Macrophage innate immune gene expression requires dynamic regulation of the nuclear paraspeckle

There is a growing appreciation for membraneless organelles (MLOs) in regulating cellular stress responses. Here, we demonstrate a role for the nuclear paraspeckle, a highly ordered biomolecular condensate that nucleates on theNeat1lncRNA, in both activating and repressing innate immune gene expression in murine macrophages. In response to a variety of innate agonists, macrophages rapidly upregulate and then downregulate paraspeckles. Paraspeckle maintenance and aggregation requires active transcription and MAPK signaling. Downregulation of paraspeckles, an adaptation seemingly unique to macrophages, is mediated by the nuclear RNA exosome, via degradation ofNeat1. Primary macrophages lackingNeat1(Neat1KO) misregulate many critical inflammatory cytokines, with a failure to upregulate genes likeIl6andCxcl9and to downregulate others (e.g.,Csf3andVegfa), at the transcript and protein levels in response to lipopolysaccharide (LPS) treatment. We propose that dynamic assembly and disassembly of paraspeckles help macrophages mount an innate immune response by controlling the availability of RNA processing machineries in the nucleus. Collectively, these data argue that stress-responsive biomolecular condensates play a prominent role in modulating immune cell function.