Nerve-myeloid cell interactions in persistent human pain: a reappraisal using updated cell subset classifications

The past 20 years have seen a dramatic shift in our understanding of the role of the immune system in initiating and maintaining pain. Myeloid cells, including macrophages, dendritic cells, Langerhans cells, and mast cells, are increasingly implicated in bidirectional interactions with nerve fibres in rodent pain models. However, our understanding of the human setting is still poor. High-dimensional functional analyses have substantially changed myeloid cell classifications, with recently described subsets such as epidermal dendritic cells and DC3s unveiling new insight into how myeloid cells interact with nerve fibres. However, it is unclear whether this new understanding has informed the study of human chronic pain. In this article, we perform a scoping review investigating neuroimmune interactions between myeloid cells and peripheral nerve fibres in human chronic pain conditions. We found 37 papers from multiple pain states addressing this aim in skin, cornea, peripheral nerve, endometrium, and tumour, with macrophages, Langerhans cells, and mast cells the most investigated. The directionality of results between studies was inconsistent, although the clearest pattern was an increase in macrophage frequency across conditions, phases, and tissues. Myeloid cell definitions were often outdated and lacked correspondence with the stated cell types of interest; overreliance on morphology and traditional structural markers gave limited insight into the functional characteristics of investigated cells. We therefore critically reappraise the existing literature considering contemporary myeloid cell biology and advocate for the application of established and emerging high-dimensional proteomic and transcriptomic single-cell technologies to clarify the role of specific neuroimmune interactions in chronic pain.