Calcineurin/NFAT signalling inhibits myeloid haematopoiesis.
Nuclear factor of activated T cells (NFAT) comprises a family of transcription factors that regulate T cell development, activation and differentiation. NFAT signalling can also mediate granulocyte and dendritic cell (DC) activation, but it is unknown whether NFAT influences their development from progenitors. Here, we report a novel role for calcineurin/NFAT signalling as a negative regulator of myeloid haematopoiesis. Reconstituting lethally irradiated mice with haematopoietic stem cells expressing an NFAT-inhibitory peptide resulted in enhanced development of the myeloid compartment. Culturing bone marrow cells in media supplemented with Flt3-L in the presence of the calcineurin/NFAT inhibitor Cyclosporin A increased numbers of differentiated DC. Global gene expression analysis of untreated DC and NFAT-inhibited DC revealed differential expression of transcripts that regulate cell cycle and apoptosis. In conclusion, these results provide evidence that calcineurin/NFAT signalling negatively regulates myeloid lineage development. The finding that inhibition of NFAT enhances myeloid development provides a novel insight into understanding how the treatment with drugs targeting calcineurin/NFAT signalling influence the homeostasis of the innate immune system.
Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.
Jan
J
Fric
Clarice X F
CX
Lim
Esther G L
EG
Koh
Benjamin
B
Hofmann
Jinmiao
J
Chen
Hock Soon
HS
Tay
Siti Aminah Bte
SA
Mohammad Isa
Alessandra
A
Mortellaro
Christiane
C
Ruedl
Paola
P
Ricciardi-Castagnoli
D000818:Animals; D019703:Calcineurin / Q000378:metabolism*; D016572:Cyclosporine / Q000494:pharmacology; D003713:Dendritic Cells / Q000166:cytology / Q000378:metabolism; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000166:cytology* / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D015854:Up-Regulation
D007166:Immunosuppressive Agents; D050778:NFATC Transcription Factors; D016572:Cyclosporine; D019703:Calcineurin