{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T11:42:38Z","timestamp":1786534958308,"version":"build-2736575974"},"reference-count":28,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T00:00:00Z","timestamp":1783987200000},"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. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>\n                      Macrophage NLRP3 activation is crucial for antifungal immunity, yet its role in chromoblastomycosis\u2014a chronic subcutaneous mycosis typically caused by\n                      <jats:italic>Fonsecaea pedrosoi<\/jats:italic>\n                      \u2014remains unclear. Unlike prior self-resolving models using conidia and hyphae, clinical disease features muriform cells, a parasitic form resistant to macrophages and linked to chronicity. Notably, chitin, a weak NLRP3 agonist, accumulates on the surface of muriform cells. This study investigates whether chitin accumulation modulates NLRP3 activation and promotes fungal persistence.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Human chromoblastomycosis lesions were analyzed by IHC (MPO, CD86, NLRP3) and RT-PCR for cytokine transcripts. WT and NLRP3\u2013\/\u2013 mice were footpad-inoculated with\n                      <jats:italic>F. pedrosoi<\/jats:italic>\n                      muriform cells for\n                      <jats:italic>in vivo<\/jats:italic>\n                      assessment. Flow cytometric bead array quantified IL-1\u03b2, IL-6, IL-10, TNF-\u03b1, and IL-17A in footpad homogenates, and the same panel (excluding IL-17A) in stimulated BMDM supernatants. NLRP3 pathway activation in BMDMs was confirmed by western blotting and immunofluorescence.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      In human lesions, marked MPO+ neutrophil recruitment encapsulated muriform cells, yet multinucleated giant cells sequestered some fungal elements from neutrophils. Despite robust NLRP3 expression and elevated IL-1\u03b2, IL-6, TNF-\u03b1, and IL-10 versus normal skin (all p &amp;lt; 0.01), muriform cells persisted in tissue. In WT mice, lesions transitioned from purulent (day 7) to granulomatous (day 90), concurrent with declining IL-1\u03b2, IL-17A, IL-6, and TNF-\u03b1. MPO+ neutrophils abundantly surrounded muriform cells at day 7; at day 90, F4\/80+ macrophages enveloped most fungi without elimination, forming multinucleated giant cells\u2014recapitulating human pathology. In NLRP3\u2013\/\u2013 mice, IL-1\u03b2 and IL-17A were produced in an NLRP3-independent manner and showed no decline over time. Muriform cells progressively budded and transitioned to hyphae both inside and outside giant cells; MPO+ neutrophils preferentially localized to hyphal areas, while macrophages remained around muriform cells, suggesting compartmentalized inflammation.\n                      <jats:italic>In vitro<\/jats:italic>\n                      , chitinase-treated muriform cells induced higher NLRP3-dependent IL-1\u03b2, IL-6, TNF-\u03b1, and IL-10 in WT BMDMs versus intact cells (all p &amp;lt; 0.01). Mechanistically, chitin accumulation partially suppressed NF-\u03baB phosphorylation, reducing NLRP3 expression, caspase-1 cleavage, and ASC speck formation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>NLRP3 mediates host defense against muriform cells yet fails to resolve chronic infection. Chitin accumulation on muriform cells attenuates NLRP3 activation, thereby promoting chromoblastomycosis chronicity.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1843553","type":"journal-article","created":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T04:21:41Z","timestamp":1784002901000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Impaired NLRP3 inflammasome activation by chitin underlies refractory chromoblastomycosis caused by Fonsecaea pedrosoi muriform cells"],"prefix":"10.3389","volume":"17","author":[{"given":"Yao","family":"Chen","sequence":"first","affiliation":[{"name":"Hubei Province & Key Laboratory of Skin Infection and Immunity, Department of Dermatology, Wuhan No.1 Hospital","place":["Wuhan, Hubei, China"]},{"name":"Hubei Provincial Clinical Research Center for Infectious Skin Diseases, Department of Dermatology, Wuhan No.1 Hospital","place":["Wuhan, Hubei, 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