Abstract
The innate immune system is vital to rapidly responding to pathogens and Toll-like receptors (TLRs) are a critical component of this response. Nanovesicular exosomes play a role in immunity, but to date their exact contribution to the dissemination of the TLR response is unknown. Here we show that exosomes from TLR stimulated cells can largely recapitulate TLR activation in distal cells in vitro. We can abrogate the action-at-a-distance signaling of exosomes by UV irradiation, demonstrating that RNA is crucial for their effector function. We are the first to show that exosomes derived from poly(I:C) stimulated cells induce in vivo macrophage M1-like polarization within murine lymph nodes. These poly(I:C) exosomes demonstrate enhanced trafficking to the node and preferentially recruit neutrophils as compared to control exosomes. This work definitively establishes the differential effector function for exosomes in communicating the TLR activation state of the cell of origin.
Highlights
The innate immune system is vital to rapidly responding to pathogens and Toll-like receptors (TLRs) are a critical component of this response
Dendritic cells exposed to the TLR4 agonist lipopolysaccharide (LPS) show a distinct gene expression response as compared with cells exposed to the TLR3 agonist poly I:C, and these gene expression profiles are known to be pathogen specific[5]
The three groups of exosomes were added to naïve cells and the gene expression profiles were compared between local TLR stimulation and distal stimulation mediated by exosomes at the 48-hour time point (Fig. 1A)
Summary
The innate immune system is vital to rapidly responding to pathogens and Toll-like receptors (TLRs) are a critical component of this response. We are the first to show that exosomes derived from poly(I:C) stimulated cells induce in vivo macrophage M1-like polarization within murine lymph nodes. These poly(I:C) exosomes demonstrate enhanced trafficking to the node and preferentially recruit neutrophils as compared to control exosomes. Toll-like receptors (TLR) are an essential arm of innate immunity as they detect highly conserved pathogen associated molecular patterns (PAMPs) and play an important role in host cell defense[2]. We wanted to further understand the effector functions of exosomes using our previously established model of lymphatic transport to elucidate the impact and potential contribution of stable lymphatic retention of exosomes by macrophages in the development of an immune response in vivo
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