Aging Leads to Increased Monocytes and Macrophages With Altered CSF-1 Receptor Expression and Earlier Tumor-Associated Macrophage Expansion in Murine Mesothelioma

Our plain-English summary of Aging Leads to Increased Monocytes and Macrophages With Altered CSF-1 Receptor Expression and Earlier Tumor-Associated Macrophage Expansion in Murine Mesothelioma, by L. Duong, F.J. Pixley, D.J. Nelson, et al (Frontiers in Aging, 2022).

The study

• Authors: L. Duong, F.J. Pixley, D.J. Nelson, C. Jackaman
• Journal: Frontiers in Aging
• Published: 2022;3:848925
• Cited by: 20 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Increased cancer incidence occurs with the emergence of immunosenescence, highlighting the indispensability of the immune system in preventing cancer and its dysregulation with aging. Tumor-associated macrophages (TAMs) are often present in high numbers and are associated with poor clinical outcomes in solid cancers, including mesothelioma. Monocytes and macrophages from the bone marrow and spleen can respond to tumor-derived factors, such as CSF-1, and initiation of the CSF-1R signaling cascade results in their proliferation, differentiation, and migration to the tumor. Age-related changes occur in monocytes and macrophages in terms of numbers and function, which in turn can impact tumor initiation and progression. Whether this is due to changes in CSF-1R expression with aging is currently unknown and was investigated in this study. We examined monocytes and macrophages in the bone marrow and spleen during healthy aging in young (3-4 months) and elderly (20-24 months) female C57BL/6J mice. Additionally, changes to these tissues and in TAMs were examined during AE17 mesothelioma tumor growth. Healthy aging resulted in an expansion of Ly6Chigh monocytes and macrophages in the bone marrow and spleen. CSF-1R expression levels were reduced in elderly splenic macrophages only, suggesting differences in CSF-1R signaling between both cell type and tissue site. In tumor-bearing mice, Ly6Chigh monocytes increased with tumor growth in the spleen in the elderly and increased intracellular CSF-1R expression occurred in bone marrow Ly6Chigh monocytes in elderly mice bearing large tumors. Age-related changes to bone marrow and splenic Ly6Chigh monocytes were reflected in the tumor, where we observed increased Ly6Chigh TAMs earlier and expansion of Ly6Clow TAMs later during AE17 tumor growth in the elderly compared to young mice. F4/80high TAMs increased with tumor growth in both young and elderly mice and were the largest subset of TAMs in the tumor. Together, this suggests there may be a faster transition of Ly6Chigh towards F4/80high TAMs with aging. Amongst TAM subsets, expression of CSF-1R was lowest in F4/80high TAMs, however Ly6Clow TAMs had higher intracellular CSF-1R expression. This suggests downstream CSF-1R signaling may vary between macrophage subsets, which can have implications towards CSF-1R blockade therapies targeting macrophages in cancer.

Copyright © 2022 Duong, Pixley, Nelson and Jackaman.

In plain English

This was a laboratory experiment in mice, not a study of people. The authors compared young (3–4 months) and elderly (20–24 months) female C57BL/6J mice. Some were healthy and some were injected under the skin with AE17 mouse mesothelioma cells. AE17 is a cell line originally generated by inoculating mice with asbestos fibers; the article does not name the fiber type. Using flow cytometry, the authors measured immune cells called monocytes and macrophages in bone marrow, spleen and tumors, and the cells' levels of the CSF-1 receptor (CSF-1R). Healthy elderly mice had more monocytes and macrophages in bone marrow and spleen than young mice, and lower CSF-1R in spleen macrophages. Among mice with large tumors, one monocyte type (Ly6Chigh) in the spleen was almost three times as common in elderly as in young mice. In tumors, early-stage Ly6Chigh tumor-associated macrophages increased earlier in elderly mice. Mature F4/80high macrophages were the largest group and had the lowest CSF-1R. The authors suggested aging may speed macrophage maturation in tumors, with possible implications for CSF-1R-blocking therapies. They noted that only female mice were studied.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: animal experiment (mice, flow cytometry of immune cells in healthy and tumor-bearing young and elderly mice)
• Who was studied: Female C57BL/6J mice from the Animal Research Centre (Murdoch, WA, Australia), housed at Curtin University: young mice aged 3–4 months and elderly mice aged 20–24 months. Group sizes were 6–9 mice per group for cell measurements and 17–19 mice per group for plasma CSF-1.
• Exposure: No direct asbestos exposure in this study. Mice were injected under the skin (subcutaneously) with 5 × 10^5 AE17 cells. AE17 is a mouse malignant mesothelioma cell line originally generated by inoculating mice with asbestos fibers; the fiber type is not named. Tumors were studied when small (under 30 mm2, 7–10 days after injection) or large (65 to 140 mm2, 18–23 days after injection).
• Main results:
  • In healthy mice, elderly mice had more total monocytes, Ly6Chigh monocytes and macrophages in both bone marrow and spleen than young mice (n = 7 mice per group).
  • In healthy elderly mice, CSF-1R (surface and intracellular) was lower in spleen macrophages than in young mice. CSF-1R was unchanged in bone marrow macrophages and monocytes.
  • In mice with large tumors, spleen Ly6Chigh monocyte proportions were almost 3-fold higher in elderly than in young mice.
  • In mice with large tumors, intracellular CSF-1R in bone marrow Ly6Chigh monocytes was higher in elderly than in young mice.
  • Circulating CSF-1 in plasma did not differ between healthy young and healthy elderly mice. It was lower in elderly mice with large tumors than in healthy elderly mice.
  • In tumors, Ly6Chigh tumor-associated macrophages increased in elderly mice early in tumor development (n = 9 mice per group).
  • F4/80high tumor-associated macrophages increased with tumor growth in both young and elderly mice and were the largest subset in the tumor.
  • F4/80high tumor-associated macrophages from elderly mice showed increased CD206 (a marker the authors call pro-tumoral) with tumor growth and compared with young mice.
  • Among tumor-associated macrophage subsets, CSF-1R was lowest in F4/80high cells, and intracellular CSF-1R was highest in Ly6Clow cells. CSF-1R was similar between young and elderly mice.
• The authors' conclusion: The authors concluded that with aging there may be a faster transition of tumor-associated macrophages from early Ly6Chigh cells toward mature F4/80high cells, with differences in CSF-1R expression. They said this may have implications for therapies that block CSF-1/CSF-1R signaling.
• Limitations the authors state:
  • Only female mice were studied; the authors said sex-specific differences need further investigation.
  • The study measured CSF-1R expression levels only. Receptor pathway activation, internalization and degradation were not examined.
  • The effects of CSF-1R inhibition on these cell populations were not tested.

Topics

Medical terms in this study, explained in our Lexicon: Macrophage, Mesothelioma.

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