**4. Cytosolic sensors for recognizing foreign nucleic acids**

Members of the cytosolic RIG-I-like receptor (RLR) family act as cytosolic sensors for genomic RNA of dsRNA viruses and dsRNA intermediates that are generated during replication of ssRNA viruses (Yoneyama et al., 2004; Kato et al., 2005; Bowzard et al., 2009; Ranjan et al., 2009). Retinoic acid-induced protein I is composed of two amino-terminal caspase activation and recruitment domains (CARDs), a central DEAD box helicase/ATPase domain, and a carboxy-terminal regulatory domain (Yoneyama et al., 2004). The latter domain plays a critical role in the specific recognition of dsRNA and 5′-triphosphorylated ssRNA. Other members of the RIG-I family include MDA5 (melanoma differentiationassociated gene 5) and LGP2 (laboratory of genetics and physiology 2). RIG-I and MDA5 distinguish between different RNA viruses and contribute to the host´s anti-viral response through recognition of either 5′-triphosphorylated and uncapped ssRNA or dsRNA, species not found among endogenous self-RNA (Kato et al., 2006). Transgenic mice, deficient in RIG-I or MDA5 expression, are highly susceptible to infection with RNA viruses compared to control mice (Kato et al., 2006). The RIG-I homolog LGP2, which lacks the amino-terminal CARDs, potentiates viral RNA recognition by RIG-I and MDA5 through its ATPase domain and has been found to be essential for type I interferon production in response to picornaviridae infection (Satoh et al., 2010). Recently, it has been shown that also DNAdependent RNA polymerase III is pivotal in sensing viral DNA in the cytoplasm (Ablasser et al., 2009; Chiu et al, 2009). AT-rich dsDNA can serve as a template for RNA polymerase III, which is transcribed enzymatically into dsRNA containing a 5'-triphosphorylated moiety. Activation of RIG-I by dsRNA ultimately induces production of type I interferon and activation of the transcription factor NF-B.

Recently, it was reported that overexpression of STING (stimulator of interferon genes), a transmembrane protein found in the endoplasmic reticulum of numerous cells such as macrophages, dendritic, endothelial and epithelial cells, induces activation of NF-B and IRF3 to stimulate type I interferon synthesis (Ishikawa et al., 2009; Barber, 2011). STINGknockout mice were susceptible to lethal infection after exposure to herpes simplex virus 1, suggesting that STING plays an important role in detecting foreign DNA.

Another cytosolic sensor for both bacterial and viral pathogens is AIM2 (absent in melanoma 2), which is essential for inflammasome activation in response to *Fransicella tularensis*, vaccinia virus, and mouse cytomegalovirus (Rathinam et al., 2010). AIM2 regulates caspase-1 dependent maturation of IL-1β and IL-18 and plays a role in natural killer cell-dependent production of interferon-, as has been shown for AIM2-deficient mice. However, the role of AIM2 in the pathogenesis of myocarditis has not been investigated so far.

itself, IRAK, and the NF-B essential modulator (NEMO) (Deng et al., 2000). Transforming growth factor--activated kinase 1 (TAK1) is recruited and ubiquitinylated by TRAF6 (Wang et al., 2001). Subsequently, the IKK complex composed of IKK, IKK and NEMO is formed which phosphorylates inhibitor of NF-B (IB) kinase-ß (IKK). The activated IKK complex then induces phosphorylation and subsequent degradation of IB by the proteasome. Upon degradation of IB, the freed NF-B is no longer sequestered in the cytosol, but translocates into the nucleus, where it drives the expression of cytokine genes. Simultaneously, TAK1 activates the mitogen-activated protein kinase (MAPK) cascade leading to the activation of the transcription factor AP-1, which also targets gene expression of cytokine genes (Wang et

Members of the cytosolic RIG-I-like receptor (RLR) family act as cytosolic sensors for genomic RNA of dsRNA viruses and dsRNA intermediates that are generated during replication of ssRNA viruses (Yoneyama et al., 2004; Kato et al., 2005; Bowzard et al., 2009; Ranjan et al., 2009). Retinoic acid-induced protein I is composed of two amino-terminal caspase activation and recruitment domains (CARDs), a central DEAD box helicase/ATPase domain, and a carboxy-terminal regulatory domain (Yoneyama et al., 2004). The latter domain plays a critical role in the specific recognition of dsRNA and 5′-triphosphorylated ssRNA. Other members of the RIG-I family include MDA5 (melanoma differentiationassociated gene 5) and LGP2 (laboratory of genetics and physiology 2). RIG-I and MDA5 distinguish between different RNA viruses and contribute to the host´s anti-viral response through recognition of either 5′-triphosphorylated and uncapped ssRNA or dsRNA, species not found among endogenous self-RNA (Kato et al., 2006). Transgenic mice, deficient in RIG-I or MDA5 expression, are highly susceptible to infection with RNA viruses compared to control mice (Kato et al., 2006). The RIG-I homolog LGP2, which lacks the amino-terminal CARDs, potentiates viral RNA recognition by RIG-I and MDA5 through its ATPase domain and has been found to be essential for type I interferon production in response to picornaviridae infection (Satoh et al., 2010). Recently, it has been shown that also DNAdependent RNA polymerase III is pivotal in sensing viral DNA in the cytoplasm (Ablasser et al., 2009; Chiu et al, 2009). AT-rich dsDNA can serve as a template for RNA polymerase III, which is transcribed enzymatically into dsRNA containing a 5'-triphosphorylated moiety. Activation of RIG-I by dsRNA ultimately induces production of type I interferon

Recently, it was reported that overexpression of STING (stimulator of interferon genes), a transmembrane protein found in the endoplasmic reticulum of numerous cells such as macrophages, dendritic, endothelial and epithelial cells, induces activation of NF-B and IRF3 to stimulate type I interferon synthesis (Ishikawa et al., 2009; Barber, 2011). STINGknockout mice were susceptible to lethal infection after exposure to herpes simplex virus 1,

Another cytosolic sensor for both bacterial and viral pathogens is AIM2 (absent in melanoma 2), which is essential for inflammasome activation in response to *Fransicella tularensis*, vaccinia virus, and mouse cytomegalovirus (Rathinam et al., 2010). AIM2 regulates caspase-1 dependent maturation of IL-1β and IL-18 and plays a role in natural killer cell-dependent production of interferon-, as has been shown for AIM2-deficient mice. However, the role of

suggesting that STING plays an important role in detecting foreign DNA.

AIM2 in the pathogenesis of myocarditis has not been investigated so far.

**4. Cytosolic sensors for recognizing foreign nucleic acids** 

and activation of the transcription factor NF-B.

al., 2001).


Table 1. Pattern recognition receptors (PRR) and their ligands engaged in myocarditis and inflammatory heart disease.

Pattern-Recognition Receptors

188.

361.

2002;99:9876-9881.

2003;9:1484-1490.

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Med. 2010;362:1248-1249.

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Chong AJ, Shimamoto A, Hampton CR, Takayama H, Spring DJ, Rothnie CL, Yada M,

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Dörner A, Kallwellis-Opara A, Pauschinger M, Kühl U, Schultheiss HP. Cardiac

Eriksson U, Ricci R, Hunziker L, Kurrer MO, Oudit GY, Watts TH, Sonderegger I, Bachmaier

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Pohlman TH, Verrier ED. Toll-like receptor 4 mediates ischemia/reperfusion

Activation of the IkappaB kinase complex by TRAF6 requires a dimeric ubiquitinconjugating enzyme complex and a unique polyubiquitin chain. Cell. 2000;103:351-

protein and potential neural tumor suppressor. Proc Natl Acad Sci USA.

K, Kopf M, Penninger JM. Dendritic cell-induced autoimmune heart failure requires cooperation between adaptive and innate immunity. Nat Med.

Toll-like receptors 2-deficient mice are protected against postischemic coronary

E, Dunne A, Gray P, Harte MT, McMurray D, Smith DE, Sims JE, Bird TA, O'Neill LA. Mal (MyD88-adapter-like) is required for Toll-like receptor-4 signal

cardiomyocytes decreases contractility and initiates an NF-kappaB dependent

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ectodomain. Science. 2005;309:581-585.
