RT Journal Article SR Electronic T1 Mast cell extracellular trap formation underlies vascular and neural injury and hyperalgesia in sickle cell disease JF Life Science Alliance JO Life Sci. Alliance FD Life Science Alliance LLC SP e202402788 DO 10.26508/lsa.202402788 VO 7 IS 11 A1 Argueta, Donovan A A1 Tran, Huy A1 Goel, Yugal A1 Nguyen, Aithanh A1 Nguyen, Julia A1 Kiven, Stacy B A1 Chen, Chunsheng A1 Abdulla, Fuad A1 Vercellotti, Gregory M A1 Belcher, John D A1 Gupta, Kalpna YR 2024 UL https://www.life-science-alliance.org/content/7/11/e202402788.abstract AB Sickle cell disease (SCD) is the most common inherited monogenetic disorder. Chronic and acute pain are hallmark features of SCD involving neural and vascular injury and inflammation. Mast cells reside in the vicinity of nerve fibers and vasculature, but how they influence these structures remains unknown. We therefore examined the mechanism of mast cell activation in a sickle microenvironment replete with cell-free heme and inflammation. Mast cells exposed to this environment showed an explosion of nuclear contents with the release of citrullinated histones, suggestive of mast cell extracellular trap (MCET) release. MCETs interacted directly with the vasculature and nerve fibers, a cause of vascular and neural injury in sickle cell mice. MCET formation was dependent upon peptidylarginine deiminase 4 (PAD4). Inhibition of PAD4 ameliorated vasoocclusion, chronic and acute hyperalgesia, and inflammation in sickle mice. PAD4 activation may also underlie neutrophil trap formation in SCD, thus providing a novel target to treat the sequelae of vascular and neural injury in SCD.