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Published on: August 19, 2021
Differential ability of proinflammatory and anti-inflammatory macrophages to perform macropinocytosis
Dar'ya S Redka1, Michael Gütschow2, Sergio Grinstein3,4,5
1Division of Cell Biology, Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
Abstract:
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.
Insights
Anti-inflammatory macrophages exhibit robust macropinocytosis, unlike their inactive proinflammatory counterparts. This difference in cellular uptake is linked to Rho-GTPase and phosphatidylinositol 3-kinase activity, regulated by calcium-sensing receptors.
Area of Science:
- Cell Biology
- Immunology
- Molecular Biology
Background:
- Macropinocytosis is crucial for antigen and nutrient uptake, regulating cell growth via mechanistic target of rapamycin complex 1 (mTORC1).
- Proinflammatory and anti-inflammatory macrophages have distinct functions, necessitating a comparison of their macropinocytic capabilities.
Purpose of the Study:
- To compare the macropinocytic ability of proinflammatory and anti-inflammatory macrophages.
- To identify the molecular mechanisms underlying differences in macropinocytosis between these macrophage subsets.
Main Methods:
- Comparison of constitutive macropinocytosis in polarized macrophages.
- Analysis of Rho-family GTPase and phosphatidylinositol 3-kinase (PtdIns3K) activity.
- Investigation of calcium-sensing receptors (CaSRs) and their role in regulating macropinocytosis.
- Assessment of macropinocytosis induction by PtdIns3K agonists in proinflammatory macrophages.
Main Results:
- Anti-inflammatory macrophages display high constitutive macropinocytosis, while proinflammatory macrophages are largely inactive.
- Reduced Rac/RhoG activity in proinflammatory macrophages underlies their deficient macropinocytosis.
- Differences in PtdIns3K activation correlate with macropinocytic activity and are linked to CaSR functionality.
- Proinflammatory macrophages can be induced to perform macropinocytosis by PtdIns3K agonists like LPS.
Conclusions:
- Macropinocytic capacity significantly differs between anti-inflammatory and proinflammatory macrophages.
- Rho-GTPase and PtdIns3K signaling pathways, modulated by CaSRs, are key determinants of this differential macropinocytosis.
- These findings highlight distinct cellular uptake mechanisms relevant to macrophage antigen presentation and metabolism.
