Extracellular Purine Metabolism Is the Switchboard of Immunosuppressive Macrophages and a Novel Target to Treat Diseases With Macrophage Imbalances

Frontiers in Immunology
Anna Ohradanova-RepicHannes Stockinger

Abstract

If misregulated, macrophage (Mϕ)-T cell interactions can drive chronic inflammation thereby causing diseases, such as rheumatoid arthritis (RA). We report that in a proinflammatory environment, granulocyte-Mϕ (GM-CSF)- and Mϕ colony-stimulating factor (M-CSF)-dependent Mϕs have dichotomous effects on T cell activity. While GM-CSF-dependent Mϕs show a highly stimulatory activity typical for M1 Mϕs, M-CSF-dependent Mϕs, marked by folate receptor β (FRβ), adopt an immunosuppressive M2 phenotype. We find the latter to be caused by the purinergic pathway that directs release of extracellular ATP and its conversion to immunosuppressive adenosine by co-expressed CD39 and CD73. Since we observed a misbalance between immunosuppressive and immunostimulatory Mϕs in human and murine arthritic joints, we devised a new strategy for RA treatment based on targeted delivery of a novel methotrexate (MTX) formulation to the immunosuppressive FRβ+CD39+CD73+ Mϕs, which boosts adenosine production and curtails the dominance of proinflammatory Mϕs. In contrast to untargeted MTX, this approach leads to potent alleviation of inflammation in the murine arthritis model. In conclusion, we define the Mϕ extracellular purine metabolism as a novel checkpoint...Continue Reading

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Citations

Oct 19, 2019·Cancers·Simone de LeveVerena Jendrossek
Jan 19, 2019·Journal of Leukocyte Biology·Anna Ohradanova-RepicVladimir Leksa
Nov 10, 2020·Blood Advances·Kajal HamidzadehDavid M Mosser
Feb 3, 2020·Cellular Immunology·Yiming MengHaozhe Piao
Jan 22, 2021·Autoimmunity Reviews·Marie-Astrid BoutetFrédéric Blanchard
Feb 23, 2021·Frontiers in Pharmacology·Anna Lisa GiulianiFrancesco Di Virgilio
Mar 18, 2021·Evidence-based Complementary and Alternative Medicine : ECAM·Fuming YangZhifang Xu
Apr 1, 2021·Physiological Reviews·Alberto L HorensteinFabio Malavasi
Oct 13, 2020·International Immunopharmacology·Jianrui ZengHuabao Xiong
Jun 20, 2021·Cancer Communications·Qi WuYi Tu
Jun 24, 2021·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Lisa EhlersTimo Gaber
Aug 28, 2021·International Journal of Molecular Sciences·Rebecca SohnZsuzsa Jenei-Lanzl
May 10, 2019·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Rui WangWei Wei
Nov 9, 2021·Frontiers in Immunology·Hao WangWenkai Ren

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Methods Mentioned

BETA
flow cytometry
FCS
PMA
PCR
Assay
protein assay
Fluorescence

Software Mentioned

Leica Application Suite Advanced Fluorescence
FlowJo
Prism
GraphPad
Fiji
limma
TM4
FACSDiva

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