Differential ability of proinflammatory and anti-inflammatory macrophages to perform macropinocytosis.

Macropinocytosis mediates the uptake of antigens and of nutrients that dictate the regulation of cell growth by mechanistic target of rapamycin complex 1 (mTORC1). Because these functions differ in proinflammatory and anti-inflammatory macrophages, we compared the macropinocytic ability of two extreme polarization states. We found that anti-inflammatory macrophages perform vigorous macropinocytosis constitutively, while proinflammatory cells are virtually inactive. The total cellular content of Rho-family GTPases was higher in anti-inflammatory cells, but this disparity failed to account for the differential macropinocytic activity. Instead, reduced activity of Rac/RhoG was responsible for the deficient macropinocytosis of proinflammatory macrophages, as suggested by the stimulatory effects of heterologously expressed guanine nucleotide-exchange factors or of constitutively active (but not wild-type) forms of these GTPases. Similarly, differences in the activation state of phosphatidylinositol 3-kinase (PtdIns3K) correlated with the macropinocytic activity of pro- and anti-inflammatory macrophages. Differences in PtdIns3K and Rho-GTPase activity were attributable to the activity of calcium-sensing receptors (CaSRs), which appear to be functional only in anti-inflammatory cells. However, agonists of PtdIns3K, including cytokines, chemokines, and LPS, induced macropinocytosis in proinflammatory cells. Our findings revealed a striking difference in the macropinocytic ability of pro- and anti-inflammatory macrophages that correlates with their antigen-presenting and metabolic activity.
(© 2018 Redka et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).)