The light side of mast cell degranulation: delivering macrophage repair through molecular condensates

Mast cell (MC) degranulation is commonly viewed as the rapid release of preformed inflammatory mediators into the extracellular environment. In a recent study published in the Journal of Experimental Medicine, Salm et al. described a more spatially controlled form of MC communication following sterile peritoneal injury. Sensory neurons activated MCs through substance P signaling, promoting the release of extracellular granules that persisted as membraneless biomolecular condensates. These condensates, enriched in more than 200 proteins, remained associated with the surface of large peritoneal macrophages (LPMs), where they contributed to rapid macrophage aggregation through the scavenger receptor MARCO and promoted a repair-like phenotype at the injury site. Lattice light sheet microscopy further revealed F-actin-containing cytonemes that captured condensates from the MC surface and distributed them to surrounding macrophages. Importantly, disruption of this process impaired condensate dispersion, LPM recruitment, and wound healing. The study expands the conventional view of MC degranulation beyond the release of inflammatory soluble mediators by showing that released granules can remain organized and be actively positioned within injured tissue, creating a localized communication system between sensory neurons, MCs, and macrophages.