Restored clearance of senescent neutrophils by tissue-resident macrophages limits organ aging

Yuting Jessy Tan, Travis E Conley, Fuwen Yao, Fernando J García-Marqués, Damilola E Akinyemi, Van Vuong Dinh, Qian Wang, Abel Bermudez, Jieun Kim, Julia A Belk, Oliver Soehnlein, Sharon J Pitteri, Katrin I Andreasson

1. 01

   Tissue-resident macrophage EP2 (PGE2 receptor) signalling gates efferocytosis of senescent neutrophils and rises with age

2. 02

   Reducing TRM EP2 signalling in aged mice preserved mitochondrial fitness and prevented cognitive decline, frailty, sarcopenia, adiposity, cardiac impairment and systemic inflammation

3. 03

   Plasma proteomics implicated the liver as a major source of age-associated immune change; restored efferocytosis prevented paracrine stress in neighbouring cells

4. 04

   Pharmacologic EP2 inhibition (not only genetic deletion) restored youthful neutrophil clearance in aged mice

5. 05

   Elevated TRM EP2 expression and accumulated senescent neutrophils were observed in aged and diseased human tissues

Study Design

preclinical

Sample Size

Not reported

Study Duration

Aged-mouse intervention study

Methodology

Aged C57BL/6 mice with conditional EP2 deletion in tissue-resident macrophages and pharmacologic EP2 antagonism; single-cell and plasma proteomic profiling; behavioural, cardiac, body-composition and frailty phenotyping; comparison with human tissue datasets.

Limitations

All intervention data are in mice; the human component is expression-level and cross-sectional, not interventional. EP2 antagonists have no aging indication, no chronic-dosing safety record in older adults, and prostaglandin signalling is broadly pleiotropic, so therapeutic-window selectivity is unresolved. No lifespan endpoint reported.