{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T06:58:40Z","timestamp":1780469920454,"version":"3.54.1"},"reference-count":15,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2018,11,24]],"date-time":"2018-11-24T00:00:00Z","timestamp":1543017600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000011","name":"Howard Hughes Medical Institute","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000011","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["R01\u2010HL\u2010112836"],"award-info":[{"award-number":["R01\u2010HL\u2010112836"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006260","name":"Rheumatology Research Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100006260","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["acrjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Arthritis &amp; Rheumatology"],"published-print":{"date-parts":[[2019,1]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>Macrophage activation syndrome (MAS) is a life\u2010threatening cytokine storm syndrome that occurs in patients with underlying rheumatic diseases. Preclinical and clinical data suggest that interferon\u2010\u03b3 (IFN\u03b3) is pathogenic in MAS, but how IFN\u03b3 may be linked to disease pathogenesis remains unknown. This study was undertaken to determine whether IFN\u03b3 signals synergize with systemic innate immune responses to drive the cytokine storm in a murine model of MAS.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>IFN\u03b3\u2010deficient mice were treated with 5 doses of the Toll\u2010like receptor 9 (TLR\u20109) agonist CpG 1826, IFN\u03b3, or a combination of the 2 stimuli over the course of 10 days. Immunopathologic features of MAS, including cytopenias, hepatitis, hepatosplenomegaly, and induction of inflammatory myelopoiesis, were assessed. Mixed bone marrow chimeras were created to determine whether TLR\u20109\u2013 and IFN\u03b3 receptor 1 (IFN\u03b3R1)\u2013dependent signals induce enhanced myelopoiesis in a cell\u2010intrinsic or cell\u2010extrinsic manner.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>IFN\u03b3\u2010deficient mice did not develop features of MAS when treated with repeated doses of either the TLR\u20109 agonist or IFN\u03b3 alone. In contrast, IFN\u03b3\u2010deficient mice treated with both the TLR\u20109 agonist and IFN\u03b3 developed cytopenias, hepatitis, and hepatosplenomegaly, reproducing major clinical features of MAS. TLR\u20109\u2013 and IFN\u03b3R1\u2010dependent signals synergized to enhance myeloid progenitor cell function and induce myelopoiesis in vivo, which occurred through cell\u2010extrinsic mechanisms and correlated with the induction of disease.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>These findings demonstrate that TLR\u20109\u2013driven signals potentiate the effects of IFN\u03b3 to initiate murine MAS, and provide evidence that induction of inflammatory myelopoiesis is a common TLR\u20109\u2013 and IFN\u03b3\u2010dependent pathway that may contribute to the pathogenesis of MAS.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.40683","type":"journal-article","created":{"date-parts":[[2018,8,7]],"date-time":"2018-08-07T00:40:12Z","timestamp":1533602412000},"page":"161-168","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Interferon\u2010\u03b3\u2013Mediated Immunopathology Potentiated by Toll\u2010Like Receptor 9 Activation in a Murine Model of Macrophage Activation Syndrome"],"prefix":"10.1002","volume":"71","author":[{"given":"Lehn K.","family":"Weaver","sequence":"first","affiliation":[{"name":"The Children\u2019s Hospital of Philadelphia  Philadelphia Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niansheng","family":"Chu","sequence":"additional","affiliation":[{"name":"The Children\u2019s Hospital of Philadelphia  Philadelphia Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward M.","family":"Behrens","sequence":"additional","affiliation":[{"name":"The Children\u2019s Hospital of Philadelphia  Philadelphia Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2018,11,24]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40674-017-0059-x"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI43157"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2015-209020"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2017.07.021"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20102538"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.33496"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.38359"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.22981"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.3899\/jrheum.100655"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng1782"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1524487113"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.37958"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2014.05.004"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-07-367706"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-065X.2008.00707.x"}],"container-title":["Arthritis &amp; 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