Transfer between cells is an unexpected addition to the mitochondrial life cycle. In this issue of Neuron, Van der Vlist et al. now provide evidence that M2-macrophages infiltrating sensory ganglia resolve pain by transferring particles containing mitochondria to neurons—thus boosting nociceptors back to normal function.
Mitochondria are known historic invaders. However—since having taken residence in early eukaryotic cells long ago in evolution—these organelles were seen as stable endosymbionts trapped in their host cells by dependency on nuclear gene transcription. In this view, mitochondria would be faithfully passed on in our body’s cell lineages, in the process being adapted by their host cell’s differentiation programs, while in converse also cell-autonomously influencing their host’s phenotype—as would any other organelle. Indeed, while some cell types are known to expunge their mitochondria, generally cells were considered unable to obtain new mitochondria, except for by biogenic divisions and growth of their own ancestral organelle pool. This dogma, however, is shifting: mounting evidence shows that mitochondria are capable of transfer between cells, in this process shaping the phenotype of their recipients in many important and—in disease settings—potentially beneficial ways, including in the nervous system.
In this issue of Neuron, a paper by van der Vlist, Raoof, Willemen, et al. makes a substantial contribution to fortifying this new view, now in the important context of how inflammatory pain resolves and chronic pain states are avoided (van der Vlist et al., 2022). By using a transient inflammatory pain model in mice, combined with genetic macrophage depletion, the authors show that resolution of the resulting transient pain state depends on macrophages of an M2-like polarization that infiltrate dorsal root ganglia (DRG), where the nociceptive neurons reside. Indeed pain resolution can be re-established by the intrathecal transfer of either non-polarized or M2-polarized bone-marrow-derived monocytes, but not by the transfer of their M1-polarized counterparts or by transfer of monocytes, in which interleukin-4 (IL-4) signaling has been genetically disrupted. These findings are in line with previous observations that outline the critical role that distinct phagocyte phenotypes in the DRG and spinal cord play during the induction and resolution of pain states (Yu et al., 2020; Niehaus et al., 2021). Furthermore, they directly implicate endogenous IL-4 as a critical immune mediator in the instruction of the pain-resolving phagocyte phenotype. The main conceptual advance of the study, however, is the subsequent mechanistic dissection of the way in which these DRG-infiltrating phagocytes prevent the perpetuation of inflammatory hyperalgesia (Figure 1). Here the authors use an elegant series of cell and vesicle transfer experiments together with targeted genetic perturbations to provide strong evidence that pain resolution by infiltrating macrophages is mediated via CD200R/iSec 1-dependent transfer of extracellular vesicles that contain mitochondria. The authors propose that these mitochondria are indeed the agent of change, perhaps by recharging the nociceptors’ depleted energy reserves.
