.

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