Yolk-sac-derived macrophages progressively expand in the mouse kidney with age

Older people are more likely to develop kidney disease, which increases their risk of having other conditions such as a heart attack or stroke and, in some cases, can lead to their death. Older kidneys are less able to repair themselves after an injury, which may help explain why aging contributes to kidney disease. Another possibility is that older kidneys are more susceptible to excessive inflammation. Learning more about the processes that lead to kidney inflammation in older people might lead to better ways to prevent or treat their kidney disease.

Immune cells called macrophages help protect the body from injury and disease. They do this by triggering inflammation, which aides healing. Too much inflammation can be harmful though, making macrophages a prime suspect in age-related kidney harm. Studying these immune cells in the kidney and how they change over the lifespan could help scientists to better understand age-related kidney disease.

Now, Ide, Yahara et al. show that one type of macrophage is better at multiplying in older kidneys. In the experiments, mice were genetically engineered to make a fluorescent red protein in one kind of macrophage. This allowed Ide, Yahara et al. to track these immune cells as the mice aged. The experiments showed that this subgroup of cells is first produced when the mice are embryos. They stay in the mouse kidneys into adulthood, and are so prolific that, over time, they eventually become the most common macrophage in older kidneys.

The fact that one type of embryonically derived macrophage takes over with age may explain the increased inflammation and reduced repair capacity seen in aging kidneys. More studies will help scientists to understand how these particular cells contribute to age-related changes in susceptibility to kidney disease.

Tissue-resident macrophages constitute a highly heterogeneous and specialized population of myeloid cells, reflecting the diversity of their developmental origins and tissue microenvironments (Mass, 2018; Ginhoux et al., 2010; Schulz et al., 2012; Yona et al., 2013; Gomez Perdiguero et al., 2015; Mass et al., 2016; Hashimoto et al., 2013; Epelman et al., 2014; Stremmel et al., 2018; Hoeffel et al., 2015). In addition to their critical roles in host defense against pathogens, macrophages are central to sterile inflammation, angiogenesis, and tissue remodeling, making them an attractive target for therapeutic intervention. Tissue-resident macrophages originate from at least three distinct progenitors: (i) macrophage colony-stimulating factor one receptor (CSF1R)-positive yolk-sac macrophages; (ii) CX3C chemokine receptor 1 (CX3CR1)-positive yolk-sac macrophages, also known as pre-macrophages; and (iii) embryonic and neonatal hematopoietic stem cells (HSC) (Mass, 2018; Ginhoux et al., 2010; Schulz et al., 2012; Yona et al., 2013; Gomez Perdiguero et al., 2015; Mass et al., 2016; Hashimoto et al., 2013; Epelman et al., 2014; Stremmel et al., 2018). These populations are maintained in situ by self-renewal, largely independent of adult hematopoiesis (Mass, 2018; Ginhoux et al., 2010; Schulz et al., 2012; Yona et al., 2013; Gomez Perdiguero et al., 2015; Mass et al., 2016; Hashimoto et al., 2013; Epelman et al., 2014; Hoeffel et al., 2015; Sawai et al., 2016; Soucie et al., 2016).

Most tissues have mixed populations of different ontogenically-derived macrophages, and their relative contributions and temporal kinetics are tissue-specific. For example, microglia, Kupffer cells, and Langerhans cells originate from the yolk-sac, with minimal contribution from HSCs (Ginhoux et al., 2010; Schulz et al., 2012; Yona et al., 2013; Gomez Perdiguero et al., 2015; Mass et al., 2016; Sawai et al., 2016). The macrophage composition in the intestinal wall is highly dynamic. Yolk-sac-derived intestinal macrophages are rapidly replaced by HSC-derived macrophages after birth, but a subpopulation of yolk-sac-derived cells persist and self-renew in the specialized intestinal niches in adults (Bain et al., 2014; De Schepper et al., 2018). Importantly, investigators now recognize that macrophage ontogeny contributes to their roles in disease processes such as cancer progression; in pancreatic cancer, for example, yolk-sac-derived macrophages are fibrogenic, while HSC-derived macrophages are immunogenic (Zhu et al., 2017). This raises the possibility that developmental programs influence how macrophages differentially respond to disease insults.

Renal macrophages are found in an intricate network surrounding the renal tubular epithelium (Stamatiades et al., 2016; Berry et al., 2017; Viehmann et al., 2018) and have mixed origins from both yolk-sac and HSC (Schulz et al., 2012; Mass et al., 2016; Epelman et al., 2014; Munro et al., 2019). They exert unique functions depending on their anatomical locations; monitoring and clearing immune complexes is a function of cortical macrophages while bacterial immunity is the responsibility of medullary macrophages (Stamatiades et al., 2016; Berry et al., 2017). Renal macrophages critically control renal inflammation and tissue remodeling after injury with robust phenotypic reprogramming (Lever et al., 2019). Despite the importance of these roles, little is known about how the proportion and distribution of macrophages of different ontogeny change over time in the normal kidney and whether this influences the increased susceptibility and poorer outcomes of older patients to acute and chronic kidney diseases (Chen et al., 2019; Chawla et al., 2014; Sato and Yanagita, 2019). While most preclinical models of kidney diseases have used young animals, recent papers highlight distinct immune responses in aged mouse kidneys. Aged kidneys exhibit more severe inflammation than young kidneys in response to ischemic and toxic insults, leading to maladaptive repair and organ dysfunction (Sato and Yanagita, 2019; Sato et al., 2016). Furthermore, there is a growing interest in aging as a fundamental determinant of macrophage heterogeneity, such as in the heart and serous cavities (Molawi et al., 2014; Bain et al., 2016; Dick et al., 2019). However, data on the effects of aging on the renal macrophage populations are lacking. Here, using complementary in vivo genetic fate-mapping and parabiotic approaches, we identify a previously unappreciated increase in the proportion of yolk-sac-derived macrophages in the mouse kidney with age.

Two complementary strategies were used to fate-map CSF1R⁺, and CX3CR1⁺ yolk-sac-derived macrophages (Figure 1 and Figure 1—figure supplement 1). Erythromyeloid progenitors (EMP) give rise to these populations, and the yolk-sac macrophages appear in the yolk-sac around E8.5. Subsequently, from E9.0 until E14.5, they proliferate, migrate, and colonize the embryo through the vascular system (Stremmel et al., 2018; Munro et al., 2019). To lineage-label these cells, we exposed Csf1r-CreERt; Rosa26^tdTomato and Cx3cr1^CreERt; Rosa26^tdTomato embryos to 4-hydroxytamoxifen (4-OHT) at E8.5 and E9.5, respectively (Figure 1A and Figure 1—figure supplement 1A), (Mass, 2018). This efficiently and irreversibly labels yolk-sac-derived macrophages with the tdTomato reporter. Importantly, the approach does not label fetal monocytes or HSCs (Gomez Perdiguero et al., 2015; Yahara et al., 2020).

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Percentage of tdTomato+ to F4/80+ cells.

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At postnatal day 0 (P0), we detected a small number of tdTomato⁺ cells in kidneys from both lines (Figure 1 and Figure 1—figure supplement 1). A previous fate-mapping strategy that labels all HSC-derived cells indicated that 40% to 50% of tissue-resident macrophages in the young adult kidney originate from HSC; the remainder was inferred to derive from yolk-sac hematopoiesis (Schulz et al., 2012). Consistent with this inference, we found CX3CR1-lineage labeled cells in kidneys from birth, with numbers increasing progressively over time (2 weeks, 2 months and 6 months; Figure 1, B and C). Surprisingly, we observed an unexpected large increase in the proportion of tdTomato-positive cells relative to total F4/80-positive cells at 6 months, especially in the cortex and outer medulla, despite no significant change in the number of F4/80-positive cells per section. This increase was maintained up to 1 year (Figure 1B). The tdTomato-labeled cells were positive for mature macrophage markers, F4/80 and CD64 (Figure 1D), (Viehmann et al., 2018; Brähler et al., 2018). By contrast, we observed only a few F4/80-positive CSF1R-lineage cells inside the kidneys (Figure 1—figure supplement 1, B and C), as reported previously (Schulz et al., 2012). As CSF1R⁺ and CX3CR1⁺ yolk-sac macrophages represent a developmental sequence of tissue-resident macrophages derived from EMP, the observed low labeling of CSF1R-lineage cells might be attributable to differences in labeling efficacies and migration kinetics of progenitors.

To further delineate the chronological shift of renal macrophages, we examined the HSC contribution to renal macrophages using the Flt3-Cre; Rosa26^tdTomato mouse line (Mass, 2018; Yahara et al., 2020; Benz et al., 2008). This mouse line irreversibly labels fetal and adult HSC-derived multipotent hematopoietic progenitors and their progeny with tdTomato expression. Consistent with the increase of yolk-sac-derived renal macrophages with age, we observed a decreased number of F4/80⁺ tdTomato⁺ cells in the kidneys from 6-month-old mice compared to those from 2-month-old mice (Figure 2, A and B). These data demonstrate that EMP-derived CX3CR1⁺ yolk-sac macrophages and their descendants are major contributors to the resident renal macrophage population in aged kidneys.

Figure 2

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Percentage of tdTomato+ F4/80+ cells to total F4/80+ cells.

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Our findings raise the question of the underlying mechanisms responsible for the chronological shift of macrophage composition. We first tested whether the proliferation of yolk-sac-derived renal macrophages can potentially contribute to their population dynamics. CX3CR1-lineage-labeled cells that express the proliferation marker, Ki67, are present in kidneys from birth to 6 months of age, indicating that yolk-sac-derived macrophages retain the potential to expand in numbers through proliferation (Figure 3, A and B). We further found that higher percentages of CX3CR1-lineage-labeled F4/80⁺ cells express Ki67 in comparison to tdTomato-negative F4/80⁺ cells at 2 weeks and 2 months of age, suggesting that CX3CR1-lineage cells have a higher proliferating capacity (Figure 3C).

Figure 3

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Percentage of Ki67+ proliferating F4/80+ cells.

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Another possibility is recruitment of yolk-sac-derived macrophages from extra-renal reservoirs through the circulation. To test this hypothesis, we generated a parabiotic union between young Cx3cr1^GFP/+ and Cx3cr1^CreERt; Rosa26^tdTomato mice that had been exposed to 4-OHT in utero at E9.5 (Figure 4A). Effective blood sharing between the pair was confirmed by detecting Cx3cr1-promoter-driven GFP expression in bone marrow cells derived from both mice (data not shown). When analyzed at 5 weeks after parabiosis, we found a few tdTomato⁺ cells in the extravascular, interstitial area of the cortex and medulla of the Cx3cr1^GFP parabiont kidneys (0.105 ± 0.04% of total F4/80⁺ cells; Figure 4, B and C). We also found that a significantly higher percentage of tdTomato-positive cells expresses Ki67 in the kidneys of Cx3cr1^GFP mice compared to the tdTomato-positive cells in the kidneys of Cx3cr1^CreERt; Rosa26^tdTomato mice (Ki67⁺tdTomato⁺ relative to tdTomato⁺; 28.55 ± 8.23% vs. 3.16 ± 0.74%) (Figure 4, D and E). While further investigation is required, these results suggest that the tdTomato-positive circulating progenitors may have a significant proliferative capacity and can slowly contribute to the adult renal macrophage pool. Currently, the origin of the circulating CX3CR1-lineage cells is not known but we speculate that one site is the spleen, which we recently identified as a reservoir of CX3CR1⁺ yolk-sac macrophages (Yahara et al., 2020).

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Percentages of Ki67+tdTomato+ cells relative to tdTomato+ cells in the kidneys of indicated genotypes.

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In conclusion, we have shown here that the proportion of yolk-sac-derived, CX3CR1-positive, macrophages increases significantly in the kidney with age, with recruitment from the circulation and proliferation being two possible mechanisms. Our findings provide a foundation for future studies to investigate the functional heterogeneity of ontogenically distinct renal macrophages in younger versus aged kidneys. These future studies may provide novel insight into age-related susceptibility of the kidney to acute and chronic diseases.

All data generated or analyzed during this study are included in the manuscript.

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Author details

1. Shintaro Ide

   1. Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, United States
   2. Regeneration Next, Duke University, Durham, United States

   Contribution

   Data curation, Formal analysis, Investigation, Writing - review and editing

   Contributed equally with

   Yasuhito Yahara

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-9301-211X

2. Yasuhito Yahara

   1. Regeneration Next, Duke University, Durham, United States
   2. Department of Orthopedic Surgery, Duke University School of Medicine, Durham, United States
   3. Department of Orthopedic Surgery, Faculty of Medicine, University of Toyama, Toyama, Japan

   Contribution

   Conceptualization, Resources, Investigation, Methodology, Writing - review and editing

   Contributed equally with

   Shintaro Ide

   Competing interests

   No competing interests declared

3. Yoshihiko Kobayashi

   Department of Cell Biology, Duke University School of Medicine, Durham, United States

   Contribution

   Resources, Methodology, Writing - review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-7031-1478

4. Sarah A Strausser

   Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, United States

   Contribution

   Investigation, Project administration

   Competing interests

   No competing interests declared

5. Kana Ide

   Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, United States

   Contribution

   Formal analysis, Investigation, Project administration

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-2845-8481

6. Anisha Watwe

   Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, United States

   Contribution

   Investigation

   Competing interests

   No competing interests declared

7. Shengjie Xu-Vanpala

   Department of Immunology, Duke University School of Medicine, Durham, United States

   Contribution

   Resources, Methodology

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-2716-6230

8. Jamie R Privratsky

   Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, United States

   Contribution

   Resources, Investigation, Methodology, Writing - review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-3598-4911

9. Steven D Crowley

   Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, United States

   Contribution

   Resources, Methodology, Writing - review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-1838-0561

10. Mari L Shinohara

    1. Department of Immunology, Duke University School of Medicine, Durham, United States
    2. Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, United States

    Contribution

    Resources, Funding acquisition, Methodology, Writing - review and editing

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0002-6808-9844

11. Benjamin A Alman

    1. Regeneration Next, Duke University, Durham, United States
    2. Department of Orthopedic Surgery, Duke University School of Medicine, Durham, United States

    Contribution

    Resources, Supervision, Funding acquisition, Methodology, Writing - review and editing

    Competing interests

    No competing interests declared

12. Tomokazu Souma

    1. Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, United States
    2. Regeneration Next, Duke University, Durham, United States

    Contribution

    Conceptualization, Supervision, Funding acquisition, Investigation, Writing - original draft, Project administration, Writing - review and editing

    For correspondence

    tomokazu.souma@duke.edu

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0002-3285-8613

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