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. 2019 Mar 20;13:110. doi: 10.3389/fncel.2019.00110

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Copyright © 2019 Mittal, Sagi, Gupta and Gupta.

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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Mast cell (MC) activation promotes hyperalgesia in sickle cell disease (SCD). MC activation leads to the release of noxious substances such as proteases, neuropeptides and cytokines as well as the release of MC extracellular traps (MCETs) with citrullinated H3 histones and DNA, which cause noxious as well as physical injury to the vasculature and nerve bundles, leading to hyperalgesia in SCD. Emerging data suggest that this process is mediated by endoplasmic reticulum (ER) stress/reactive oxygen species (ROS) production and may engage FcεR1 and toll-like receptor 4 (TLR4) leading to Syk associated downstream protein kinase B (PKB/Akt) signaling. Consequent peptidylarginine deiminase-4 (PAD-4) activation may stimulate the release of extracellular traps, while inflammasome signaling may further augment inflammation.