TNFR1 signaling in sympathetic nerves dampens the inflammatory response in the bone marrow

Hematological malignancies and cytotoxic therapy induce sympathetic neuropathy in the bone marrow (BM), leading to niche remodeling, disease progression, and impaired hematopoiesis regeneration after myeloablative therapy. Vincristine induces pro-inflammatory cytokine production in the BM, including tumor necrosis factor a (TNF-a), impairs hematopoietic stem cell function, and harms sympathetic neurons. Deleting TNF receptor R1 (TNFR1) in sympathetic nerves exacerbated hematopoietic stem cell exhaustion. Mechanistically, loss of sympathetic nerve-specific TNFR1 signaling prevented the increase of norepinephrine levels in the BM after vincristine treatment, leading to delayed inflammation resolution due to elevated IL-6 production by BM endothelial cells. Therefore, TNFR1 signaling in sympathetic nerves plays a role in the resolution of the inflammatory state after vincristine treatment. Therapeutic strategies meant to reduce inflammation should be considered to prevent long-term hematopoietic damage in cancer patients. 3000 hematopoietic stem cells (Lin- Kit+ Sca-1+ CD48- Cd150+) from TH:cre-TNFR1f/f and TH:cre+TNFR1f/f mice were sorted for bulkRNAseq 48h after 6 weeks vincristine treatment. 1500 mesenchymal stromal cells (CD45- Ter119- Sca1+ CD31-) and 1500 endothelial cells (CD45- Ter119- Sca1+ CD31+) from TH:cre-TNFR1f/f and TH:cre+TNFR1f/f mice were sorted for bulkRNAseq 72h after vicristine injection.