Fibroblasts - the neglected cell type in peripheral sensitization and chronic pain? - A systematic view on the current state of the literature.

Chronic pain and its underlying biological mechanisms have been studied for many decades, with a myriad of molecules, receptors and cell types known to contribute to abnormal pain sensations. We now know that besides an obvious role for neuronal populations in the peripheral and central nervous system, immune cells like microglia, macrophages and T cells are also important drivers of persistent pain. While neuroinflammation has therefore been widely studied in pain research, there is one cell-type that appears to be rather neglected in this context: the humble fibroblast. Fibroblasts may seem unassuming, but actually play a major part in regulating immune cell function and driving chronic inflammation. What is known about them in the context chronic pain? Here we set out to analyze the literature on this topic - using systematic screening and data extraction methods to obtain a balanced view on what has been published. We found that there has been surprisingly little research in this area: 134 articles met our inclusion criteria, only a tiny minority of which directly investigated interactions between fibroblasts and peripheral neurons. We categorized the articles we included - stratifying them according to what was investigated, the estimated quality of results, and any common conclusions. Fibroblasts are a ubiquitous cell type and a prominent source of many pro-algesic mediators in a wide variety of tissues. We think that they deserve a more central role in pain research and propose a new, testable model of how fibroblasts might drive peripheral neuron sensitization.