Impaired NLRP3 inflammasome activation by chitin underlies refractory chromoblastomycosis caused by

Introduction: Macrophage NLRP3 activation is crucial for antifungal immunity, yet its role in chromoblastomycosis-a chronic subcutaneous mycosis typically caused by Methods: Human chromoblastomycosis lesions were analyzed by IHC (MPO, CD86, NLRP3) and RT-PCR for cytokine transcripts. WT and NLRP3-/- mice were footpad-inoculated with Results: 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-1β, IL-6, TNF-α, and IL-10 versus normal skin (all p < 0.01), muriform cells persisted in tissue. In WT mice, lesions transitioned from purulent (day 7) to granulomatous (day 90), concurrent with declining IL-1β, IL-17A, IL-6, and TNF-α. MPO+ neutrophils abundantly surrounded muriform cells at day 7; at day 90, F4/80+ macrophages enveloped most fungi without elimination, forming multinucleated giant cells-recapitulating human pathology. In NLRP3-/- mice, IL-1β 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. Conclusion: 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.