| First Author | Anirudh S | Year | 2020 |
| Journal | Cells | Volume | 9 |
| Issue | 5 | PubMed ID | 32429067 |
| Mgi Jnum | J:304179 | Mgi Id | MGI:6694387 |
| Doi | 10.3390/cells9051223 | Citation | Anirudh S, et al. (2020) TNFalpha Rescues Dendritic Cell Development in Hematopoietic Stem and Progenitor Cells Lacking C/EBPalpha. Cells 9(5):1223 |
| abstractText | Dendritic cells (DCs) are crucial effectors of the immune system, which are formed from hematopoietic stem and progenitor cells (HSPCs) by a multistep process regulated by cytokines and distinct transcriptional mechanisms. C/EBPalpha is an important myeloid transcription factor, but its role in DC formation is not well defined. Using a Cebpa(Cre)-EYFP reporter mouse model, we show that the majority of splenic conventional DCs are derived from Cebpa-expressing HSPCs. Furthermore, HSPCs isolated from Cebpa knockout (KO) mice exhibited a marked reduced ability to form mature DCs after in vitro culture with FLT3L. Differentiation analysis revealed that C/EBPalpha was needed for the formation of monocytic dendritic progenitors and their transition to common dendritic progenitors. Gene expression analysis and cytokine profiling of culture supernatants showed significant downregulation of inflammatory cytokines, including TNFalpha and IL-1beta as well as distinct chemokines in KO HSPCs. In addition, TNFalpha-induced genes were among the most dysregulated genes in KO HSPCs. Intriguingly, supplementation of in vitro cultures with TNFalpha at least partially rescued DC formation of KO HSPCs, resulting in fully functional, mature DCs. In conclusion, these results reveal an important role of C/EBPalpha in early DC development, which in part can be substituted by the inflammatory cytokine TNFalpha. |
