Quorum Sensing by Gelsolin Regulates Programmed Cell Death 4 Expression and a Density-Dependent Phenotype in Macrophages

Quorum-sensing mechanisms that sense the density of immune cells at the site of inflammation to initiate inflammation resolution have recently been demonstrated as a major determinant of the inflammatory response. We observed a density-dependent increase in expression of the inflammatory tumor suppressor protein programmed cell death 4 (PDCD4) in mouse macrophage cells. Conditioned medium from high-density cells upregulated PDCD4 expression, revealing the presence of a secreted factor(s) acting as a macrophage quorum sensor. Secreted gelsolin (GSN) was identified as the quorum-sensing autoinducer. Alteration of GSN levels changed PDCD4 expression and the density-dependent phenotype of cells. LPS induced the expression of microRNA miR-21, which downregulated both GSN and PDCD4 expression, and reversed the high-density phenotype. The high-density phenotype was correlated with an anti-inflammatory gene expression program, which was counteracted by inflammatory stimulus. Together, our observations establish the miR-21-GSN-PDCD4 regulatory network as a crucial mediator of a macrophage quorum-sensing mechanism for the control of inflammatory responses.