Mesenchymal stromal cell-derived CCL2 suppresses plasma cell immunoglobulin production via STAT3 inactivation and PAX5 induction.
We demonstrate that the secretome of mesenchymal stromal cells (MSCs) suppresses plasma cell (PC) immunoglobulin (Ig) production, induces plasmablast proliferation, and leads to interleukin-10-mediated blockade in vitro. We found that these effects are the result of MSC-derived CC chemokine ligands CCL2 and CCL7. More specifically, MSCs further processed these CC chemokines by the activity of matrix metalloproteinases (MMPs), leading to the generation of proteolytically processed antagonistic CCL2 variant. Neutralizing CCL2 or inhibiting MMP enzymatic activity abolished the PC-suppressive effect of MSCs. We also observed that MMP-processed CCL2 suppresses signal transducer and activator of transcription 3 (STAT3) activation in PC. As a result, the transcription factor PAX5 is induced, thus explaining the inhibition of Ig synthesis. The absence of inhibitory effects by MSC on the humoral response of CCR2(-/-) mice to xenoantigen suggests that MMP-cleaved CCL2/CCR2 interaction as well as downstream phosphatase activity is necessary for antagonistic effect. We tested syngeneic MSCs in hemophilic B6 mice with predeveloped antihuman factor VIII (hFVIII) antibodies and demonstrated a robust decrease in hFVIII-specific IgG levels. Thus, MSCs may play a role in modulating Ig production by PCs via MMP processing of CCL2 and may represent an appealing cell therapy approach for pathologic humoral responses.
Rafei
Moutih
M
Montreal Centre for Experimental Therapeutics in Cancer, Département de Chimie, Centre BIOMED, Université du Québec à Montréal, Montreal, QC.
Hsieh
Jeremy
J
Fortier
Simon
S
Li
Mengyang
M
Yuan
Shala
S
Birman
Elena
E
Forner
Kathy
K
Boivin
Marie-Noelle
MN
Doody
Karen
K
Tremblay
Michel
M
Annabi
Borhane
B
Galipeau
Jacques
J
D000818:Animals; D018932:Chemokine CCL2 / Q000276:immunology*; D054410:Chemokine CCL7 / Q000276:immunology; D007136:Immunoglobulins / Q000096:biosynthesis*; D020782:Matrix Metalloproteinases / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000276:immunology*; D051379:Mice; D051757:PAX5 Transcription Factor / Q000235:genetics*; D010950:Plasma Cells / Q000276:immunology / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D017154:Stromal Cells / Q000276:immunology*; D015533:Transcriptional Activation / Q000276:immunology
D018932:Chemokine CCL2; D054410:Chemokine CCL7; D007136:Immunoglobulins; D051757:PAX5 Transcription Factor; C497282:Pax5 protein, mouse; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D020782:Matrix Metalloproteinases