| Autor: |
Wang, Shao-bin, Narendran, Siddharth, Hirahara, Shuichiro, Varshney, Akhil, Pereira, Felipe, Apicella, Ivana, Ambati, Meenakshi, Ambati, Vidya L., Yerramothu, Praveen, Ambati, Kameshwari, Nagasaka, Yosuke, Argyle, Dionne, Huang, Peirong, Baker, Kirstie L., Marion, Kenneth M., Gupta, Kartik, Liu, Bo, Hinton, David R., Canna, Scott W., Sallam, Tamer |
| Zdroj: |
Science Immunology; 2021, Vol. 6 Issue 66, p1-14, 14p |
| Abstrakt: |
Inflammasome activation by retrotransposon RNAs: Short interspersed nuclear elements (SINEs) are noncoding retrotransposons that can be transcribed during cell stress and accumulate in immune-mediated diseases such as atrophic macular degeneration (AMD) and lupus. In mouse and human macrophages, Wang et al. demonstrate that SINE RNAs activate an NLRC4 inflammasome leading to IL-1β/IL-18 secretion, which required cytoplasmic detection by DEAD-box helicase 17 (DDX17). Conversely, SINE RNA–induced inflammasome activation was independent of NLR family apoptosis inhibitory proteins (NAIPs) that are classically required for NLRC4 inflammasome assembly after bacterial infection. In a mouse model of SINE RNA–driven AMD, genetic loss of Nlrc4 or Ddx17 protected mice against retinal degeneration. These results identify NAIP-independent NLRC4 inflammasome activation by retrotransposon RNAs and highlight how endogenous activation of innate immune pathways may contribute to disease pathogenesis (see the related Focus commentary by Barnett et al.). Detection of microbial products by multiprotein complexes known as inflammasomes is pivotal to host defense against pathogens. Nucleotide-binding domain leucine-rich repeat (NLR) CARD domain containing 4 (NLRC4) forms an inflammasome in response to bacterial products; this requires their detection by NLR family apoptosis inhibitory proteins (NAIPs), with which NLRC4 physically associates. However, the mechanisms underlying sterile NLRC4 inflammasome activation, which is implicated in chronic noninfectious diseases, remain unknown. Here, we report that endogenous short interspersed nuclear element (SINE) RNAs, which promote atrophic macular degeneration (AMD) and systemic lupus erythematosus (SLE), induce NLRC4 inflammasome activation independent of NAIPs. We identify DDX17, a DExD/H box RNA helicase, as the sensor of SINE RNAs that licenses assembly of an inflammasome comprising NLRC4, NLR pyrin domain–containing protein 3, and apoptosis-associated speck-like protein–containing CARD and induces caspase-1 activation and cytokine release. Inhibiting DDX17-mediated NLRC4 inflammasome activation decreased interleukin-18 release in peripheral blood mononuclear cells of patients with SLE and prevented retinal degeneration in an animal model of AMD. Our findings uncover a previously unrecognized noncanonical NLRC4 inflammasome activated by endogenous retrotransposons and provide potential therapeutic targets for SINE RNA–driven diseases. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
|
