Senescent peripheral fibroblasts initiate chemotherapy-induced peripheral neuropathy
Malachowski, T.; Raut, G.; Ren, Q.; Mishra, R.; Bagchi, S. M.; Deavers, D.; Luo, X.; Staff, N.; Price, T. J.; Haroutounian, S.; Stewart, S.
Show abstract
Chemotherapy-induced peripheral neuropathy (CIPN) is a common, debilitating complication of cancer therapy. Although axonal degeneration defines CIPN, the initiating cellular events remain unknown. Here, we show that CIPN is initiated by senescent peripheral fibroblasts rather than by the neuron itself. Across the mechanistically distinct chemotherapeutic agents paclitaxel and cisplatin, chemotherapy-induced senescence is unexpectedly restricted to peripheral fibroblasts rather than neurons and acts upstream of neuronal SARM1 activation. Genetic or pharmacological ablation of senescent fibroblasts prevents neuropathy and reverses established disease, demonstrating that these cells are required for both disease initiation and maintenance. Mechanistically, senescent fibroblasts drive neuropathic injury through an MK2-dependent senescence-associated secretory phenotype (SASP), and genetic or pharmacological inhibition of MK2 suppresses the SASP, preserves peripheral innervation and restores sensory function. Together, these findings redefine the cellular origin of CIPN and identify MK2-dependent fibroblast senescence as a therapeutic target.
Matching journals
The top 7 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Macrophage depletion blocks congenital SARM1-dependent neuropathy 94%
- A pathologically expanded, clonal lineage of IL-21 producing CD4+ T cells drives Inflammatory neuropathy 93%
- Annexin A1 drives macrophage skewing towards a resolving phenotype to accelerate the regeneration of muscle injury through AMPK activation 92%
Similar papers in this journal
Similar papers in this journal
- α-Synuclein aggregates induce mitochondrial damage and trigger innate immunity to drive neuron-microglia communication 93%
- Endosome maturation is orchestrated by inside-out proton signaling through a Na+/H+ exchanger and pH-dependent Rab GTPase cycling 92%
- Genetically perturbed myelin as a risk factor for neuroinflammation-driven axon degeneration 92%
Similar papers in this journal
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.