Trained immunity of alveolar macrophages enhances injury resolution via KLF4-MERTK-mediated efferocytosis

Author:

Chakraborty Sreeparna1ORCID,Singh Abhalaxmi2ORCID,Wang Li13ORCID,Wang Xinge134ORCID,Sanborn Mark A.13ORCID,Ye Zijing13ORCID,Maienschein-Cline Mark5ORCID,Mukhopadhyay Amitabha2ORCID,Ganesh Balaji B.5ORCID,Malik Asrar B.2ORCID,Rehman Jalees12346ORCID

Affiliation:

1. University of Illinois College of Medicine 1 Department of Biochemistry and Molecular Genetics, , Chicago, IL, USA

2. University of Illinois College of Medicine 2 Department of Pharmacology and Regenerative Medicine, , Chicago, IL, USA

3. University of Illinois College of Medicine 3 Division of Cardiology, Department of Medicine, , Chicago, IL, USA

4. University of Illinois College of Medicine 4 Department of Biomedical Engineering, , Chicago, IL, USA

5. Research Resources Center, University of Illinois Chicago 5 , Chicago, Illinois, USA

6. University of Illinois Cancer Center 6 , Chicago, IL, USA

Abstract

Recent studies suggest that training of innate immune cells such as tissue-resident macrophages by repeated noxious stimuli can heighten host defense responses. However, it remains unclear whether trained immunity of tissue-resident macrophages also enhances injury resolution to counterbalance the heightened inflammatory responses. Here, we studied lung-resident alveolar macrophages (AMs) prechallenged with either the bacterial endotoxin or with Pseudomonas aeruginosa and observed that these trained AMs showed greater resilience to pathogen-induced cell death. Transcriptomic analysis and functional assays showed greater capacity of trained AMs for efferocytosis of cellular debris and injury resolution. Single-cell high-dimensional mass cytometry analysis and lineage tracing demonstrated that training induces an expansion of a MERTKhiMarcohiCD163+F4/80low lung-resident AM subset with a proresolving phenotype. Reprogrammed AMs upregulated expression of the efferocytosis receptor MERTK mediated by the transcription factor KLF4. Adoptive transfer of these trained AMs restricted inflammatory lung injury in recipient mice exposed to lethal P. aeruginosa. Thus, our study has identified a subset of tissue-resident trained macrophages that prevent hyperinflammation and restore tissue homeostasis following repeated pathogen challenges.

Funder

National Institutes of Health

Publisher

Rockefeller University Press

Subject

Immunology,Immunology and Allergy

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