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Updated: Jan 23, 2026
Alveolar Macrophage Phagocytosis and Bacteria Clearance in Mice
Published on: March 2, 2019
Age-dependent effect between MARCO and TLR4 on PMMA particle phagocytosis by macrophages
Chiaki Yamada1, Camila Beron-Pelusso1, Neira Algazzaz2
1College of Dental Medicine, Nova Southeastern University, Fort Lauderdale, Florida.
Abstract:
Progressive generation of total joint implant-derived wear particles is one of the major risk factors in development of peri-prosthetic osteolysis especially in the aging society. It is commonly accepted that macrophages predominantly drive the inflammatory response to wear debris particles. Among various surface receptors that activate the macrophages to phagocytize particles, it is believed that the Toll-like receptor 4 (TLR4) and the scavenger macrophage receptor with collagenous structure (MARCO) play key roles in recognition of wear debris particles. However, a strong body of evidence indicates an age-dependent diminished function of human TLRs. Thus, we hypothesized that the MARCO receptor may be more engaged than TLRs in the phagocytosis of wear debris particles which in turn up-regulate production of pro-inflammatory cytokines from aged macrophages. We demonstrated that peritoneal macrophages isolated from aged mice show elevated expression of MARCO receptor compared to that from young mice. In contrast the expression of TLR4 was significantly decreased on the surface of aged macrophages. Furthermore, using anti-MARCO and anti-TLR4 neutralizing mAbs, we demonstrated the age-dependent pathogenic role of MARCO, but not TLR4, receptor in promoting poly-methyl methacrylate (PMMA) bone cement particles phagocytosis by macrophages leading to the release of pro-inflammatory cytokines migration inhibitory factor and tumour necrosis factor in vitro. These data also suggest that the approach to neutralize MARCO may lead to the development of therapeutic regimen for the prevention of particle-induced osteolysis in aged patients.
Insights
In aging patients, the MARCO receptor, not TLR4, drives inflammatory responses to joint implant wear particles. Neutralizing MARCO may prevent osteolysis in older individuals.
Area of Science:
- Biomedical Engineering
- Immunology
- Gerontology
Background:
- Total joint implant wear particles contribute to peri-prosthetic osteolysis, a significant concern in aging populations.
- Macrophages are key players in the inflammatory response to wear debris, recognizing particles via receptors like Toll-like receptor 4 (TLR4) and scavenger macrophage receptor with collagenous structure (MARCO).
- Human TLR function is known to decline with age, suggesting alternative pathways may dominate in elderly patients.
Purpose of the Study:
- To investigate the age-dependent roles of MARCO and TLR4 in macrophage phagocytosis of wear particles.
- To determine if MARCO, rather than TLR4, is more involved in the inflammatory response to wear debris in aged macrophages.
- To explore potential therapeutic strategies targeting MARCO for preventing particle-induced osteolysis in the elderly.
Main Methods:
- Isolated peritoneal macrophages from young and aged mice for comparative analysis.
- Quantified the expression levels of MARCO and TLR4 on macrophages using flow cytometry.
- Utilized anti-MARCO and anti-TLR4 neutralizing monoclonal antibodies (mAbs) to assess receptor function in vitro.
- Measured the release of pro-inflammatory cytokines, including migration inhibitory factor and tumor necrosis factor, following particle exposure.
Main Results:
- Aged macrophages exhibited significantly elevated MARCO expression compared to young macrophages.
- Conversely, TLR4 expression was markedly decreased on aged macrophages.
- MARCO neutralization, but not TLR4 neutralization, inhibited phagocytosis of poly-methyl methacrylate (PMMA) bone cement particles by aged macrophages.
- Inhibition of MARCO reduced the release of pro-inflammatory cytokines from aged macrophages exposed to PMMA particles.
Conclusions:
- MARCO plays a critical age-dependent role in the recognition and phagocytosis of joint implant wear particles by macrophages.
- TLR4 function appears diminished in aged macrophages concerning wear particle recognition.
- Targeting the MARCO receptor presents a promising therapeutic avenue for preventing and treating particle-induced osteolysis in aging patients.
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