Natural Killer Cells Degenerate Intact Sensory Afferents following Nerve Injury

Abstract

SummarySensory axons degenerate following separation from their cell body, but partial injury to peripheral nerves may leave the integrity of damaged axons preserved. We show that an endogenous ligand for the natural killer (NK) cell receptor NKG2D, Retinoic Acid Early 1 (RAE1), is re-expressed in adult dorsal root ganglion neurons following peripheral nerve injury, triggering selective degeneration of injured axons. Infiltration of cytotoxic NK cells into the sciatic nerve by extravasation occurs within 3 days following crush injury. Using a combination of genetic cell ablation and cytokine-antibody complex stimulation, we show that NK cell function correlates with loss of sensation due to degeneration of injured afferents and reduced incidence of post-injury hypersensitivity. This neuro-immune mechanism of selective NK cell-mediated degeneration of damaged but intact sensory axons complements Wallerian degeneration and suggests the therapeutic potential of modulating NK cell function to resolve painful neuropathy through the clearance of partially damaged nerves.

Natural killer cells modulate motor neuron-immune cell cross talk in models of Amyotrophic Lateral Sclerosis

“…A new paradigm that emerged from our data is that motor neuron degeneration results from direct cell-to-cell contacts with NK cells, with mechanisms involving granule exocytosis and perforin expression. A recent report on a model of peripheral nerve injury, describes that the NKG2D ligand Rae1 is upregulated in the lumbar DRG of adult mice upon cutting the corresponding spinal nerve, and that neurite fragmentation is boosted by IL-2 stimulated NK cells 17 . Our data that both in CNS tissue of ALS patient and in hSOD1 G93A mice, motor neurons express different NKG2D ligands, identify NKG2D on NK cells as possible molecular targets to reduce motor neuron loss.…”

“…NK cells regulate both the adaptive and innate immune responses, and CNS infiltrating NK cells modulate neuroinflammation in neurodegenerative diseases [11][12][13][14] , and affect microglial phenotype in cerebral tumors 15,16 . In addition, it was recently described that in pathological conditions, damaged neurons express NKG2D ligands and selectively succumb to NK cell-mediated degeneration 17 . Previous longitudinal cohort studies of peripheral blood from ALS patients revealed an increased number of NK cells in patients 18 ; additionally, end-stage hSOD1 G93A mice showed high NK cell frequency in the spinal cord 19 .…”

A pharmacological interactome platform for discovery of pain mechanisms and targets

“…This suggests that recruitment of these immune cells to the peripheral nerve may be a key factor in driving persistent pain rather than plasticity in the transcriptomes of these cell types. This notion is supported by recent studies in rodent models (Krukowski et al, 2016;Davies et al, 2019;Yu et al, 2020) and patient transcriptional profiling (North et al, 2019). This cell-type and gene module bi-clustering approach reveals specific ligand-receptor interactions for peripheral cell types with sensory neurons that can be further mined for identification of new pain targets.…”

“…These ECM and adhesion molecule interactions may also play a critical role in recruitment and proliferation of immune cells to peripheral nerves and the DRG after nerve injury. Insofar as these neuro-immune interactions in the periphery are emerging as key players in nerve regeneration (Davies et al, 2019) and neuropathic pain (Ji et al, 2016;Yu et al, 2020), gaining a better understanding of how this occurs will yield new insight into disease states. Therefore, this is almost certainly an area that is ripe for further exploration from the perspective of fundamental neurobiology knowledge and therapeutic target discovery.…”

“…We focused on 2 module interactomes enriched in immune cell types for graphically presentation: the macrophage and leukocyte enriched cluster, and the T-cell and natural killer cell enriched cluster. We chose these based on the key role these immune cell types play in neuropathic pain models in male and/or female mice (Willemen et al, 2014;Sorge et al, 2015;Krukowski et al, 2016;Davies et al, 2019;Rosen et al, 2019;Yu et al, 2020). The ligand-receptor interactomes emerging from this gene cluster enrichment analysis revealed distinct factors expressed by these immune cells that are known to play a role in neuropathic pain states.…”