Sphingosine 1-Phosphate Receptor 3–Deficient Dendritic Cells Modulate Splenic Responses to Ischemia-Reperfusion Injury

Bajwa, Amandeep; Huang, Liping; Kurmaeva, Elvira; Gigliotti, Joseph C.; Zhang, Pengcheng; Miller, James; Rosin, Diane L.; Lobo, Peter I.; Okusa, Mark D.

doi:10.1681/asn.2015010095

Cited by 53 publications

(51 citation statements)

References 65 publications

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“…Another possibility is that regulatory DC could inhibit innate mediated inflammatory responses through other mechanisms. For example, in a similar murine model of renal IRI, 0.5 × 10 6 regulatory BMDC, generated by pretreatment with an A2aR agonist, suppressed the innate inflammatory response by altering the function of effector cells through mechanism that did not increase Tregs (17). Data in our studies would indicate that the infused IgM/LPS pretreated regulatory BMDC instruct the host regulatory mechanisms via production of anti-inflammatory cytokines (e.g IL10) and the PD1 receptor.…”

Section: Discussionmentioning

confidence: 99%

“…Cell lysates isolated from BMDC pretreated with IgM and LPS (400ng/ml) at 37°C for 1 hr were subjected to Western blotting using previously published techniques (17). Tubulin was detected with mouse anti-β-tubulin (clone 3F3-G2, Santa Cruz Biotechnology, Dallas, TX) and a secondary IRDye 800CW labelled goat anti-mouse (LI-COR Biosciences, Lincoln,NE).…”

Section: Methodsmentioning

confidence: 99%

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

Lobo

Schlegel

Bajwa

et al. 2015

The Journal of Immunology

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We have previously shown that polyclonal natural IgM protects mice from renal IRI by inhibiting the reperfusion inflammatory response. We hypothesized that a potential mechanism involved IgM modulation of dendritic cells as we observed high IgM binding to splenic DC. To test this hypothesis, we pre-treated BMDC with polyclonal murine or human IgM prior to LPS activation and demonstrate that 0.5 × 106 IgM/LPS pretreated BMDC, when injected into WT-B6 mice, 24 hours 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 non-apoptotic BMDC receptors. Regulatory BMDC require IL-10 and PD1 as well as downregulation of CD40 and p65NF-κB phosphorylation to protect in renal IRI. Blocking the PD1 ligand binding site just before intravenous injection of IgM/LPS pretreated BMDC or using IL-10ko BMDC fails to induce protection. Similarly, IgM/LPS pretreated BMDC are rendered non-protective by increasing CD40 expression and phosphorylation of p65NF-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 i.e. CD25+ T cells, B cells, IL10 and circulating IgM. There was no increase in Foxp3+ Tregs in the spleen either before or after renal IRI. Collectively, these findings show that natural IgM anti-leucocyte antibodies can switch BMDC to a regulatory phenotype despite the presence of LPS that ordinarily induces BMDC maturation.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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

Lobo

Schlegel

Bajwa

et al. 2015

The Journal of Immunology

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“…TNF-α, chemokine (C-C motif) ligand 2, and C-X-C motif chemokine 10) by renal cells. A recent study by Bajwa et al [73] has also shown that bone marrow-derived dendritic cells deficient in sphingosine 1-phosphate receptor 3 can prevent ischemia-repufusion-induced AKI via a spleen-dependent mechanism and splenic T-regulatory cell expansion. These experimental results are in line with a recent clinical study showing inflammatory cytokine (IL-8), which augments the prediction of kidney recovery and mortality in AKI patients on renal replacement therapy [74] .…”

Section: Immune Responsementioning

confidence: 97%

Acute Kidney Injury: Tubular Markers and Risk for Chronic Kidney Disease and End-Stage Kidney Failure

Tan¹,

Yap

Qian

2016

Blood Purif

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Acute kidney injury (AKI) is a common clinical syndrome directly related to patient short-term and long-term morbidity and mortality. Over the last decade, the occurrence rate of AKI has been increasing, and there has also been a growing epidemic of chronic kidney diseases (CKD) and end-stage kidney disease (ESRD) linked to severe and repeated episodes of AKIs. The detection and management of AKI are currently far from satisfactory. A large proportion of AKI patients, especially those with preexisting CKD, are at an increased risk of non-resolving AKI and progressing to CKD and ESRD. Proposed pathological processes that contribute to the transition of AKI to CKD and ESRD include severity and frequency of kidney injury, alterations of tubular cell phenotype with cells predominantly in the G2/M phase, interstitial fibrosis and microvascular rarification related to loss of endothelial-pericyte interactions and pericyte dedifferentiation. Innate immune responses, especially dendritic cell responses related to inadequate adenosine receptor (2a)-mediated signals, autophagic insufficiency and renin-angiotensin system activation have also been implicated in the progression of AKI and transitions from AKI to CKD and ESRD. Although promising advances have been made in understanding the pathophysiology of AKI and AKI consequences, much more work needs to be done in developing biomarkers for detecting early kidney injury, prognosticating kidney disease progression and developing strategies to effectively treat AKI and to minimize AKI progression to CKD and ESRD.

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“…Immature DCs secrete higher level of IL-10 than do mature DCs, and IL-10 produced by DCs induces immune suppression by modulating CD4 + T cells [52]. Injection of immature DCs reduced renal IRI by generating more Tregs [53]. Other studies have indicated that the protective effect of immature DCs on the kidney is partly attributed to IL-10-mediated activation of Tregs [54].…”

Section: Discussionmentioning

confidence: 99%

Delayed Ischemic Preconditioning Attenuated Renal Ischemia-Reperfusion Injury by Inhibiting Dendritic Cell Maturation

Zhang

Song

Fang

et al. 2018

Cell Physiol Biochem

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Background/Aims: Even though delayed ischemic preconditioning (DIPC) has been reported to produce renal protection, the underlying mechanism remains poorly understood. We reported that a 15-minute renal ischemic preconditioning (IPC) 4 days before subsequent ischemia-reperfusion attenuated renal injury Kidney dendritic cells (DCs) are abundant in the renal tubulointerstitium and, depending on their status, can induce immune activation or tolerance. The aim of the present study was to investigate the role of DCs in IPC of the kidney. Methods: Mouse kidneys were challenged by transient brief episodes of sublethal ischemia followed by subsequent prolonged ischemia. DC abundance and maturation in the spleen and kidney were measured by flow cytometry and immunohistochemical staining. To confirm the function of mature DCs in the renoprotective effect of IPC on renal ischemia-reperfusion injury the A2 adenosine receptor (A2AR) antagonist SCH58261 was administered to stimulate DC maturation prior to assessment of renal functional and histological injury and the inflammatory reaction. Results: Compared with sham-operated animals, preconditioned mice had a reduced injury with less CD11c⁺ cells, lower levels of the pro-inflammatory cytokine IL-17 and reduced expression of the mature DC marker CCR7. Preconditioned mice also produced more of the anti-inflammatory cytokine IL-10. Both renal cells and splenocytes from these mice had more DCs (CD45⁺/CD11c⁺/F4/80^-), but fewer of these DCs were mature (CD45⁺/CD11c⁺/ F4/80^-/MHC-II⁺/CD80⁺) compared with those from sham-treated animals, suggesting that the immunomodulatory effect of renal ischemic preconditioning is both local and systemic. Additionally, injection of the A2AR antagonist SCH58261 reversed IPC-induced inhibition of DC maturation and mitigated the protective effect of preconditioning, suggesting that DC maturation contributes to immune cell-mediated ischemic preconditioning. Conclusion: Our results show that DIPC of the kidney provides local and systemic immunosuppression by inhibiting DC maturation and hence mediates a renal protective effect.

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Sphingosine 1-Phosphate Receptor 3–Deficient Dendritic Cells Modulate Splenic Responses to Ischemia-Reperfusion Injury

Cited by 53 publications

References 65 publications

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

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

Acute Kidney Injury: Tubular Markers and Risk for Chronic Kidney Disease and End-Stage Kidney Failure

Delayed Ischemic Preconditioning Attenuated Renal Ischemia-Reperfusion Injury by Inhibiting Dendritic Cell Maturation

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