Ischemic Injury Enhances Dendritic Cell Immunogenicity via TLR4 and NF-κB Activation

Jurewicz, Mollie; Takakura, Ayumi; Augello, Andrea; Naini, Said Movahedi; Ichimura, Takaharu; Zandi‐Nejad, Kambiz; Abdi, Reza

doi:10.4049/jimmunol.0901889

Cited by 36 publications

(40 citation statements)

References 86 publications

(117 reference statements)

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“…The autoreactive T-cell assay was performed as above using NOR MSCs in an ELISPOT assay as previously described (16). ELISPOT kits (BD Biosciences) to assess IFN-γ and IL-6 production were used according to the manufacturer's instructions.…”

Section: Methodsmentioning

confidence: 99%

“…To assess cytokine production of murine serum and culture supernatant samples, a 21-plex cytokine kit (Millipore, St. Charles, MO) was used according to the manufacturer's instructions and as previously described (16). To assess production of IFN-α, M-CSF, and Flt3L, murine ELISA kits (R&D Systems, Minneapolis, MN) were used according to the manufacturer's instructions.…”

Section: Methodsmentioning

confidence: 99%

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Congenic Mesenchymal Stem Cell Therapy Reverses Hyperglycemia in Experimental Type 1 Diabetes

et al. 2010

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OBJECTIVEA number of clinical trials are underway to test whether mesenchymal stem cells (MSCs) are effective in treating various diseases, including type 1 diabetes. Although this cell therapy holds great promise, the optimal source of MSCs has yet to be determined with respect to major histocompatibility complex matching. Here, we examine this question by testing the ability of congenic MSCs, obtained from the NOR mouse strain, to reverse recent-onset type 1 diabetes in NOD mice, as well as determine the immunomodulatory effects of NOR MSCs in vivo.RESEARCH DESIGN AND METHODSNOR MSCs were evaluated with regard to their in vitro immunomodulatory function in the context of autoreactive T-cell proliferation and dendritic cell (DC) generation. The in vivo effect of NOR MSC therapy on reversal of recent-onset hyperglycemia and on immunogenic cell subsets in NOD mice was also examined.RESULTSNOR MSCs were shown to suppress diabetogenic T-cell proliferation via PD-L1 and to suppress generation of myeloid/inflammatory DCs predominantly through an IL-6-dependent mechanism. NOR MSC treatment of experimental type 1 diabetes resulted in long-term reversal of hyperglycemia, and therapy was shown to alter diabetogenic cytokine profile, to diminish T-cell effector frequency in the pancreatic lymph nodes, to alter antigen-presenting cell frequencies, and to augment the frequency of the plasmacytoid subset of DCs.CONCLUSIONSThese studies demonstrate the inimitable benefit of congenic MSC therapy in reversing experimental type 1 diabetes. These data should benefit future clinical trials using MSCs as treatment for type 1 diabetes.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Congenic Mesenchymal Stem Cell Therapy Reverses Hyperglycemia in Experimental Type 1 Diabetes

et al. 2010

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“…Proinflammatory cytokine expression by DCs is an important indicator of DC activity 23,24 and our data for mRNA expressions of these cytokines on BMDC after coculture are provided in Supplemental Figure S1 (see Supplementary Material and Supplementary Fig. S1, http://www.iovs.org/ lookup/suppl/doi:10.1167/iovs.12-9547/-/DCSupplemental).…”

Section: Ded Induces Corneal Expression Of Endogenous Tlr4 Ligandsmentioning

confidence: 99%

Expression of Toll-Like Receptor 4 Contributes to Corneal Inflammation in Experimental Dry Eye Disease

Lee¹,

Hattori²,

Park³

et al. 2012

Invest. Ophthalmol. Vis. Sci.

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PURPOSE.To investigate the corneal expression of toll-like receptor (TLR) 4 and determine its contribution to the immunopathogenesis of dry eye disease (DED).METHODS. Seven to 8-week-old female C57BL/6 mice were housed in a controlled environment chamber and administered scopolamine to induce experimental DED. Mice received intravenous TLR4 inhibitor (Eritoran) to block systemic TLR4-mediated activity. The expression of TLR4 by the corneal epithelium and stroma was evaluated using real-time polymerase chain reaction and flow cytometry. Corneal fluorescein staining (CFS) was performed to evaluate clinical disease severity. The corneal expression of proinflammatory cytokines (IL-1b, IL-6, TNF, and CCL2), corneal infiltration of CD11b 3 Recent studies have demonstrated that corneal epithelial cells respond to hyperosmolar stress by producing proinflammatory cytokines, chemokines, and matrix metalloproteinases (MMPs).4,5 Furthermore, hyperosmolar stress and proinflammatory cytokines such as interferon (IFN)-c promote epithelial cell apoptosis. [5][6][7][8] Toll-like receptors (TLRs) are pattern recognition receptors of the innate immune system that recognize highly conserved microbial structures and products.9,10 To date, 12 murine TLRs have been identified, and TLRs are expressed by a variety of cell types, including epithelial cells, dendritic cells, macrophages, and lymphocytes.10-13 TLR stimulation leads to the activation of nuclear factor-kappaB (NF-jB) that upregulates the production of proinflammatory cytokines and antimicrobial proteins.10,14 The NF-jB signaling pathway is important for the induction of innate and adaptive immune responses. 10,14 TLR4 recognizes the Gram-negative bacterial cell wall component lipopolysaccharide (LPS) in association with cofactors such as CD14, LPS-binding protein (LBP), and myeloid differentiation factor-2 (MD-2). 15,16 It has also been suggested that TLR4 is a receptor for endogenous ligands associated with noninfectious diseases such as myocardial ischemia-reperfusion injury and central nervous system autoimmune disease. 17,18 We hypothesized that DED-induced corneal inflammation and injury may lead to the production of endogenous TLR4 ligands that activate the immune system. Therefore, we investigated the corneal expression of TLR4 and sought to determine the expression pattern of TLR4 in DED. MATERIALS AND METHODS AnimalsSeven to 8-week-old female C57BL/6 mice (Charles River Laboratories, Wilmington, MA) were used for these experiments. The experimental protocol was approved by the Institutional Animal Care and Use Committee, and all animals were managed according to the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research. Dry Eye ModelDED was induced by placing mice in a controlled environment chamber (CEC) and administering scopolamine (Sigma-Aldrich, St. Louis, MO) to maximize ocular surface dryness, as previously described. 19,20 Mice placed in the CEC were exposed to a relative humidity < 25%, temperature of 20 to 228C, and airflow of 15 L/min, 2...

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“…In a more recent study on an in vitro -induced ischemia model, bone marrow–derived DCs were shown to augment allogeneic T-cell proliferation as well as the interferon-gamma response (Jurewicz et al, 2010). In this study, TLR4 ligation was also shown to occur in ischemic DCs, most likely – as concluded by the authors – in response to HSP70, which was found to be elevated in DCs after ischemic injury.…”

Section: Role Of Heat Shock Protein 70 In Innate Alloimmunitymentioning

confidence: 99%

Role of Heat Shock Protein 70 in Innate Alloimmunity

Land¹

2012

Front. Immun.

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This article briefly describes our own experience with the proven demonstration of heat shock protein 70 (HSP70) in reperfused renal allografts from brain-dead donors and reflects about its potential role as a typical damage-associated molecular pattern (DAMP) in the setting of innate alloimmunity. In fact, our group was able to demonstrate a dramatic up-regulation of HSP70 expression after postischemic reperfusion of renal allografts. Of note, up-regulation of this stress protein expression, although to a lesser extent, was already observed after cold storage of the organ indicating that this molecule is already induced in the stressed organism of a brain-dead donor. However, whether or not the dramatic up-regulation of HSP70 expression contributes to mounting an innate alloimmune response cannot be judged in view of these clinical findings. Nevertheless, HSP70, since generated in association with postischemic reperfusion-induced allograft injury, can be called a typical DAMP – as can every molecule be termed a DAMP that is generated in association with any stressful tissue injury regardless of its final positive or negative regulatory function within the innate immune response elicited by it. In fact, as we discuss in this article, the context-dependent, even contradistinctive activities of HSP70 reflect the biological phenomenon that, throughout evolution, mammals have developed an elaborate network of positive and negative regulatory mechanisms, which provide balance between defensive and protective measures against unwarranted destruction of the host. In this sense, up-regulated expression of HSP70 in an injured allograft might reflect a pure protective response against the severe oxidative injury of a reperfused donor organ. On the other hand, up-regulated expression of this stress protein in an injured allograft might reflect a (futile) attempt of the innate immune system to restore homeostasis with the aim to eliminate the “unwanted foreign allograft invader” by contributing to development of an adaptive alloimmune response. However, this adaptive immune response against donor histocompatibility alloantigens – in its evolutionary sense aimed to restore homeostasis – is by no means protective from a recipient’s view point but tragically ends up with allograft rejection. Indeed: in this sense, allograft rejection is the result of a fateful confusion by the immune system of danger and benefit!

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Ischemic Injury Enhances Dendritic Cell Immunogenicity via TLR4 and NF-κB Activation

Cited by 36 publications

References 86 publications

Congenic Mesenchymal Stem Cell Therapy Reverses Hyperglycemia in Experimental Type 1 Diabetes

Congenic Mesenchymal Stem Cell Therapy Reverses Hyperglycemia in Experimental Type 1 Diabetes

Expression of Toll-Like Receptor 4 Contributes to Corneal Inflammation in Experimental Dry Eye Disease

Role of Heat Shock Protein 70 in Innate Alloimmunity

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