Abstract
Macrophages play an important role in the initiation, progression and resolution of inflammation in many human diseases. Effective regulation of their activation and immune responses could be a promising therapeutic strategy to manage various inflammatory conditions. Nanodevices that naturally target macrophages are ideal agents to regulate immune responses of macrophages. Here we described a special tryptophan (Trp)-containing hexapeptide-coated gold nanoparticle hybrid, PW, which had unique immunomodulatory activities on macrophages. The Trp residues enabled PW higher affinity to cell membranes, and contributed to inducing mild pro-inflammatory responses of NF-κB/AP-1 activation. However, in the presence of TLR stimuli, PW exhibited potent anti-inflammatory activities through inhibiting multiple TLR signaling pathways. Mechanistically, PW was internalized primarily through micropinocytosis pathway into macrophages and attenuated the endosomal acidification process, and hence preferentially affected the endosomal TLR signaling. Interestingly, PW could induce the expression of the TLR negative regulator IRAK-M, which may also contribute to the observed TLR inhibitory activities. In two acute lung injury (ALI) mouse models, PW could effectively ameliorate lung inflammation and protect lung from injuries. This work demonstrated that nanodevices with thoughtful design could serve as novel immunomodulatory agents to manage the dysregulated inflammatory responses for treating many chronic and acute inflammatory conditions, such as ALI.
Highlights
Understanding the interactions between nanodevices and the immune system is pivotal to guide nanomaterial design for better biomedical application outcome
We demonstrated that the FF region in the peptide sequence plays an important role for Toll-like receptor (TLR) inhibition, and the hydrophobicity of this region contributes to the potency of such inhibitory activity [11]
These results suggested that peptide coating on the gold nanoparticle (GNP) surface significantly improved the stability of GNPs at the physiological condition
Summary
Understanding the interactions between nanodevices and the immune system is pivotal to guide nanomaterial design for better biomedical application outcome. With increasing understanding of the roles of specific immune cells in the pathophysiological process of human diseases, the phagocytotic properties of innate immune cells to grasp nanodevices could be advantageous for modulation of immune reactions, opening new avenues to treat inflammatory disorders that currently lack of an effective cure. A luminol-conjugated b-cyclodextrin based nanoparticle (LCD NP) was synthesized to effectively inhibit the inflammatory responses, oxidative stress and migration of neutrophils and macrophages to treat acute and chronic inflammatory disorders [9]. These findings are encouraging that with proper design, nanoparticles could regulate immune responses, aiding to new immunotherapies to treat various diseases
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