ABSTRACT
The abnormal innate immune response is a prominent feature underlying autoimmune diseases. One emerging factor that can trigger dysregulated immune activation is cytosolic mitochondrial double-stranded RNAs (mt-dsRNAs). However, the mechanism by which mt-dsRNAs stimulate immune responses remains poorly understood. Here, we discover SRA stem-loop interacting RNA binding protein (SLIRP) as a key amplifier of mt-dsRNA-triggered antiviral signals. In autoimmune diseases, SLIRP is commonly upregulated, and targeted knockdown of SLIRP dampens the interferon response. We find that the activation of melanoma differentiation-associated gene 5 (MDA5) by exogenous dsRNAs upregulates SLIRP, which then stabilizes mt-dsRNAs and promotes their cytosolic release to activate MDA5 further, augmenting the interferon response. Furthermore, the downregulation of SLIRP partially rescues the abnormal interferon-stimulated gene expression in autoimmune patients' primary cells and makes cells vulnerable to certain viral infections. Our study unveils SLIRP as a pivotal mediator of interferon response through positive feedback amplification of antiviral signaling.
ABSTRACT
Aggression is an evolutionarily conserved behavior that controls social hierarchies and protects valuable resources like mates, food, and territory. In mice, aggressive behaviour can be broken down into an appetitive phase, which involves approach and investigation, and a consummatory phase, which involves biting, kicking, and wrestling. By performing an unsupervised weighted correlation network analysis on whole-brain c-Fos expression, we identified a cluster of brain regions including hypothalamic and amygdalar sub-regions and olfactory cortical regions highly co-activated in male, but not female aggressors (AGG). The posterolateral cortical amygdala (COApl), an extended olfactory structure, was found to be a hub region based on the number and strength of correlations with other regions in the cluster. Our data further show that estrogen receptor 1 (ESR1)-expressing cells in the COApl exhibit increased activity during attack behaviour, and during bouts of investigation which precede an attack, in male mice only. Chemogenetic or optogenetic inhibition of COApl ESR1 cells in AGG males reduces aggression and increases pro-social investigation without affecting social reward/reinforcement behavior. We further confirmed that COApl ESR1 projections to the ventrolateral portion of the ventromedial hypothalamus and central amygdala are necessary for these behaviours. Collectively, these data suggest that in aggressive males, COApl ESR1 cells respond specifically to social stimuli, thereby enhancing their salience and promoting attack behaviour.
