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Extracell Vesicles Circ Nucleic Acids 2020;1:20-56 I http://dx.doi.org/10.20517/evcna.2020.10 Page 31

pyroptosis. Consistent with this result, a dose-dependent cytokine response was detected in the extracellular
fluids of mice challenged intraperitoneally with S. aureus EVs. Pore-forming toxins associated with EVs were
critical for NLRP3-dependent caspase-1 activation of human macrophages, but not for TLR2 signaling. In
contrast, EV-associated lipoproteins not only mediated TLR2 signaling to initiate the priming step of NLRP3
activation but also modulated the toxin content and the biogenesis of EVs, resulting in alterations in IL-1b, IL-
18, and caspase-1 activity. Our study describes mechanisms by which S. aureus EVs induces inflammasome
activation and reveals an unexpected role of staphylococcal lipoproteins in EV biogenesis. S. aureus EVs may
serve as a novel secretory pathway to transport protected cargo to host cells during infection to modulate
cellular functions.

13. Beta-glucan stimulated neutrophils secrete IL-1α through exosomes

Authors: Bridget Ratitong, Michaela E. Marshall, Eric Pearlman
E-mail: bratiton@uci.edu
Affiliations: Department of Physiology and Biophysics, University of California, Irvine, CA, USA.
Abstracts: Interleukin-1α (IL-1α) and IL-1b are leaderless pro-inflammatory members of the IL-1 family
of cytokines that are secreted via unconventional, ER and Golgi-independent pathways. Secretion of
processed, bioactive IL-1b by macrophages is mediated by Gasdermin D (GSDMD); in contrast, little
is known about the mechanism of IL-1α release by myeloid cells. Here, we demonstrate that IL-1α
production by macrophages is completely dependent on Gasdermin D. We found that neutrophils produce
IL-1α following inflammation induced by Aspergillus fumigatus spores that express cell surface b -glucan,
and show that in contrast to macrophages, IL-1α secretion by b-glucan stimulated neutrophils occurs
independently of GSDMD. Instead, we found intracellular IL-1α co-localized with extracellular vesicle
(EV) markers CD63, CD9, and CD81, and that IL-1α is encapsulated in EVs isolated from b-glucan
stimulated neutrophils. Preincubation of neutrophils with GW4869 inhibited exosome release and
significantly reduced IL-1α levels in cell-free supernatant. Further, we found that exosomal IL-1α can
signal through its receptor, IL-1R1, and EVs isolated from neutrophils, and can activate macrophages as
measured by proinflammatory cytokines IL-6 and TNFα release. Collectively, these findings demonstrate
that the mechanism for IL-1α secretion in neutrophils is distinct from macrophages and identify a role for
neutrophil extracellular vesicles, specifically exosomes, in this process.

14. Hypoxia-responsive bovine milk exosomes as targeted carrier for chemotherapeutics

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Authors: Jessica Pullan , Li Feng , Kaitlin Dailey , Sangeeta Bhallamudi , James Froberg , Lina Alhalhooly ,
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Amanda Brooks , Sathish Venkatachalem , Yongki Choi , Sanku Mallik 1
E-mail: jessica.pullan@ndsu.edu
Affiliations:
1 Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND, USA.
2 Department of Physics, North Dakota State University, Fargo, ND, USA.
3 Department of Research and Scholarly Activity, Rocky Vista University, Ivins, UT, USA.
Abstracts: Exosomes are secreted nanosized extracellular vesicles with innate transportation ability making
them ideal candidates for drug delivery. The inherent cellular cargo of an exosome can negatively impact
its ability to carry and deliver cargo safely. Bovine milk exosomes have not shown the same effect as other
sources in throughout the literature and therefore are a safe and effective source of exosomes. In order to
increase targeting and predictable control drug release of bovine exosomes, a neuropilin receptor agonist
peptide (iRGD) and a hypoxia-responsive lipid have been incorporated into the lipid bilayer of bovine