The innate immune system in host mice targets cells with allogenic mitochondrial DNA

Ishikawa, Kaori; Toyama–Sorimachi, Noriko; Nakada, Kazuto; Morimoto, Michio; Imanishi, Hirotake; Yoshizaki, Mariko; Sasawatari, Shigemi; Niikura, Mamoru; Takenaga, Keizo; Yonekawa, Hiromichi; Hayashi, Jun‐Ichi

doi:10.1084/jem.20092296

Cited by 43 publications

(43 citation statements)

References 27 publications

(35 reference statements)

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“…4A). Considering recent reports that mitochondria are expulsed in early apoptosis (53) and that mtDNA stimulates either TLR9 in inflammation and transplant rejection (49,50) or, alternatively, the AIM2 inflammasome and/ or caspase-1 in sepsis (51), we initially argued that the pronounced immunostimulatory activity of MMP DNA could be attributed to selective accumulation of mtDNA in MMP derived from apoptotic cells (Fig. 5A).…”

Section: Discussionmentioning

confidence: 97%

Induction of Type I IFN Is a Physiological Immune Reaction to Apoptotic Cell-Derived Membrane Microparticles

Schiller

Parčina

Heyder

et al. 2012

The Journal of Immunology

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Membrane microparticles (MMP) released from apoptotic cells deliver signals that secure the anti-inflammatory response beyond the nearest proximity of the apoptotic cell. Plasmacytoid dendritic cells (pDC) are sentinels prepared to detect cellular processes that endanger the organism. They play a key role in the regulation of both pro- and anti-inflammatory immune responses. Based on the assumption that pDC could participate in the initiation of the anti-inflammatory response to apoptotic cells, we investigated the effects of apoptotic cell-derived MMP on human pDC. The results obtained in our experiments confirmed that MMP released from apoptotic cells trigger IFN-α secretion from human pDC. They further suggest that pDC activation results from sensing of DNA contained in MMP. MMP-DNA displays a particularly strong stimulatory activity compared with MMP-RNA and other sources of DNA. Inhibition of MMP-induced IFN-α secretion by cytochalasin D, chloroquine, and an inhibitory G-rich oligodeoxynucleotide identify TLR9 as the receptor for MMP-DNA. In marked contrast to the pDC response in autoimmune patients, in healthy subjects MMP-mediated stimulation of pDC-derived IFN-α was found to be independent of FcγRIIA (CD32A). Based on our findings, we conclude that induction of pDC-derived IFN-α by MMP is a physiological event; future investigations are necessary to elucidate whether pDC activation promotes inflammation or propagates tolerance in the context of apoptotic cell clearance.

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Section: Discussionmentioning

confidence: 97%

Induction of Type I IFN Is a Physiological Immune Reaction to Apoptotic Cell-Derived Membrane Microparticles

Schiller

Parčina

Heyder

et al. 2012

The Journal of Immunology

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“…Here, even with small numbers, we found patients of donors with W and U had an increased risk of GVHD. In further support of immune function effects, mt cybrids have differential sensitivity to NK cell mediated attack, apparent in a murine orthotropic tumor model where tumor cybrids showed differential growth rates based on NK cell recognition [4]. Moreover, it is also possible that the genetic differences between donor and recipient mtDNA may serve as a minor histocompatibility antigen, leading to T cell recognition and increased aGVHD.…”

Section: Discussionmentioning

confidence: 99%

“…Mt provide cells energy through oxidative phosphorylation (OXPHOS) and electron transport, regulate cell survival and death, and are increasingly thought to play a key role in innate and adaptive immune system responses [2–4]. While most mitochondrial DNA (mtDNA) was incorporated into human nuclear DNA throughout evolution, there remains a 16.6kb closed double-stranded circular mitochondrial genome that contains 37 genes encoding 22 tRNAs, 2 rRNAs and 13 proteins that play an integral role in OXPHOS [5, 6].…”

Section: Introductionmentioning

confidence: 99%

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An Exploratory Analysis of Mitochondrial Haplotypes and Allogeneic Hematopoietic Cell Transplantation Outcomes

Ross

Tolar

Spector

et al. 2015

Biology of Blood and Marrow Transplantation

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Certain mitochondrial haplotypes (mthaps) are associated with disease, possibly through differences in oxidative phosphorylation and/or immunosurveillance. We explored whether mthaps are associated with allogeneic HCT outcomes. Recipient (n=437) and donor (n=327) DNA was genotyped for common European mthaps (H, J, U, T, Z, K, V, X, I, W, K2). HCT outcomes for mthap matched siblings (n=198), all recipients, and all donors were modeled using relative risks (RR) and 95% confidence intervals and compared to mthap H, the most common. Siblings with I and V were significantly more likely to die within 5 years (RR=3.0; 1.2–7.9 and 4.6; 1.8–12.3, respectively). W siblings experienced higher aGVHD II–IV events (RR=2.1; 1.1–2.4) with no events for K or K2. Similar results were observed for all recipients combined, although J recipients experienced lower GVHD and higher relapse. Patients with I donors had a 2.7 fold (1.2–6.2) increased risk of death in five years, while few patients with K2 or W donors died. No patients with K2 donors and few patients with U donors relapsed. Mthap may be an important consideration in HCT outcomes, although validation and functional studies are needed. If confirmed, it may be feasible to select donors based on mthap to increase positive or decrease negative outcomes.

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“…ESCs generated through SCNT are in principle, heterogeneous in their genetic composition as they contain nuclear DNA of the nucleus donor and mitochondrial DNA of the egg donor (Evans et al, 1999). This raises the possibility that SCNT-derived ESCs could be rejected by the innate immune system of the host with which the ESCs share the same nuclear but not mitochondrial genetic material (Ishikawa et al, 2010). Fig.…”

Section: Overcoming Immunorejectionmentioning

confidence: 99%

Embryonic Stem Cells for Therapies – Challenges and Possibilities

Yeo¹,

Lim²

2011

Embryonic Stem Cells - Basic Biology to Bioengineering

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The innate immune system in host mice targets cells with allogenic mitochondrial DNA

Abstract: Tumors or embryonic stem cells bearing foreign mitochondrial DNA are rejected by the innate immune system via a mechanism that depends on MyD88.

Cited by 43 publications

References 27 publications

Induction of Type I IFN Is a Physiological Immune Reaction to Apoptotic Cell-Derived Membrane Microparticles

Induction of Type I IFN Is a Physiological Immune Reaction to Apoptotic Cell-Derived Membrane Microparticles

An Exploratory Analysis of Mitochondrial Haplotypes and Allogeneic Hematopoietic Cell Transplantation Outcomes

Embryonic Stem Cells for Therapies – Challenges and Possibilities

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