Inflammasomes,
a critical component of the innate immune system,
mediate much of the inflammatory response manifested by engineered
nanomaterials. Iron oxide nanoparticles (IONPs), a type of nanoparticles
that have gained widespread acceptance in preclinical and clinical
settings, are known to induce inflammasome activation, but how morphology
affects the inflammasome-activating property of IONPs has not been
addressed. In this report, we have synthesized four morphologically
distinct IONPs having the same aspect ratio and similar surface charge,
thus offering an ideal system to assess the impact of morphology on
nanoparticle-elicited biological effect. We show that morphology was
a critical determinant for IONP-induced IL-1β release and pyroptosis,
with the octapod and plate IONPs exhibiting significantly higher activity
than the cube and sphere IONPs. The inflammasome-activating capacity
of different IONPs correlated with their respective ability to elicit
intracellular reactive oxygen species generation, lysosomal damage,
and potassium efflux, three well-known mechanisms for nanoparticle-facilitated
inflammasome activation. Furthermore, we demonstrate that the release
of IL-1β induced by IONPs was only partly mediated by NLRP3,
suggesting that inflammasomes other than NLRP3 are also involved in IONP-induced inflammasome
activation. Our results may have implications for designing safer
nanoparticles for in vivo applications.
The intestine, a high-turnover tissue, plays a critical role in regulating aging and health in both vertebrates and invertebrates. Maintaining the epithelial barrier function of the intestine by preserving innate immune homeostasis significantly delays aging and prevents mortality. In an effort to explore effective chemicals and materials that can improve intestinal integrity, we performed a nonbiased screen utilizing
Drosophila
as an animal model. We showed that long-term uptake of aspirin markedly prevented age-onset gut leakage, the over-proliferation of intestinal stem cells, and the dysbiosis of commensal microbiota in fruit flies. Mechanistically, aspirin efficiently downregulated chronic activation of intestinal immune deficiency signaling during aging. Furthermore, our
in vivo
and
in vitro
biochemical analyses indicated that aspirin is a negative modulator in control of the K63-linked ubiquitination of Imd. Our findings uncover a novel regulatory mechanism by which aspirin positively modulates intestinal homeostasis, thus delaying aging, in
Drosophila
.
Negative regulators of the inflammatory responses are essential for the maintenance of immune homeostasis and organismal fitness. In Drosophila, the deubiquitinase (Dub) dTrbd selectively restricts the K63-linked ubiquitination modification of dTak1, a pivotal kinase of the IMD signaling pathway, to regulate the IMD innate immune response. However, which domain and how it functions to enable dTrbd’s activity remain unexplored. Here, we provide compelling evidence showing that the NZF domain of dTrbd is essential for its association with dTak1. Meanwhile, the Linker region of dTrbd is involved in modulating its condensation, a functional state representing the Dub enzymatical activity of dTrbd. Of interest, the activated IMD signals following bacterial stimuli enhance the dTrbd/dTak1 interaction, as well as the condensate assembly and Dub enzymatical activity of dTrbd. Collectively, our studies shed light on the dual mechanisms by which the IMD signaling-mediated feedback loop of dTrbd/dTak1 precisely regulates the innate immune response in Drosophila.
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