HDAC6-Mediated NLRP3 Inflammasome Activation Is Involved in Nickel Nanoparticle-Induced Pulmonary Inflammation and Fibrosis.

Abstract

Nickel nanoparticles (Nano-Ni) are increasingly utilized in industrial and biomedical applications, drawing growing attention to their potential adverse health effects. Our previous studies have demonstrated that Nano-Ni exposure induces severe, widespread, and persistent pulmonary inflammation and fibrosis. However, the underlying mechanisms are still unclear. The NLRP3 inflammasome is a vital component of the innate immune system and inflammatory signaling. In this study, we investigated whether Nano-Ni exposure activated the NLRP3 inflammasome and also examined its role in Nano-Ni-induced pulmonary inflammation and fibrosis. Our findings demonstrated that intratracheal instillation of wild-type mice (C57BL/6J) with 50 μg Nano-Ni per mouse resulted in NLRP3 inflammasome activation, IL-1β production, and extensive pulmonary inflammation and fibrosis. In contrast, Nano-Ni exposure induced only mild pulmonary inflammation and fibrosis in Nlrp3^-/- mice (lacking functional NLRP3 inflammasome) or Il-1r1^-/- mice (unresponsive to IL-1), highlighting the critical role of NLRP3 inflammasome activation in Nano-Ni-induced pulmonary damage. Further investigations using mouse alveolar macrophages (MH-S) revealed that Nano-Ni acts as a secondary activation signal for the NLRP3 inflammasome, triggering its activation in LPS-primed but not unprimed cells. Moreover, siRNA-mediated knockdown experiments demonstrated that this activation depended on Nano-Ni-induced upregulation of HDAC6. These findings suggest that Nano-Ni activates the NLRP3 inflammasome via HDAC6 as a second activation signal, leading to IL-1β production and subsequent pulmonary inflammation and fibrosis.