Secreted exosome-associated DNA (SEAD) from migrating neutrophils regulates the resolution of inflammation

---

Presentation Time: 11:30 AM - 12:45 PM
Poster Board Number: B825
Abstract ID: 4295

Presenting Author:
Subhash B Arya , Postdoc at Michigan Med., Univ. of Michigan

Abstract:

Neutrophils control infections and injury through phagocytosis, exocytosis, and (neutrophil extracellular traps) NET formation. Excessive NETs worsen inflammation, causing delayed resolution and tissue injury. Despite understanding neutrophils' inflammatory role, their contribution to resolution remains unclear. Pioneer neutrophils release leukotriene B4 (LTB₄) exosomes in response to injury, generating strong chemoattractant gradients for distant neutrophil recruitment. We discovered LTB4-containing exosome pathway from nuclear envelope (NE) budding, distinct from conventional CD63-exosome route. High-resolution microscopy unveiled nuclear DNA within NE-derived multivesicular bodies, containing 5-LO-positive intraluminal vesicles. We observed real-time DNA secretion from chemotaxing neutrophils, dependent on LBR and facilitated by LTB4-mediated histone acetylation. Disrupting secreted exosome-associated DNA (SEAD) impeded neutrophil migration, indicating SEADs create tracks for chemotaxis. Intravenous DNase in TPA-induced contact dermatitis mouse model inhibited normal inflammation resolution. High LTB4 concentrations activate PPARα, initiating an anti-inflammatory pathway. Topical PPARα agonist/antagonist application revealed that SEADs increase local LTB4 concentration to initiate resolution. Understanding the interplay of SEADs and LTB4 signaling in inflammation and resolution may explain limited success of DNase in diseases with elevated NETs.