{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T17:48:03Z","timestamp":1790617683383,"version":"4.1.0"},"posted":{"date-parts":[[2023,3,7]]},"group-title":"Immunology","reference-count":47,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2023,3,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Objective<\/jats:title>\n                  <jats:p>Inflammasomes modulate the release of bioactive IL-1\u03b2. Excessive IL-1\u03b2 levels are detected in patients with systemic juvenile idiopathic arthritis (sJIA) and cytokine storm syndrome (CSS) with mutated and unmutated inflammasome components, raising questions on the mechanisms of IL-1\u03b2 regulation in these disorders.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>\n                    To investigate how the NLRP3 inflammasome is modulated in sJIA, we focused on Tmem178, a negative regulator of calcium levels in macrophages, and measured IL-1\u03b2 and caspase-1 activation in wild-type (WT) and\n                    <jats:italic>Tmem178<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>-\/-<\/jats:italic>\n                    <\/jats:sup>\n                    macrophages following calcium chelators, silencing of Stim1, a component of store-operated calcium entry (SOCE), or by expressing a Tmem178 mutant lacking Stim1 binding site. Mitochondrial function in both genotypes was assessed by measuring oxidative respiration, mitochondrial reactive oxygen species (mtROS), and mitochondrial damage. CSS development was analyzed in\n                    <jats:italic>Perforin<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>-\/-<\/jats:italic>\n                    <\/jats:sup>\n                    <jats:italic>\/Tmem178<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>-\/-<\/jats:italic>\n                    <\/jats:sup>\n                    mice infected with LCMV in which inflammasome or IL-1 signaling was pharmacologically inhibited. Human\n                    <jats:italic>TMEM178<\/jats:italic>\n                    and\n                    <jats:italic>IL-1B<\/jats:italic>\n                    transcripts were analyzed in a dataset of peripheral blood monocytes from healthy controls and active sJIA patients.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    <jats:italic>TMEM178<\/jats:italic>\n                    levels are reduced in monocytes from sJIA patients while IL-1B show increased levels. Accordingly,\n                    <jats:italic>Tmem178<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>-\/-<\/jats:italic>\n                    <\/jats:sup>\n                    macrophages produce elevated IL-1\u03b2 compared to WT cells. The elevated intracellular calcium levels following SOCE activation in\n                    <jats:italic>Tmem178<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>-\/-<\/jats:italic>\n                    <\/jats:sup>\n                    macrophages induce mitochondrial damage, release mtROS, and ultimately, promote NLRP3 inflammasome activation.\n                    <jats:italic>In vivo<\/jats:italic>\n                    , inhibition of inflammasome or IL-1 neutralization prolongs\n                    <jats:italic>Tmem178<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>-\/-<\/jats:italic>\n                    <\/jats:sup>\n                    mouse survival to LCMV-induced CSS.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>Downregulation of Tmem178 levels may represent a new biomarker to identify sJIA\/CSS patients that could benefit from receiving drugs targeting inflammasome signaling.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2023.03.07.531385","type":"posted-content","created":{"date-parts":[[2023,3,7]],"date-time":"2023-03-07T22:00:14Z","timestamp":1678226414000},"source":"Crossref","is-referenced-by-count":1,"title":["Tmem178 negatively regulates IL-1\u03b2 production through inhibition of the NLRP3 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