Restored clearance of senescent neutrophils by tissue-resident macrophages limits organ aging
Abstract
Aging disrupts tissue homeostasis across organ systems. Here, we identify tissue-resident macrophages (TRMs) as central coordinators of age-related organ decline through impaired clearance of senescent neutrophils, a process regulated by the immunomodulatory prostaglandin E2 (PGE 2 ) receptor EP2. Reducing TRM EP2 signaling in aged mice preserved youthful mitochondrial fitness and prevented cognitive decline, frailty, sarcopenia, adiposity, cardiac impairment, and systemic inflammation. Plasma proteomics implicated the liver as a major source of age-associated immune change, in which reduced TRM EP2 signaling rescued neutrophil efferocytosis and prevented paracrine stress in neighboring cells. Elevated TRM EP2 expression and senescent neutrophils were also observed in aged and diseased human tissues. Pharmacologic EP2 inhibition restored youthful neutrophil clearance, establishing impaired TRM efferocytosis as a reversible driver of organ decline in aging.
Article Details
Journal Info
Science
American Association for the Advancement of Science
Authors (13)
Yuting Jessy Tan
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
Travis E. Conley
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
Fuwen Yao
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
Fernando J. García-Marqués
Department of Radiology, Stanford University School of Medicine, Palo Alto, CA, USA.
Damilola E. Akinyemi
Institute for Experimental Pathology (ExPat), Centre for Molecular Biology of Inflammation (ZMBE), University of Münster, Münster, NRW, Germany.
Van Vuong Dinh
Institute for Experimental Pathology (ExPat), Centre for Molecular Biology of Inflammation (ZMBE), University of Münster, Münster, NRW, Germany.
Qian Wang
Abel Bermudez
Department of Radiology, Stanford University School of Medicine, Palo Alto, CA, USA.
Jieun Kim
Neurosciences Preclinical Imaging Laboratory, Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA.
Julia A. Belk
Oliver Soehnlein
Sharon J. Pitteri
Department of Radiology, Stanford University School of Medicine, Palo Alto, CA, USA.
Katrin I. Andreasson
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.