Nanomaterial Helps Promote Inflammatory Activation

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This study was carried out collaboratively by Dr. Shu-Hong Yu, Dr. Long-Ping Wen, and Dr. Kun Qu from China University of Science and Technology, with Professor Yang Lu from Hefei University of Technology.

Various stimuli trigger the activation of three inflammasomes: NLRP3, NLRC4, and AIM2. NiCo NCs suppress the inflammasome assembly process by downregulating the long non-coding Neat1 RNA, thereby inhibiting the activation of the three inflammasomes. Image Credit: © Science China Press

Too much inflammasome activation has been linked to several diseases, such as atherosclerosis, Alzheimer’s disease, gout, and type 2 diabetes.

Given the critical role of macrophages in nanoparticle phagocytosis and inflammation activation, breakthrough anti-inflammatory nanoparticles, particularly those targeting macrophages, can more efficiently modulate the inflammatory response while reducing off-target effects on other cell types.

But most of the currently reported nanomaterials have been found to promote rather than inhibit inflammation activation.

The study demonstrated that nickel-cobalt alloy nanocrystals exhibited remarkable efficacy in suppressing the activation of three inflammasomes in major macrophages, namely NLRP3, AIM2, and NLRC4.

Then, the scientists used two disease models, colitis and acute peritonitis, to assess the effect of nickel-cobalt alloy nanocrystals in treating inflammatory overactivation.

The results show how nickel-cobalt alloy nanocrystals efficiently improve disease symptoms in mice in a colitis model, such as restoring colon length, reducing weight loss, and reducing damage to the intestinal mucosal epithelium. Moreover, in a model of acute peritonitis, such nanocrystals severely attenuated neutrophil chemotaxis within the mouse peritoneal cavity.

To verify whether nickel-cobalt alloy nanocrystals require cellular internalization to exert their anti-inflammatory effect, the authors performed experiments with the aid of a widely used endocytosis inhibitor named cytochalasin D.

Treatment performed with cytochalasin D greatly reduced the internalization of nickel–cobalt alloy nanocrystals by macrophages. In addition, inhibiting the internalization of nanocrystals by macrophages has resulted in a decrease in their anti-inflammatory effect. This indicates that the anti-inflammatory action of nickel-cobalt alloy nanocrystals is dependent on their cellular uptake.

To analyze whether the anti-inflammatory impact of nickel-cobalt alloy nanocrystals exerted on their elemental composition or geometric morphology, the authors synthesized cobalt nanoparticles and nickel nanoparticles under identical conditions as controls. It displays diverse morphologies compared to nickel-cobalt alloy nanocrystals.

But the cobalt nanoparticles and nickel nanoparticles also strongly resisted inflammatory activation.

Therefore, the authors assigned the inhibitory effect of nickel-cobalt alloy nanocrystals to their elemental composition instead of their geometric shape. These findings indicate that nanomaterials consisting of cobalt and nickel can provide opportunities for developing nanodrugs with anti-inflammatory properties.

Disclosure of the biological mechanisms underlying the action of nanomaterials is considered important for their possible medical applications. But clarifying the biological mechanisms by which such broad-spectrum anti-inflammatory nanocrystals curb inflammasome activation poses considerable difficulties using traditional biologic experimental approaches.

To fulfill this, the scientists performed RNA sequencing and assays for transposase-accessible chromatin by sequencing (ATAC-Seq). This resulted in the identification of the previously reported non-coding RNA, Neat1, which is thought to be involved in inflammasome assembly.

After treatment with nickel-cobalt alloy nanocrystals, Neat1 expression was markedly decreased. Previous studies have illustrated that downregulating Neat1 expression alone significantly prevents activation of the inflammasome NLRC4, NLRP3, and AIM2.

The ATAC-Seq results revealed a considerable reduction in chromatin accessibility of the gene body and Neat1 promoter region in the group treated with nickel-cobalt alloy nanocrystals. This suggests that inhibition of inflammatory activation by nickel–cobalt alloy nanocrystals has been obtained by suppressing Neat1 transcription instead of promoting its degradation.