Immunometabolic cues recompose and reprogram the microenvironment around biomaterials

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

doi:10.1101/2023.07.30.551180

Cited by 3 publications

(1 citation statement)

References 54 publications

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“…However, in our study, OSCC demonstrated functional increases in both glycolysis and OXPHOS among the same cell population. While such metabolic profile is appreciated in sterile inflammatory responses to implanted biomaterials [21][22][23]45,61 , it is still uncharacterized in cancer biology, and has only been documented in a resistant clone of PDAC cancer stem cells (CSC) where suppression of MYC and increase in PGC-1α underlie increment in both OXPHOS and glycolysis 62 . Importantly, OSCC cells did not reveal a compensatory increase in glycolytic flux following inhibition of mitochondrial respiration by rotenone and antimycin A, suggesting that OSCC may be susceptible to therapies that target OXPHOS.…”

Section: Discussionmentioning

confidence: 99%

Flavinated SDHA underlies the change in intrinsic optical properties of oral cancers

Marumo,

Maduka,

Ural

et al. 2023

Commun Biol

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The molecular basis of reduced autofluorescence in oral squamous cell carcinoma (OSCC) cells relative to normal cells has been speculated to be due to lower levels of free flavin adenine dinucleotide (FAD). This speculation, along with differences in the intrinsic optical properties of extracellular collagen, lies at the foundation of the design of currently-used clinical optical detection devices. Here, we report that free FAD levels may not account for differences in autofluorescence of OSCC cells, but that the differences relate to FAD as a co-factor for flavination. Autofluorescence from a 70 kDa flavoprotein, succinate dehydrogenase A (SDHA), was found to be responsible for changes in optical properties within the FAD spectral region, with lower levels of flavinated SDHA in OSCC cells. Since flavinated SDHA is required for functional complexation with succinate dehydrogenase B (SDHB), decreased SDHB levels were observed in human OSCC tissue relative to normal tissues. Accordingly, the metabolism of OSCC cells was found to be significantly altered relative to normal cells, revealing vulnerabilities for both diagnosis and targeted therapy. Optimizing non-invasive tools based on optical and metabolic signatures of cancers will enable more precise and early diagnosis leading to improved outcomes in patients.

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Section: Discussionmentioning

confidence: 99%

Flavinated SDHA underlies the change in intrinsic optical properties of oral cancers

Marumo,

Maduka,

Ural

et al. 2023

Commun Biol

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Regulating the proinflammatory response to implanted composite biomaterials comprising polylactide and hydroxyapatite by targeting immunometabolism

Maduka,

Makela,

Ural

et al. 2023

Preprint

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Composite biomaterials comprising polylactide (PLA) and hydroxyapatite (HA) are applied in bone, cartilage and dental regenerative medicine, where HA confers osteoconductive properties. However, after surgical implantation, adverse immune responses to these composites can occur, which have been attributed to size and morphology of HA particles. Approaches to effectively modulate these adverse immune responses have not been described. PLA degradation products have been shown to alter immune cell metabolism, which drives the inflammatory response. Therefore, we aimed to modulate the inflammatory response to composite biomaterials by regulating glycolytic flux with small molecule inhibitors incorporated into composites comprised of amorphous PLA (aPLA) and HA (aPLA+HA). Inhibition at specific steps in glycolysis reduced proinflammatory (CD86+CD206-) and increased pro-regenerative (CD206+) immune cell populations around implanted aPLA+HA resulting in a pro-regenerative microenvironment. Notably, neutrophil and dendritic cell (DC) numbers along with proinflammatory monocyte and macrophage populations were decreased, and Arginase 1 expression among DCs was increased. Targeting immunometabolism to control the inflammatory response to biomaterial composites, and creating a pro-regenerative microenvironment, is a significant advance in tissue engineering where immunomodulation enhances osseointegration, and angiogenesis, which will lead to improved bone regeneration.

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The role of mitochondrial complex I in the proinflammatory response to polylactide implants

Maduka,

Makela,

Tundo

et al. 2024

Preprint

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During the foreign body response, immune cells are metabolically rewired after exposure to breakdown products of various biomaterials, including polylactide (PLA) and polyethylene. Particles of polyethylene interact with Toll-like receptor 4 on macrophages, resulting in increased oxygen consumption that forms reactive oxygen species at complex I of the mitochondrial electron transport chain (mETC). However, PLA degradation products bind to monocarboxylate transporters for downstream signaling with elevated oxygen consumption rates, whose functional implication is unclear and remains inferred from cellular responses to polyethylene biomaterials. By chemically probing the function of the mETC, we show that proinflammatory macrophages activated by exposure to amorphous PLA (aPLA) breakdown products rely on mitochondrial respiration for ATP production, independent of oxygen consumption rates. In contrast, macrophages activated by semi-crystalline PLA (cPLA) breakdown products exhibit a metabolic phenotype wherein ATP levels are unaffected by changing oxygen consumption rates. In subcutaneous implants, the incorporation of metformin in aPLA or cPLA to chemically inhibit complex I did not effectively modulate the proinflammatory response to biomaterials, suggesting that PLA degradation products elicit a distinct metabolic program, thus providing an alternative perspective on the role of mitochondrial respiration in the inflammatory response to biomaterials.

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Immunometabolic cues recompose and reprogram the microenvironment around biomaterials

Cited by 3 publications

References 54 publications

Flavinated SDHA underlies the change in intrinsic optical properties of oral cancers

Flavinated SDHA underlies the change in intrinsic optical properties of oral cancers

Regulating the proinflammatory response to implanted composite biomaterials comprising polylactide and hydroxyapatite by targeting immunometabolism

The role of mitochondrial complex I in the proinflammatory response to polylactide implants

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