Biomaterial mediated simultaneous delivery of spermine and alpha ketoglutarate modulate metabolism and innate immune cell phenotype in sepsis mouse models

Sahil Inamdar, Tina Tylek, Abhirami Thumsi, Abhirami P. Suresh, Madhan Mohan Chandra Sekhar Jaggarapu, Michelle Halim, Shivani Mantri, Arezoo Esrafili, Nathan D. Ng, Elizabeth Schmitzer, Kelly Lintecum, Camila de Ávila, John D. Fryer, Ying Xu, Kara L. Spiller, Abhinav P. Acharya

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

Although different metabolic pathways have been associated with distinct macrophage phenotypes, the field of utilizing metabolites to modulate macrophage phenotype is in a nascent stage. In this report, we developed microparticles based on polymerization of alpha-ketoglutarate (a Krebs cycle metabolite), with or without encapsulation of spermine (a polyamine metabolite), to modulate cell phenotype that are critical for resolution of inflammation. Poly (alpha-ketoglutarate) microparticles encapsulated and released spermine (spermine (encap)paKG MPs) in vitro, which was accelerated in an acidic environment. When delivered to bone marrow-derived-macrophages, spermine (encap)paKG MPs induced a complex phenotypic profile outside of the typical M1/M2 paradigm, with distinct effects in the presence or absence of the pro-inflammatory stimulus lipopolysaccharide. Of particular interest was the increase in expression of CD163, which has been linked to anti-inflammatory responses in sepsis. Therefore, we systemically administered spermine (encap)paKG MPs to two different murine models of sepsis using acute or chronic injection of LPS. Macrophages and neutrophils in the liver and spleen of animals treated with spermine (encap)paKG MPs increased expression of CD163, concomitant with normalizing of glycolysis and oxidative phosphorylation, in both models. Overall, these results show that spermine (encap)paKG MPs modulate macrophage phenotype in vitro and in vivo, with potential applications in inflammation-associated diseases.

Original languageEnglish (US)
Article number121973
JournalBiomaterials
Volume293
DOIs
StatePublished - Feb 2023

Keywords

  • Biomaterials
  • Immunoengineering
  • Immunometabolism
  • Macrophages
  • Sepsis

ASJC Scopus subject areas

  • Mechanics of Materials
  • Ceramics and Composites
  • Bioengineering
  • Biophysics
  • Biomaterials

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