{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T14:19:32Z","timestamp":1790691572690,"version":"4.1.0"},"reference-count":45,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"10","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2025,3,11]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>\n                      Ca\n                      <jats:sup>2+<\/jats:sup>\n                      release-activated Ca\n                      <jats:sup>2+<\/jats:sup>\n                      channel regulator 2A (CRACR2A) has been linked to immunodeficiency attributable to T-cell dysfunction in humans. We discovered that neutrophil CRACR2A promotes neutrophil adhesive and migratory functions by facilitating Ca\n                      <jats:sup>2+<\/jats:sup>\n                      mobilization and \u03b22 integrin activation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>\n                      Myeloid-specific Cracr2a conditional knockout mice and intravital microscopy were used to investigate the physiologic role of neutrophil Cracr2a in neutrophil recruitment in vascular inflammation. Cracr2a-deficient neutrophils or dHL-60 (differentiated human promyelocytic leukemia) cells and Cracr2a-derived peptides were used in flow cytometry, immunoprecipitation, cytosolic Ca\n                      <jats:sup>2+<\/jats:sup>\n                      mobilization, and flow chamber assays to elucidate the molecular mechanism. Four-dimensional confocal intravital microscopy of mice after focal brain ischemia and single neutrophil behavioral analysis demonstrated the pathologic role of neutrophil Cracr2a in brain damage.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      Compared with wild-type control mice, Cracr2a conditional knockout mice exhibited significantly reduced adhesion, crawling, and transmigration of neutrophils on ear and cremaster venules in tumor necrosis factor\u2013\u03b1\u2013induced sterile inflammation. Neutrophil Cracr2a rapidly interacts with Stim1 (stromal interaction molecule 1) after agonist stimulation and facilitates Ca\n                      <jats:sup>2+<\/jats:sup>\n                      mobilization, increasing the ligand-binding function of \u03b22 integrin. Our findings in Cracr2a-deficient mouse neutrophils are recapitulated in dHL-60 cells, in which CRACR2A is deleted by CRISPR\/Cas9. Furthermore, overexpression of CRACR2A in CRACR2A KO dHL-60 cells restores normal function. Using a series of peptides covering the coiled-coil region of Cracr2a, we identified a palmitoylated 20-mer that blocks Stim1-Cracr2a interaction. Treating neutrophils with this 20-mer inhibits Ca\n                      <jats:sup>2+<\/jats:sup>\n                      mobilization and \u03b22 integrin activation after agonist stimulation, reducing neutrophil recruitment to an activated endothelial cell monolayer under venous shear stress and to ear venules in tumor necrosis factor\u2013\u03b1\u2013challenged mice. Cerebral 4-dimensional intravital microscopy of mice after focal brain ischemia revealed that neutrophil Cracr2a enhances the emergence of highly migratory neutrophils by increasing the surface level of \u03b1M\u03b22 integrin, thereby facilitating neutrophil infiltration into brain tissue and exacerbating brain injury.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>Our results demonstrate that neutrophil CRACR2A promotes neutrophil recruitment to sites of sterile inflammation, such as ischemic stroke. Blocking the STIM1\u2013CRACR2A interaction may be a novel therapeutic strategy to mitigate inflammation and consequent tissue injury.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circulationaha.124.070487","type":"journal-article","created":{"date-parts":[[2024,11,27]],"date-time":"2024-11-27T05:01:11Z","timestamp":1732683671000},"page":"696-715","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":17,"title":["Neutrophil CRACR2A Promotes Neutrophil Recruitment in Sterile Inflammation and Ischemic Stroke"],"prefix":"10.1161","volume":"151","author":[{"given":"Jingu","family":"Lee","sequence":"first","affiliation":[{"name":"Division of Hematology, Department of Medicine (J.L., B.B., A.S., V.K., J.C.), Washington University School of Medicine, St Louis, MO."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brett","family":"Balzraine","sequence":"additional","affiliation":[{"name":"Division of Hematology, Department of Medicine (J.L., B.B., A.S., V.K., J.C.), Washington University School of Medicine, St Louis, MO."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexis","family":"Schweizer","sequence":"additional","affiliation":[{"name":"Division of Hematology, Department of Medicine (J.L., B.B., A.S., V.K., J.C.), Washington University School of Medicine, St Louis, MO."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vasilisa","family":"Kuzmanova","sequence":"additional","affiliation":[{"name":"Division of Hematology, Department of Medicine (J.L., B.B., A.S., V.K., J.C.), Washington University School of Medicine, St Louis, MO."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2821-9245","authenticated-orcid":true,"given":"Yousang","family":"Gwack","sequence":"additional","affiliation":[{"name":"Department of Physiology, David Geffen School of Medicine, University of California, Los Angeles (Y.G.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7172-9240","authenticated-orcid":true,"given":"Babak","family":"Razani","sequence":"additional","affiliation":[{"name":"Vascular Medicine Institute, Department of Medicine, University of Pittsburgh School of Medicine and UPMC, PA (B.R.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3979-0906","authenticated-orcid":true,"given":"Jin-Moo","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Neurology (J.-M.L.), Washington University School of Medicine, St Louis, MO."},{"name":"Hope Center for Neurological Disorders (J.-M.L.), Washington University School of Medicine, St Louis, MO."},{"name":"Mallinckrodt Institute of Radiology (J.-M.L.), Washington University School of Medicine, St Louis, MO."},{"name":"Department of Biomedical Engineering (J.-M.L.), Washington University School of Medicine, St Louis, MO."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deane F.","family":"Mosher","sequence":"additional","affiliation":[{"name":"Departments of Biomolecular Chemistry (D.F.M.)), University of Wisconsin\u2013Madison."},{"name":"Medicine (D.F.M.), University of Wisconsin\u2013Madison."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2404-3446","authenticated-orcid":true,"given":"Jaehyung","family":"Cho","sequence":"additional","affiliation":[{"name":"Division of Hematology, Department of Medicine (J.L., B.B., A.S., V.K., J.C.), Washington University School of Medicine, St Louis, MO."},{"name":"and Department of Pathology and Immunology (J.C.), Washington University School of Medicine, St Louis, 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