Metabololipidomic and proteomic profiling reveals aberrant macrophage activation and interrelated immunomodulatory mediator release during aging

GND
1249122120
ORCID
0000-0002-9586-6653
Affiliation
Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy Friedrich‐Schiller University Jena Germany
Schädel, Patrick;
GND
1266766782
ORCID
0000-0002-6849-7020
Affiliation
Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy Friedrich‐Schiller University Jena Germany
Czapka, Anna;
GND
1214206581
ORCID
0000-0002-7659-3426
Affiliation
Leibniz Institute on Aging – Fritz Lipmann Institute (FLI) Jena Germany
Gebert, Nadja;
GND
130267279
ORCID
0000-0002-6033-9984
Affiliation
Leibniz Institute for Natural Product Research and Infection Biology – Hans Knoell Institute (HKI) Jena Germany
Jacobsen, Ilse Denise;
GND
1205180893
ORCID
0000-0002-3046-0871
Affiliation
Leibniz Institute on Aging – Fritz Lipmann Institute (FLI) Jena Germany
Ori, Alessandro;
GND
1022335375
ORCID
0000-0002-5064-4379
Affiliation
Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy Friedrich‐Schiller University Jena Germany
Werz, Oliver

Abstract Macrophages adapt distinct pro‐inflammatory (M1‐like) and pro‐resolving (M2‐like) phenotypes with specific tasks in the immune response and tissue homeostasis. Altered macrophage responses with age are causative for unresolved inflammation, so‐called inflammaging, and lead to higher infection susceptibility with unfavorable progression. Here, we reveal molecular determinants of age‐related changes in phenotypic functions of murine peritoneal macrophages (PM) by employing comprehensive mass spectrometry‐based proteomics (4746 protein groups) and metabololipidomics (>40 lipid mediators). Divergent expression of various macrophage‐specific marker proteins and signaling pathways indicates aberrant PM phenotypes in old mice which detrimentally impact their capabilities to release immunomodulatory chemokines and cytokines. We show that aging strikingly compromises the polarization process of macrophages to adapt either pro‐inflammatory or pro‐resolving phenotypes, thereby yielding aberrant and afunctional macrophage subtypes that cannot be readily assigned to either a typical M1 or M2 phenotype. In particular, the phenotypic adaptation of the bacteria‐challenged metabololipidome in macrophages related to inflammation is severely limited by age, which persists across ex vivo polarization towards M1 and M2a macrophages. Our results establish distinct age‐associated PM phenotypes outside of the simplified M1 and M2 dichotomy and challenge the dogma of increased pro‐inflammatory macrophage pre‐activation due to aging by revealing maladaptive functions throughout all phases of inflammation, including resolution.

Aging impacts macrophage polarization towards pro‐inflammatory (M1) or pro‐resolving phenotypes (M2a). We show that the metabololipidome of peritoneal macrophages prior and after ex vivo polarization is limited by age, affecting initiation and resolution of inflammation. Proteome profiling revealed distinct age‐associated phenotypes outside of the simplified M1 and M2 dichotomy, strengthening the need to expand classification to address age‐related aberrations in their immunological competence. image

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