Poster Presentation 14th Lorne Infection and Immunity 2024

Myeloid derived NLRP3 inflammasomes exacerbate disease in a murine model of Silicosis (#109)

Kristian Barry 1 2 , Maggie Lam 2 , Christopher Hodges 2 , Christopher Harpur 2 , Ashley Mansell 2 , Michelle Tate 2
  1. Translation and Molecular Sciences, Monash University, Melbourne, Victoria, Australia
  2. Hudson Institute of Medical Research, Clayton, VIC, Australia

Silicosis is an irreversible occupational respiratory disease caused by the inhalation of respirable silica particles which induce a non-resolving chronic inflammation of the lung that leads to fibrosis. Critically, there are currently no therapeutic treatments for silicosis to halt or reverse fibrosis. Previous studies have identified that silica particles activate the NLRP3 inflammasome and drive pathology in murine models of silicosis, and that NLRP3 deficient mice have reduced pulmonary fibrosis. While NLRP3 has been implicated in driving disease pathology, the cellular compartment of NLRP3-induced inflammation is not well understood. We have generated a novel myeloid-specific knockout of NLRP3 (LysM-Cre/NLRP3fl/fl) to elucidate the role of NLRP3 during silicosis. We demonstrate that LysM/NLRP3fl/fl macrophages do not express NLRP3 protein, fail to respond to multiple NLRP3 agonists, and that NLRP3 expression in the lung is significantly reduced in LysM-Cre/NLRP3fl/fl mice. Interestingly, myeloid specific depletion of NLRP3 has no significant effect on inflammatory cytokine production or inflammatory cell infiltrates into the lung 3 days after silica challenge. Critically however, LysM-Cre/NLRP3fl/fl mice display significantly reduced numbers and size of silicotic nodules at day 14, as well as reduced collagen deposition, suggesting a decreased burden of disease compared to control mice. These data suggest that the myeloid derived NLRP3 inflammasome activity plays a role in the progression and pathogenesis of silicosis, however early NLRP3-derived inflammatory response to silica challenge may be myeloid-independent. Further research will be required to identify the mechanism by which NLRP3 induces fibrosis associated with silicosis, but these studies may suggest that therapeutic targeting of myeloid NLRP3 activity may slow or reduce the disease pathology associated with silicosis.