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      Mitochondrial DNA in innate immune responses and inflammatory pathology

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      Author(s): 1 , 2
      Publication date (Electronic):
      Journal: Nature reviews. Immunology

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          Abstract

          Mitochondrial DNA (mtDNA) — which is well known for its role in oxidative phosphorylation and maternally inherited mitochondrial diseases — is increasingly recognized as an agonist of the innate immune system that influences antimicrobial responses and inflammatory pathology. On entering the cytoplasm, extracellular space or circulation, mtDNA can engage multiple pattern-recognition receptors in cell-type- and context-dependent manners to trigger pro-inflammatory and type I interferon responses. Here, we review the expanding research field of mtDNA in innate immune responses to highlight new mechanistic insights and discuss the physiological and pathological relevance of this exciting area of mitochondrial biology.

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          TLR signaling augments macrophage bactericidal activity through mitochondrial ROS

          A. West, Igor E. Brodsky, Christoph Rahner … (2011)
          Reactive oxygen species (ROS) are essential components of the innate immune response against intracellular bacteria, and it is thought that professional phagocytes generate ROS primarily via the phagosomal NADPH oxidase (Phox) machinery 1 . However, recent studies have suggested that mitochondrial ROS (mROS) also contribute to macrophage bactericidal activity, although the mechanisms linking innate immune signaling to mitochondria for mROS generation remain unclear 2-4 . Here we demonstrate that engagement of a subset of Toll-like receptors (TLR1, TLR2 and TLR4) results in the recruitment of mitochondria to macrophage phagosomes and augments mROS production. This response involves translocation of the TLR signaling adapter tumor necrosis factor receptor-associated factor 6 (TRAF6) to mitochondria where it engages evolutionarily conserved signaling intermediate in Toll pathways (ECSIT), a protein implicated in mitochondrial respiratory chain assembly 5 . Interaction with TRAF6 leads to ECSIT ubiquitination and enrichment at the mitochondrial periphery, resulting in increased mitochondrial and cellular ROS generation. ECSIT and TRAF6 depleted macrophages exhibit decreased levels of TLR-induced ROS and are significantly impaired in their ability to kill intracellular bacteria. Additionally, reducing macrophage mROS by expressing catalase in mitochondria results in defective bacterial killing, confirming the role of mROS in bactericidal activity. These results therefore reveal a novel pathway linking innate immune signaling to mitochondria, implicate mROS as important components of antibacterial responses, and further establish mitochondria as hubs for innate immune signaling.
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            Mitochondrial DNA That Escapes from Autophagy Causes Inflammation and Heart Failure

            Takafumi Oka, Shungo Hikoso, Osamu Yamaguchi … (2012)
            Heart failure is a leading cause of morbidity and mortality in industrialized countries. Although infection with microorganisms is not involved in the development of heart failure in most cases, inflammation has been implicated in the pathogenesis of heart failure 1 . However, the mechanisms responsible for initiating and integrating inflammatory responses within the heart remain poorly defined. Mitochondria are evolutionary endosymbionts derived from bacteria and contain DNA similar to bacterial DNA 2,3,4 . Mitochondria damaged by external hemodynamic stress are degraded by the autophagy/lysosome system in cardiomyocytes 5 . Here, we show that mitochondrial DNA that escapes from autophagy cell-autonomously leads to Toll-like receptor (TLR) 9-mediated inflammatory responses in cardiomyocytes and is capable of inducing myocarditis, and dilated cardiomyopathy. Cardiac-specific deletion of lysosomal deoxyribonuclease (DNase) II showed no cardiac phenotypes under baseline conditions, but increased mortality and caused severe myocarditis and dilated cardiomyopathy 10 days after treatment with pressure overload. Early in the pathogenesis, DNase II-deficient hearts exhibited infiltration of inflammatory cells and increased mRNA expression of inflammatory cytokines, with accumulation of mitochondrial DNA deposits in autolysosomes in the myocardium. Administration of the inhibitory oligodeoxynucleotides against TLR9, which is known to be activated by bacterial DNA 6 , or ablation of Tlr9 attenuated the development of cardiomyopathy in DNase II-deficient mice. Furthermore, Tlr9-ablation improved pressure overload-induced cardiac dysfunction and inflammation even in mice with wild-type Dnase2a alleles. These data provide new perspectives on the mechanism of genesis of chronic inflammation in failing hearts.
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              Carcinoma-astrocyte gap junctions promote brain metastasis by cGAMP transfer

              Qing Chen, Adrienne Boire, Xin Jin … (2016)
              SUMMARY Brain metastasis represents a substantial source of morbidity and mortality in various cancers, and is characterized by high resistance to chemotherapy. Here we define the role of the most abundant cell type in the brain, the astrocyte, in promoting brain metastasis. Breast and lung cancer cells express protocadherin 7 (PCDH7) to favor the assembly of carcinoma-astrocyte gap junctions composed of connexin 43 (Cx43). Once engaged with the astrocyte gap-junctional network, brain metastatic cancer cells employ these channels to transfer the second messenger cGAMP to astrocytes, activating the STING pathway and production of inflammatory cytokines IFNα and TNFα. As paracrine signals, these factors activate the STAT1 and NF-κB pathways in brain metastatic cells, which support tumour growth and chemoresistance. The orally bioavailable modulators of gap junctions meclofenamate and tonabersat break this paracrine loop, and we provide proof-of-principle for the applicability of this therapeutic strategy to treat established brain metastasis.
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                Author and article information

                Journal
                Journal ID (nlm-journal-id): 101124169
                Journal ID (pubmed-jr-id): 27017
                Journal ID (nlm-ta): Nat Rev Immunol
                Journal ID (iso-abbrev): Nat. Rev. Immunol.
                Title: Nature reviews. Immunology
                ISSN (Print): 1474-1733
                ISSN (Electronic): 1474-1741
                Publication date Nihms-submitted: 22 May 2020
                Publication date (Electronic): 10 April 2017
                Publication date (Print): June 2017
                Publication date PMC-release: 11 June 2020
                Volume: 17
                Issue: 6
                Pages: 363-375
                Affiliations
                [1 ]Department of Microbial Pathogenesis and Immunology, Texas A&M University Health Science Center, 470 Reynolds Medical Building, TAMU 1114, College Station, Texas 77843, USA
                [2 ]Departments of Pathology and Genetics and Yale Center for Research on Aging, Yale School of Medicine, 310 Cedar Street, BML 371, New Haven, Connecticut 06520, USA
                Author notes
                Article
                Accession ID: PMC7289178 Pmcid ID: PMC7289178 Pmc-uid ID: 7289178 Manuscript ID: nihpa1595922
                DOI: 10.1038/nri.2017.21
                PMC ID: 7289178
                PubMed ID: 28393922
                SO-VID: 80c6e7ef-8886-45f6-ac66-0f3c57193ed2
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