Figure 6: Summary diagram of potential role of PAR2 and downstream signaling in paclitaxel-induced neuropathy.

The figure summarizes our hypothesis of how PAR2 signaling on a specific subset of nociceptors might lead to loss of epidermal nerve fibers, satellite cell gliosis and pain. A key feature of the model is that paclitaxel-induced changes may begin with a small subset of sensory fibers, but gene expression changes in DRG cell bodies driven by PAR2 activation could cause spread of satellite cell gliosis causing sensitization of additional subsets of DRG nociceptors. Some conclusions summarized in the figure are from previously published studies including PAR2 signaling inducing changes in translation regulation⁹⁹, the important role of MNKeIF4E signaling in paclitaxel CIPN model⁶⁹, and the key role of satellite cell gliosis in CIPN^{27, 59, 87}.