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Postoperative pain attenuation by macrophage-derived small extracellular vesicles requires monocyte-dependent immunomodulation
Dissertation

Postoperative pain attenuation by macrophage-derived small extracellular vesicles requires monocyte-dependent immunomodulation

Deepa Reddy
Doctor of Philosophy (Ph.D.), Drexel University
Apr 2026
DOI:
https://doi.org/10.17918/00011330
pdf
Reddy_Deepa_20264.42 MB
PDF Embargoed Access, Embargo ends: 30 Apr 2027

Abstract

Exosomes Innate immune system Postoperative pain Small extracellular vesicles Immunology Pain
Surgeries induce postoperative pain that must be alleviated to limit suffering and promote recovery. Postoperative pain is not effectively managed in >80% of patients in the US. Small extracellular vesicles (sEVs) are released by all cells and regulate intercellular communication by carrying biomolecular cargo between distant cells. In exploring safer, non-opioid therapies, we found that intraplantar macrophage-derived sEVs given three hours before hind paw incision reduced postoperative pain in male and female mice by altering innate immune cell trafficking and phenotypes. Flow cytometry studies on postoperative days one, three, and five showed fewer total numbers of immune cells in the paw from sEV treated mice. sEV treatment also resulted in elevated neutrophil infiltration, decreased macrophage abundance, and a delay in early monocyte recruitment. We observed increased neutrophil activation and at later time points, an increased shift towards pro-resolution macrophage and monocyte phenotypes in sEV mice in vivo. Mirroring these findings in vitro, sEV treated macrophages showed an initial increase in pro-inflammatory mediators followed by a quicker shift toward pro-resolution phenotypes. Depletion of neutrophils or paw resident macrophages in vivo did not prevent the ability of sEVs to attenuate postoperative pain. In contrast, inhibition of monocyte recruitment impaired sEV-mediated pain resolution and diminished the ability of sEVs to enhance neutrophil activation and promote a shift in macrophages toward a pro-resolution state. Together, these data indicate that monocytes are essential for sEV-mediated postoperative pain attenuation and the associated innate immune cell dynamics, characterized by an early inflammatory phase followed by a more rapid progression toward pro-resolution phenotypes. These findings support sEVs as a novel immunomodulatory strategy to attenuate postoperative pain and accelerate pro-resolution innate immune responses.

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