NLRP3 inflammasome signaling orchestrates hepatic granuloma organization and protective immunity
- 1Department of Cellular and Molecular Biology, School of Medicine of Ribeirao Preto, University of Sao Paulo. Ribeirao Preto, SP 14049-900, Brazil
Abstract
Granulomas are organized immune structures that contribute to host defense against persistent pathogens, yet the mechanisms that coordinate their assembly and protective function remain incompletely understood. Here, using experimental visceral leishmaniasis caused by Leishmania infantum and samples from patients with active disease, we identify the NLRP3 inflammasome as a regulator of protective hepatic granulomatous immunity. Inflammasome-associated mediators were elevated in patients and correlated with systemic inflammation. In mice, L. infantum induced NLRP3 inflammasome activation within hepatic granulomas, while single-cell and spatial transcriptomic analyses revealed enrichment of inflammasome-associated transcription in hepatic macrophages and granuloma-associated regions. NLRP3 deficiency did not prevent granuloma initiation but impaired granuloma expansion, cellular organization, and leukocyte accumulation. This response required Caspase-1/11 and IL-18, but was independent of IL-1{beta}. Loss of NLRP3 also impaired parasite control despite reducing hepatic inflammation and histopathological alterations. Together, our findings identify NLRP3-Caspase-1/11-IL-18 signaling as a mechanism that coordinates the cellular and spatial organization of protective hepatic granulomas, revealing granuloma architecture as a previously unrecognized function of inflammasome-mediated immunity and providing mechanistic insight into host resistance in visceral leishmaniasis, a potentially fatal neglected tropical disease.
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BibTeX
@misc{oliveira2026nlrp3,
title = {{NLRP3 inflammasome signaling orchestrates hepatic granuloma organization and protective immunity}},
author = {I. M. de Oliveira and M. M. Chaves and J. Costa-Madeira and A. L. Barbosa and P. S. Corradi and B. de Oliveira and A. M. Becerra and P. H. Marques and T. S. Rodrigues and A. Simizo and L. Lorenzon and S. S. Batah and A. J. Herrera and H. I. Nakaya and A. M. da Silva and R. T. Gazzinelli and A. K. Cruz and C. M. Takiya and A. T. Fabro and G. B. Menezes and C. H. Costa and D. S. Zamboni},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.18.752760},
url = {https://www.biorxiv.org/content/10.64898/2026.09.18.752760v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - NLRP3 inflammasome signaling orchestrates hepatic granuloma organization and protective immunity
AU - I. M. de Oliveira
AU - M. M. Chaves
AU - J. Costa-Madeira
AU - A. L. Barbosa
AU - P. S. Corradi
AU - B. de Oliveira
AU - A. M. Becerra
AU - P. H. Marques
AU - T. S. Rodrigues
AU - A. Simizo
AU - L. Lorenzon
AU - S. S. Batah
AU - A. J. Herrera
AU - H. I. Nakaya
AU - A. M. da Silva
AU - R. T. Gazzinelli
AU - A. K. Cruz
AU - C. M. Takiya
AU - A. T. Fabro
AU - G. B. Menezes
AU - C. H. Costa
AU - D. S. Zamboni
PY - 2026
DA - 2026/09/18
PB - bioRxiv
DO - 10.64898/2026.09.18.752760
UR - https://www.biorxiv.org/content/10.64898/2026.09.18.752760v1
AB - Granulomas are organized immune structures that contribute to host defense against persistent pathogens, yet the mechanisms that coordinate their assembly and protective function remain incompletely understood. Here, using experimental visceral leishmaniasis caused by Leishmania infantum and samples from patients with active disease, we identify the NLRP3 inflammasome as a regulator of protective hepatic granulomatous immunity. Inflammasome-associated mediators were elevated in patients and correlated with systemic inflammation. In mice, L. infantum induced NLRP3 inflammasome activation within hepatic granulomas, while single-cell and spatial transcriptomic analyses revealed enrichment of inflammasome-associated transcription in hepatic macrophages and granuloma-associated regions. NLRP3 deficiency did not prevent granuloma initiation but impaired granuloma expansion, cellular organization, and leukocyte accumulation. This response required Caspase-1/11 and IL-18, but was independent of IL-1{beta}. Loss of NLRP3 also impaired parasite control despite reducing hepatic inflammation and histopathological alterations. Together, our findings identify NLRP3-Caspase-1/11-IL-18 signaling as a mechanism that coordinates the cellular and spatial organization of protective hepatic granulomas, revealing granuloma architecture as a previously unrecognized function of inflammasome-mediated immunity and providing mechanistic insight into host resistance in visceral leishmaniasis, a potentially fatal neglected tropical disease.
ER -