Broad-spectrum inhibition of inflammasome activation by inorganic nanomaterials

July 24, 2023

(Nanowerk News) Excessive inflammasome activation is associated with various diseases, including gout, Alzheimer’s disease, atherosclerosis, and type 2 diabetes. Given the important role of macrophages in inflammasome activation and phagocytosis of nanoparticles, the discovery of anti-inflammatory nanoparticles that specifically target macrophages could more effectively modulate the inflammatory response while minimizing off-target effects on other cell types. However, most of the nanomaterials reported so far have been found to promote rather than inhibit inflammatory activation.

This study demonstrated that nickel-cobalt alloy nanocrystals exhibited remarkable efficacy in suppressing the activation of three inflammasomes, namely NLRP3, NLRC4, and AIM2, in primary macrophages. Next, the researchers used two disease models, colitis and acute peritonitis, to evaluate the impact of nickel-cobalt alloy nanocrystals in treating overactivation of inflammation.

Findings revealed that nickel-cobalt alloy nanocrystals effectively ameliorated disease symptoms in mice in a colitis model, including reducing weight loss, restoring intestinal length, and reducing damage to the intestinal mucosal epithelium. Furthermore, in a model of acute peritonitis, these nanocrystals significantly attenuated neutrophil chemotaxis in the rat peritoneal cavity.

To confirm whether nickel-cobalt alloy nanocrystals require cellular internalization to exert their anti-inflammatory effect, the authors performed experiments using the widely used endocytosis inhibitor, cytochalasin D. Treatment with cytochalasin D significantly reduced internalization of nickel-cobalt alloy nanocrystals by macrophages.

In addition, inhibiting the internalization of nanocrystals by macrophages led to a decrease in the anti-inflammatory effect, indicating that the anti-inflammatory action of nickel-cobalt alloy nanocrystals is dependent on their cellular uptake.

To investigate whether the anti-inflammatory effect of nickel-cobalt alloy nanocrystals is associated with their geometric morphology or elemental composition, the authors synthesized nickel nanoparticles and cobalt nanoparticles under conditions identical to those of the control, which showed different morphology compared to nickel-cobalt alloy nanocrystals.

However, nickel nanoparticles and cobalt nanoparticles also significantly inhibited inflammatory activation. Therefore, the authors attributed the inhibitory effect of nickel-cobalt alloy nanocrystals to their elemental composition rather than their geometric shape. These findings indicate that nickel and cobalt-containing nanomaterials may offer opportunities for designing nanodrugs with anti-inflammatory properties.

Unraveling the biological mechanisms underlying the action of nanomaterials is essential for their potential medical applications. However, elucidating the biological mechanisms by which these broad-spectrum anti-inflammatory nanocrystals inhibit inflammasome activation poses significant challenges using conventional biologic experimental approaches. To address this, the researchers performed RNA sequencing and assays for transposase-accessible chromatin by sequencing (ATAC-Seq), leading to the identification of a previously reported non-coding RNA, Neat1, known to be involved in inflammasome assembly.

After treatment with nickel-cobalt alloy nanocrystals, Neat1 expression was significantly reduced. Previous studies have shown that downregulating Neat1 expression alone significantly inhibits inflammatory activation of NLRP3, NLRC4, and AIM2. The ATAC-Seq results revealed a significant reduction in chromatin accessibility of the gene body and promoter region of Neat1 in the group treated with nickel–cobalt alloy nanocrystals, indicating that inhibition of inflammatory activation by nickel–cobalt alloy nanocrystals is achieved through suppression of Neat1 transcription rather than promoting its degradation.

this lesson (National Science Review, “Nickel-cobalt alloy nanocrystals inhibit inflammation activation”) was carried out collaboratively by Dr. Shu-Hong Yu, Dr. Long-Ping Wen, and Dr. Kun Qu from China University of Science and Technology, together with Professor Yang Lu from Hefei University of Technology.

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