Immunometabolic cues recompose and reprogram the microenvironment around implanted biomaterials

Chima V Maduka; Axel D Schmitter-Sánchez; Ashley V Makela; Evran Ural; Katlin B Stivers; Hunter Pope; Maxwell M Kuhnert; Oluwatosin M Habeeb; Anthony Tundo; Mohammed Alhaj; Artem Kiselev; Shoue Chen; Alexis Donneys; Wade P Winton; Jenelle Stauff; Peter J H Scott; Andrew J Olive; Kurt D Hankenson; Ramani Narayan; Sangbum Park; Jennifer H Elisseeff; Christopher H Contag

doi:10.1038/s41551-024-01260-0

Immunometabolic cues recompose and reprogram the microenvironment around implanted biomaterials

Nat Biomed Eng. 2024 Oct;8(10):1308-1321. doi: 10.1038/s41551-024-01260-0. Epub 2024 Oct 4.

Authors

Chima V Maduka^#^{1

2

3

4}, Axel D Schmitter-Sánchez^#^{5

6}, Ashley V Makela^#^{7

5}, Evran Ural^{7

5}, Katlin B Stivers⁸, Hunter Pope⁵, Maxwell M Kuhnert^{7

5}, Oluwatosin M Habeeb^{7

5}, Anthony Tundo^{7

5}, Mohammed Alhaj⁹, Artem Kiselev^{5

10

11}, Shoue Chen¹², Alexis Donneys¹³, Wade P Winton¹⁴, Jenelle Stauff¹⁴, Peter J H Scott¹⁴, Andrew J Olive^{15

16}, Kurt D Hankenson¹³, Ramani Narayan⁹, Sangbum Park^{5

10

11}, Jennifer H Elisseeff^{8

17}, Christopher H Contag^{18

19

20}

Affiliations

¹ Comparative Medicine and Integrative Biology, Michigan State University, East Lansing, MI, USA. [email protected].
² Department of Biomedical Engineering, Michigan State University, East Lansing, MI, USA. [email protected].
³ Institute for Quantitative Health Science and Engineering, Michigan State University, East Lansing, MI, USA. [email protected].
⁴ BioFrontiers Institute, University of Colorado, Boulder, CO, USA. [email protected].
⁵ Institute for Quantitative Health Science and Engineering, Michigan State University, East Lansing, MI, USA.
⁶ Cell and Molecular Biology Program, College of Natural Science, Michigan State University, East Lansing, MI, USA.
⁷ Department of Biomedical Engineering, Michigan State University, East Lansing, MI, USA.
⁸ Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁹ Department of Chemical Engineering and Materials Science, Michigan State University, East Lansing, MI, USA.
¹⁰ Department of Medicine, College of Human Medicine, Michigan State University, East Lansing, MI, USA.
¹¹ Department of Pharmacology and Toxicology, College of Human Medicine, Michigan State University, East Lansing, MI, USA.
¹² School of Packaging, Michigan State University, East Lansing, MI, USA.
¹³ Department of Orthopedic Surgery, University of Michigan Medical School, Ann Arbor, MI, USA.
¹⁴ Department of Radiology, University of Michigan, Ann Arbor, MI, USA.
¹⁵ Department of Microbiology, Genetics and Immunology, Michigan State University, East Lansing, MI, USA.
¹⁶ College of Osteopathic Medicine, Michigan State University, East Lansing, MI, USA.
¹⁷ Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹⁸ Department of Biomedical Engineering, Michigan State University, East Lansing, MI, USA. [email protected].
¹⁹ Institute for Quantitative Health Science and Engineering, Michigan State University, East Lansing, MI, USA. [email protected].
²⁰ Department of Microbiology, Genetics and Immunology, Michigan State University, East Lansing, MI, USA. [email protected].

^# Contributed equally.

PMID: 39367264
DOI: 10.1038/s41551-024-01260-0

Abstract

Circulating monocytes infiltrate and coordinate immune responses in tissues surrounding implanted biomaterials and in other inflamed tissues. Here we show that immunometabolic cues in the biomaterial microenvironment govern the trafficking of immune cells, including neutrophils and monocytes, in a manner dependent on the chemokine receptor 2 (CCR2) and the C-X3-C motif chemokine receptor 1 (CX3CR1). This affects the composition and activation states of macrophage and dendritic cell populations, ultimately orchestrating the relative composition of pro-inflammatory, transitory and anti-inflammatory CCR2⁺, CX3CR1⁺ and CCR2⁺ CX3CR1⁺ immune cell populations. In amorphous polylactide implants, modifying immunometabolism by glycolytic inhibition drives a pro-regenerative microenvironment principally by myeloid cells. In crystalline polylactide implants, together with arginase-1-expressing myeloid cells, T helper 2 cells and γδ⁺ T cells producing interleukin-4 substantially contribute to shaping the metabolically reprogrammed pro-regenerative microenvironment. Our findings inform the premise that local metabolic states regulate inflammatory processes in the biomaterial microenvironment.

MeSH terms

Animals
Biocompatible Materials* / pharmacology
CX3C Chemokine Receptor 1 / metabolism
Cellular Microenvironment*
Dendritic Cells / immunology
Dendritic Cells / metabolism
Inflammation / immunology
Macrophages / immunology
Macrophages / metabolism
Mice
Mice, Inbred C57BL
Monocytes / immunology
Monocytes / metabolism
Neutrophils / immunology
Neutrophils / metabolism
Polyesters* / chemistry
Prostheses and Implants
Receptors, CCR2* / metabolism

Substances

Biocompatible Materials
Polyesters
Receptors, CCR2
poly(lactide)
CX3C Chemokine Receptor 1
Cx3cr1 protein, mouse
Ccr2 protein, mouse