Brain-wide mapping of immune receptors uncovers a neuro-modulatory role of interleukin-17E and the receptor IL-17RB.

Cytokines engage with their receptor complexes to orchestrate diverse processes -- from immune responses to modulating behaviors. Interleukin-17A (IL-17A) mediates protective immune responses by binding to IL-17 receptor A (IL-17A) and IL-17RC subunits. IL-17A also modulates social interaction, but the role of cytokine receptors in this process and their expression in the brain is not well characterized. Here, we mapped the brain-region-specific expression of all major IL-17R subunits and discovered that IL-17RB, not IL-17RC, expression in the cortex plays a role in social behaviors. Through genetic experiments, we further showed that IL-17E, a ligand for the IL-17RB-containing receptor complex, enhances social interaction by directly impacting IL-17RB-expressing neurons in the cortex. These findings highlight a novel IL-17 circuit operating within the cortex to modulate social behaviors. Thus, characterizing spatially restricted cytokine receptor expression can be leveraged to elucidate how cytokines function as critical messengers mediating neuro-immune interactions to shape animal behaviors. Overall design: Cell type-specific profiling of IL-17RA+, IL-17RB+, and IL-17RC+ cells in the primary somatosensory cortex of Il-17ra-, Il-17rb-, and Il-17Rc-Cre mice, respectively, using Translating Ribosome Affinity Purification (TRAP).