Polymeric IgA1 controls erythroblast proliferation and accelerates erythropoiesis recovery in anemia.
Anemia because of insufficient production of and/or response to erythropoietin (Epo) is a major complication of chronic kidney disease and cancer. The mechanisms modulating the sensitivity of erythroblasts to Epo remain poorly understood. We show that, when cultured with Epo at suboptimal concentrations, the growth and clonogenic potential of erythroblasts was rescued by transferrin receptor 1 (TfR1)-bound polymeric IgA1 (pIgA1). Under homeostatic conditions, erythroblast numbers were increased in mice expressing human IgA1 compared to control mice. Hypoxic stress of these mice led to increased amounts of pIgA1 and erythroblast expansion. Expression of human IgA1 or treatment of wild-type mice with the TfR1 ligands pIgA1 or iron-loaded transferrin (Fe-Tf) accelerated recovery from acute anemia. TfR1 engagement by either pIgA1 or Fe-Tf increased cell sensitivity to Epo by inducing activation of mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) signaling pathways. These cellular responses were mediated through the TfR1-internalization motif, YXXΦ. Our results show that pIgA1 and TfR1 are positive regulators of erythropoiesis in both physiological and pathological situations. Targeting this pathway may provide alternate approaches to the treatment of ineffective erythropoiesis and anemia.
Centre National de la Recherche Scientifique (CNRS) Unité Mixte Recherche (UMR) 8147, Université Paris Descartes, Faculté de Médecine, Hôpital Necker, Paris, France.
Séverine
S
Coulon
Michaël
M
Dussiot
Damien
D
Grapton
Thiago Trovati
TT
Maciel
Pamella Huey Mei
PH
Wang
Celine
C
Callens
Meetu Kaushik
MK
Tiwari
Saurabh
S
Agarwal
Aurelie
A
Fricot
Julie
J
Vandekerckhove
Houda
H
Tamouza
Yael
Y
Zermati
Jean-Antoine
JA
Ribeil
Kamel
K
Djedaini
Zeliha
Z
Oruc
Virginie
V
Pascal
Geneviève
G
Courtois
Bertrand
B
Arnulf
Marie-Alexandra
MA
Alyanakian
Patrick
P
Mayeux
Tomas
T
Leanderson
Marc
M
Benhamou
Michel
M
Cogné
Renato C
RC
Monteiro
Olivier
O
Hermine
Ivan C
IC
Moura
D000740:Anemia / Q000503:physiopathology*; D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D004900:Erythroblasts / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D004920:Erythropoiesis / Q000502:physiology*; D004921:Erythropoietin / Q000494:pharmacology; D006801:Humans; D000860:Hypoxia / Q000378:metabolism; D007070:Immunoglobulin A / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011990:Receptors, Transferrin / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D014168:Transferrin / Q000494:pharmacology
D007070:Immunoglobulin A; D011990:Receptors, Transferrin; D014168:Transferrin; C110714:holotransferrin; D004921:Erythropoietin; D019869:Phosphatidylinositol 3-Kinases; D020928:Mitogen-Activated Protein Kinases