GM-CSF instructs vertebral emergency myelopoiesis in neuropathic pain

Abstract

Meningeal immune cells have recently emerged as critical modulators of neural function in both physiological and pathological states1,2. In particular, immune cells within the meninges surrounding the dorsal root ganglia (DRG) have been implicated in the pathogenesis of neuropathic pain3-5. Yet, the cellular complexity of the meningeal immune landscape and the neuroimmune interactions linking this niche to neuropathic pain remain poorly understood. Here, we show that peripheral nerve injury induces both the recruitment of leukocytes to the DRG meninges and their transcriptional reprogramming across innate (primarily myeloid cells) and adaptive immune compartments. The accumulation of myeloid cells, predominantly neutrophils and classical monocytes, within the DRG meninges originates from local vertebral bone marrow (BM) emergency myelopoiesis, followed by their migration through ossified vertebral channels. Further analysis identified meningeal granulocyte-macrophage colony- stimulating factor (GM-CSF), produced mainly by group 2 innate lymphoid cells (ILC2s), as a key mediator that instructs vertebral BM emergency myelopoiesis after peripheral nerve injury, thereby promoting neuropathic pain. These findings uncover a fundamental process linking meningeal immunity to vertebral BM emergency myelopoiesis in the pathophysiological cascade of neuropathic pain and highlight meningeal GM-CSF as the instructive signal orchestrating this neuroimmune axis.