Macrophage uptake and accumulation of folates are polarization-dependent in vitro and in vivo and are regulated by activin A

J Leukoc Biol. 2014 May;95(5):797-808. doi: 10.1189/jlb.0613345. Epub 2014 Jan 7.


Vitamin B9, commonly known as folate, is an essential cofactor for one-carbon metabolism that enters cells through three major specialized transporter molecules (RFC, FR, and PCFT), which differ in expression pattern, affinity for substrate, and ligand-binding pH dependency. We now report that the expression of the folate transporters differs between macrophage subtypes and explains the higher accumulation of 5-MTHF-the major folate form found in serum-in M2 macrophages in vitro and in vivo. M1 macrophages display a higher expression of RFC, whereas FRβ and PCFT are preferentially expressed by anti-inflammatory and homeostatic M2 macrophages. These differences are also seen in macrophages from normal tissues involved in folate transit (placenta, liver, colon) and inflamed tissues (ulcerative colitis, RA), as M2-like macrophages from normal tissues express FRβ and PCFT, whereas TNF-α-expressing M1 macrophages from inflamed tissues are RFC+. Besides, we provide evidences that activin A is a critical factor controlling the set of folate transporters in macrophages, as it down-regulates FRβ, up-regulates RFC expression, and modulates 5-MTHF uptake. All of these experiments support the notion that folate handling is dependent on the stage of macrophage polarization.

Keywords: folate metabolism; folate receptor beta; folate transporters; macrophage metabolism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activins / immunology*
  • Cell Polarity / drug effects*
  • Cell Polarity / immunology
  • Folate Receptor 2 / immunology*
  • Folic Acid Transporters / immunology*
  • Folic Acid* / pharmacokinetics
  • Folic Acid* / pharmacology
  • Humans
  • Macrophages / immunology*


  • FOLR2 protein, human
  • Folate Receptor 2
  • Folic Acid Transporters
  • activin A
  • Activins
  • Folic Acid