{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T06:31:11Z","timestamp":1786516271623,"version":"build-2736575974"},"reference-count":31,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T00:00:00Z","timestamp":1786492800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>\n                      Erythema Nodosum Leprosum (ENL) is an inflammatory complication of leprosy that is associated with the progression of peripheral nerve damage and the resultant physical disabilities. Neutrophil-mediated inflammation plays a crucial role in the emergence of ENL. Recent evidence suggests that\n                      <jats:italic>Mycobacterium leprae<\/jats:italic>\n                      triggers neutrophil degranulation and the generation of Low-Density Neutrophils (LDN). This study aimed to investigate whether inhibition of critical regulators of human neutrophil activation can regulate\n                      <jats:italic>M. leprae<\/jats:italic>\n                      -induced neutrophil degranulation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      To explore the mechanisms underlying inflammation\n                      <jats:italic>in vitro<\/jats:italic>\n                      , whole-blood cultures were incubated with\n                      <jats:italic>M. leprae<\/jats:italic>\n                      . The effects of selective inhibitors in\n                      <jats:italic>M. leprae<\/jats:italic>\n                      co-cultures were subsequently evaluated by measuring surface expression of granule markers, levels of inflammatory cytokines, and release of granule-related proteins, including MMP-9, PTX3, and MPO.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We found that at least 8 h of\n                      <jats:italic>M. leprae<\/jats:italic>\n                      incubation was necessary to trigger primary and secondary granule degranulation, while tertiary granules began to degranulate within 4 h. At this 4-h mark, LDNs were observed in cell cultures. By 24 h, we confirmed neutrophil degranulation and LDN generation. We observed a correlation between the release of pro-inflammatory cytokines and degranulation markers. The secretion of IL-8 and IL-6 was associated with secondary and tertiary granule degranulation. Selective inhibition of p38 MAPK affected the release of tertiary and secondary granules as well as IL-6 secretion. Moreover, mito-TEMPO treatment showed that mitochondrial ROS production seems to be crucial for\n                      <jats:italic>M. leprae<\/jats:italic>\n                      -induced primary and secondary granules degranulation. Finally, the inhibition of TGF-\u03b2 receptor 1 indicates that TGF-\u03b2 modulates\n                      <jats:italic>M. leprae<\/jats:italic>\n                      -induced neutrophil degranulation and LDN generation through binding to the receptor.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>\n                      These results indicate that p38 MAPK pathway and mitochondrial ROS production are important contributors to\n                      <jats:italic>M. leprae<\/jats:italic>\n                      -induced neutrophil degranulation, while TGF-\u03b2\/TGF-\u03b2R1 signaling exerts an important regulatory effect. These findings advance our knowledge of the molecular mechanisms underlying\n                      <jats:italic>M. leprae<\/jats:italic>\n                      -induced degranulation and raise the possibility of new potential therapeutic strategies for targeting ENL-related degranulation.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1883257","type":"journal-article","created":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T05:57:04Z","timestamp":1786514224000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Differential regulation of neutrophil degranulation by p38 MAPK and mitochondrial ROS during Mycobacterium leprae infection"],"prefix":"10.3389","volume":"17","author":[{"given":"Isabella Forasteiro","family":"Tavares","sequence":"first","affiliation":[{"name":"Funda\u00e7\u00e3o Oswaldo Cruz, Fiocruz, Instituto Oswaldo Cruz, Laborat\u00f3rio de Hansen\u00edase","place":["Rio de Janeiro, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafaela de Souza","family":"Andrade","sequence":"additional","affiliation":[{"name":"Funda\u00e7\u00e3o Oswaldo Cruz, Fiocruz, Instituto Oswaldo Cruz, Laborat\u00f3rio de Hansen\u00edase","place":["Rio de Janeiro, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natasha","family":"Cabral","sequence":"additional","affiliation":[{"name":"Funda\u00e7\u00e3o Oswaldo Cruz, Fiocruz, Instituto Oswaldo Cruz, Laborat\u00f3rio de Hansen\u00edase","place":["Rio de Janeiro, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberta Olmo","family":"Pinheiro","sequence":"additional","affiliation":[{"name":"Funda\u00e7\u00e3o Oswaldo Cruz, Fiocruz, Instituto Oswaldo Cruz, Laborat\u00f3rio de Hansen\u00edase","place":["Rio de Janeiro, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veronica","family":"Schmitz","sequence":"additional","affiliation":[{"name":"Funda\u00e7\u00e3o Oswaldo Cruz, Fiocruz, Instituto Oswaldo Cruz, Laborat\u00f3rio de Hansen\u00edase","place":["Rio de Janeiro, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,12]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1209","DOI":"10.1016\/S0140-6736(04)15952-7","article-title":"Leprosy","volume":"363","author":"Britton","year":"2004","journal-title":"Lancet"},{"key":"B2","doi-asserted-by":"publisher","first-page":"e0007368","DOI":"10.1371\/journal.pntd.0007368","article-title":"Neutrophil extracellular traps contribute to the pathogenesis of leprosy type 2 reactions. 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