SINE RNA Receptor DDX17 Mediates Lupus & AMD

Article: Link Found Between Lupus, Macular Degeneration 
Source: University of Virginia Medicine
Published: December 7, 2021
Article: Retrotransposon RNA Triggers NLRC4 Inflammasome Formation
Source: The Scientist
Published: December 10, 2021

Jayakrishna Ambati, MD, has been a prolific researcher, publishing three papers this year regarding his discoveries connecting atrophic macular degeneration (AMD) with cytoplasmic cDNA and its activation of the inflammasome. His fourth paper this year presents another finding linking triggers of the inflammasome with another disease: lupus. Ambati remarks, "It appears that the new inflammatory pathway we identified could be therapeutically targeted for many chronic diseases." The inflammasome, or pairs of inflammasomes, responsible in this case is the NLRC4-NLRP3 inflammasome. Each are individually large multi-protein complexes that play an important role in protecting the body from pathogens. However, in noninfectious, chronic inflammatory diseases such as lupus and macular degeneration, the researchers found that the NLRC4 inflammasome includes the NLRP3 inflammasome, and is instead independent of NLR family apoptosis inhibitory proteins (NAIPs) that are classically required for NLRC4 inflammasome assembly after bacterial infection. In the "sterile" environment of chronic diseases, that is, in the absence of pathogenic etiologies, researchers wondered what triggers the formation of inflammasomes.

Subretinal injection of SINE RNAs in a mouse model of AMD led to RPE degeneration
in wildtype mice (left), but not in mice engineered with genetic loss of Nlrc4 (middle) or Ddx17 (right)

The new research uncovered that the NLRC4-NLRP3 inflammasome is triggered by short interspersed nuclear element RNAs (SINE RNAs), mobile genetic elements known as retrotransposons that make up more than 10% of our genome and is transcribed in response to cellular stresses. SINE RNAs were found to be elevated in both lupus and AMD, among other diseases in previous work. Notably, using human cells transfected with SINE RNA, the research team identified a receptor called DEAD-box helicase 17 (DDX17). When DDX17 was unavailable, there was less interaction between the NLRC4 and NLRP3 proteins in SINE RNA-transfected cells, suggesting that DDX17 is an essential mediator in sterile activation of the NLRC4 inflammasome by SINE RNAs. The finding that DDX17 is colocalized with SINE RNA in the cytoplasm is confirmed in white blood cells isolated from people with active lupus. Additionally, subretinal injection of SINE RNAs in a mouse model of atrophic macular degeneration led to retinal pigmented epithelium (RPE) degeneration in wildtype mice but not in mice engineered with genetic loss of Nlrc4  or Ddx17, demonstrating that the NLRC4 inflammasome and its receptor DDX17 are both necessary to trigger the retinal disease. The finding that there are two inflammasomes involved, both of which are necessary to form an active NLRC4 inflammasome when the complex is triggered by SINE RNAs, also informs therapeutic strategies for both the NLRC4 and NLRP3 inflammasomes. Ambati further comments, “[N]ow that we know what is the sensor—at least a sensor—of SINE retrotransposons, that opens up a whole new intersection between RNA biology and immunology.”

My rating of this study: ⭐⭐⭐

Wang S, Narendran S, Hirahara S, et al. "DDX17 is an essential mediator of sterile NLRC4 inflammasome activation by retrotransposon RNAs." Science Immunology.  6:66. 3 December 2021. https://doi.org/10.1126/sciimmunol.abi4493