Sickle cell disease (SCD) is a common hereditary hematologic disorder. SCD patients suffer from acute vaso-occlusive episodes (VOEs), chronic organ damage, and premature death, with few therapeutic options. Although severe pain is a major clinical manifestation of SCD, it remains unknown whether nociception plays a role in SCD pathogenesis. To address this question, we generated nociceptor-deficient SCD mice and found, unexpectedly, that the absence of nociception led to more severe and more lethal VOE, indicating that somatosensory nerves protect SCD mice from VOE. Mechanistically, the beneficial effects of sensory nerves were induced by the neuropeptide calcitonin gene–related peptide (CGRP), which acted on hematopoietic cells. Additionally, oral capsaicin consumption, which can activate somatosensory nerves by binding to TRPV1, dramatically alleviated acute VOE and significantly prevented chronic liver and kidney damage in SCD mice. Thus, the manipulation of nociception may provide a promising approach to treat SCD.
Nociceptors protect sickle cell disease mice from vaso-occlusive episodes and chronic organ damage
Disclosures: P.S. Frenette reported grants from the National Institutes of Health during the conduct of the study; personal fees from Pfizer, grants from Ironwood Pharmaceuticals, and "other" from Cygnal Therapeutics outside the submitted work. He has served as consultant for Pfizer, received research funding from Ironwood Pharmaceuticals, and owns shares of Cygnal Therapeutics. No other disclosures were reported.
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Chunliang Xu, Maria Gulinello, Paul S. Frenette; Nociceptors protect sickle cell disease mice from vaso-occlusive episodes and chronic organ damage. J Exp Med 4 January 2021; 218 (1): e20200065. doi: https://doi.org/10.1084/jem.20200065
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