Nanoparticle‐Induced Exosomes Target Antigen‐Presenting Cells to Initiate Th1‐Type Immune Activation

Abstract

The mechanisms associated with the induction of systemic immune responses by nanoparticles are not fully understood, but their elucidation is critical to address safety issues associated with the broader medical application of nanotechnology. In this study, a key role of nanoparticle-induced exosomes (extracellularly secreted membrane vesicles) as signaling mediators in the induction of T helper cell type 1 (Th1) immune activation is demonstrated. In vivo exposure to magnetic iron oxide nanoparticles (MIONs) results in significant exosome generation in the alveolar region of Balb/c mice. These act as a source of nanoparticle-induced, membrane-bound antigen/signaling cargo, which transfer their components to antigen-presenting cells (APCs) in the reticuloendothelial system. Through exosome-initiated signals, immature dendritic cells (iDCs) undergo maturation and differentiation to the DC1 subtype, while macrophages go through classical activation and differentiation to the M1 subtype. Simultaneously, iDCs and macrophages release various Th1 cytokines (including interleukin-12 and tumor necrosis factor α) driving T-cell activation and differentiation. Activated APCs (especially DC1 and M1 subtypes) consequently prime T-cell differentiation towards a Th1 subtype, thereby resulting in an orchestrated Th1-type immune response. Th1-polarized immune activation is associated with delayed-type hypersensitivity, which might underlie the long-term inflammatory effects frequently associated with nanoparticle exposure. These studies suggest that nanoparticle-induced exosomes provoke the immune activation and inflammatory responses that can accompany nanoparticle exposure.

Materials for cardiac tissue engineering

“…In particular, in those individuals who already have pre-existing allergic conditions (known as sensitised individuals), the generated exosomes may result in a delayed type of hypersensitivity reaction and subsequent severe allergic responses; whereas in unsensitised individuals, the resulting immune activation response may be much lower. Furthermore, a key role of nanoparticle-induced exosomes as signalling mediators in the induction of immune activation via T helper cell type 1 has been reported [129]. Taken together, these studies suggest that the generated exosomes aggravate the immune activation and inflammatory responses induced by exposure to nanoparticles.…”

It takes two to tango: Understanding the interactions between engineered nanomaterials and the immune system

“…Zhu et al [90] reported that exposure to magnetic iron oxide nanoparticles results in significant exosome generation in the alveolar region of Balb/c mice. Through exosome-initiated signals, immature DCs were found to undergo maturation and differentiation, while macrophages were activated and differentiated to the M1 subtype.…”

Perturbation of physiological systems by nanoparticles

“…They were quickly translocated into system circulation, stimulated the maturation of dendritic cells, and activated Th1-type immune response. 85,155 This mechanism may account for the long-term inflammatory effects associated with nanoparticle exposure 156 and suggests that the control of immune signal transduction via exosomes may minimize the adverse immune responses caused by the inhaled nanoparticles. An IL-1a mediated molecular mechanism has also been proposed.…”