{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T05:24:29Z","timestamp":1790659469506,"version":"4.1.0"},"reference-count":67,"publisher":"SAGE Publications","issue":"4","license":[{"start":{"date-parts":[[2021,1,8]],"date-time":"2021-01-08T00:00:00Z","timestamp":1610064000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Antioxidants &amp; Redox Signaling"],"published-print":{"date-parts":[[2021,2]]},"abstract":"<jats:sec>\n                    <jats:title>Aims:<\/jats:title>\n                    <jats:p>\n                      Lifelong pain is a hallmark feature of sickle cell disease (SCD). How sickle pathobiology evokes pain remains unknown. We hypothesize that increased cell-free heme due to ongoing hemolysis activates toll-like receptor 4 (\n                      <jats:italic toggle=\"yes\">TLR4<\/jats:italic>\n                      ), leading to the formation of reactive oxygen species (ROS) and endoplasmic reticulum (ER) stress. Together, these processes lead to spinal microglial activation and neuroinflammation, culminating in acute and chronic pain.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>\n                      Spinal heme levels, TLR4 transcripts, oxidative stress, and ER stress were significantly higher in sickle mice than controls.\n                      <jats:italic toggle=\"yes\">In vitro<\/jats:italic>\n                      , TLR4 inhibition in spinal cord microglial cells attenuated heme-induced ROS and ER stress. Heme treatment led to a time-dependent increase in the characteristic features of sickle pain (mechanical and thermal hyperalgesia) in both sickle and control mice; this effect was absent in TLR4-knockout sickle and control mice. TLR4 deletion in sickle mice attenuated chronic and hypoxia\/reoxygenation (H\/R)-evoked acute hyperalgesia. Sickle mice treated with the TLR4 inhibitor resatorvid; selective small-molecule inhibitor of TLR4 (TAK242) had significantly reduced chronic hyperalgesia and had less severe H\/R-evoked acute pain with quicker recovery. Notably, reducing ER stress with salubrinal ameliorated chronic hyperalgesia in sickle mice.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Innovation:<\/jats:title>\n                    <jats:p>Our findings demonstrate the causal role of free heme in the genesis of acute and chronic sickle pain and suggest that TLR4 and\/or ER stress are novel therapeutic targets for treating pain in SCD.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion:<\/jats:title>\n                    <jats:p>\n                      Heme-induced microglial activation\n                      <jats:italic toggle=\"yes\">via<\/jats:italic>\n                      TLR4 in the central nervous system contributes to the initiation and maintenance of sickle pain\n                      <jats:italic toggle=\"yes\">via<\/jats:italic>\n                      ER stress in SCD.\n                      <jats:italic toggle=\"yes\">Antioxid. Redox Signal<\/jats:italic>\n                      . 34, 279\u2013293.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1089\/ars.2019.7913","type":"journal-article","created":{"date-parts":[[2020,7,30]],"date-time":"2020-07-30T05:13:27Z","timestamp":1596086007000},"page":"279-293","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":44,"title":["Heme Causes Pain in Sickle Mice\n                    <i>via<\/i>\n                    Toll-Like Receptor 4-Mediated Reactive Oxygen Species- and Endoplasmic Reticulum Stress-Induced Glial Activation"],"prefix":"10.1177","volume":"34","author":[{"given":"Jianxun","family":"Lei","sequence":"first","affiliation":[{"name":"Vascular Biology Center, Division of Hematology, Oncology &amp; Transplantation, Department of Medicine, University of Minnesota, Minneapolis, Minnesota, 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