Age-related macular degeneration (AMD) is a neurodegenerative disorder which develops in elderly individuals and is a major cause of visual impairments in developed countries. In the early stages of AMD, lipoprotein deposits called drusen accumulate in the subretinal space between the photoreceptors and retinal pigment epithelium (RPE). Drusen are associated with the degeneration of the RPE which then leads to a dysfunction or loss of the photoreceptors. Choroidal (CNVs) develop in the subretinal space, and the CNVs lead to degeneration of the photoreceptor cells, infiltration by inflammatory cells, activation of microglia, and ganglion cell loss (Beck et al., 2016; Copland et al., 2018).

The pathology of AMD is coupled with senescence-associated para-inflammation, which is characterized by the secretion of IL-6, IL-8, CCL2, and CX3CL1 (Sasaki et al., 2010). Of these, CCL2 plays an important role in recruiting bone marrow cells, monocytes, and macrophages to the ocular neovascularizations. In this disease process, the bone marrow plays an important role by supplying new vascular endothelial cells and macrophages to the retina (Gao et al., 2016; Zhou et al., 2017). Thus, the bone marrow plays a key role in the repair of damaged tissues.

The M1 macrophages are functionally classified as pro-inflammatory, and the M2 macrophages are classified as anti-inflammatory, and both types are recruited to damaged tissues. The M2 macrophages are induced by IL-4, and it has been suggested that they have disease-regulating functions as opposed to the M1 macrophages (Zhou et al., 2017).

The concept of IL-4 as a regulatory and neuroprotective cytokine is supported by the findings in other neurodegenerative diseases including Alzheimer’s disease (Kiyota et al., 2010) and Parkinson’s disease (Chitnis and Weiner, 2017; Zhao et al., 2006). Moreover, IL-4 is known to be a potent inhibitor of angiogenesis (Haas et al., 2006; Volpert et al., 1998), and thus may prevent pathological angiogenesis in eyes with AMD.

The purpose of this study was to determine whether bone marrow cells and IL-4 protect the photoreceptors from neurodegeneration, and whether they play regulatory roles in eyes with g AMD. To accomplish this, we first determined the concentration of IL-4 and other inflammatory cytokines in the aqueous humor of the eyes of AMD patients (Sasaki et al., 2012). We then determined whether IL-4 and bone marrow cells play roles in protecting the eye from abnormal angiogenesis. This was done by functional assays and global transcriptional profiling of bone marrow cells derived from endothelial progenitor cells (EPC).

Our results showed that IL-4 played a crucial role in the pathogenesis of CNVs by directing the migration and activating the angiogenic bone marrow cells. IL-4 is the canonical Th2 cytokine and is secreted by an array of inflammatory cells including macrophages, monocytes, and activated retinal pigment epithelial cells (Leung et al., 2009). IL-4 is also recognized as a neuroprotective cytokine, and its action is not limited to the retina (Adão-Novaes et al., 2009). In axotomized retinas, the retinal ganglion cells are severely damaged by nitric oxide synthesis by activated glial cells. IL-4 significantly increases the survival of retinal ganglion cells, and prevents neurodegeneration caused by glial cell activation (Koeberle et al., 2004). In the thapsigargin-induced rod photoreceptor cell death model, IL-4 can completely block the death of the photoreceptors (Adão-Novaes et al., 2009). During the differentiation of the retina, IL-4 modulates the proliferation of the retinal cells and promotes photoreceptor differentiation (da Silva et al., 2008). In addition, a number of studies have shown that IL-4 can inhibit the death of photoreceptors and RGCs.

IL-4 is a multifaceted cytokine and is known to have anti-angiogenic capabilities. IL-4 inhibits tumor growth by inhibiting angiogenesis (Volpert et al., 1998) and also blocks corneal neovascularization induced by basic fibroblast growth factor. Thus, IL-4 can function as an anti-inflammatory cytokine and prevent neuronal death and angiogenesis. However, such properties of IL-4 appear to be context dependent.

We found that the IL-4 level was significantly elevated in the aqueous humor of patients with AMD (Table 1, Table 2; Sasaki et al., 2012). Together with this, our analyses of the bone marrow cells and chimeric mice supports the idea that elevations of IL-4- and IL-4 receptor-bearing cells are associated with the development of abnormal vessels in the lesions of eyes with AMD.

Although the IL-4/IL-4Rα axis appears neuroprotective in the retina, retinal injury requires a recruitment or activation of cells with regenerative properties for its repair. The bone marrow cells are a major supplier of mesenchymal stem cells and hematopoietic stem cells. However, abnormally activated bone marrow cells by IL-4 in the retina promote pathological angiogenic responses.

To explain the dysregulated repair process after organ damage, the concept of cell level and organ level quorum sensing has been recently proposed (Antonioli et al., 2018). Quorum sensing was originally proposed as a phenomenon of bacterial cells, and it was described as a mechanism that senses the environment and integrity of a population of cells. Hair follicle injury sensed by a macrophage-mediated circuit via CCL2 is a well-known example of quorum sensing at the organ level (Chen et al., 2015; Feng et al., 2017). The quorum sensing circuit mediated by microglia-derived CCL2 also appears to operate in new vessel formation in the retina together with a late IL-4 modulator.

We observed the presence of CD11b in the CNV lesions at 12 hr which would indicate that monocyte/macrophage cells had arrived soon after the beginning of the CNV. In contrast, the induction of IL-4 and IL-4 receptors was delayed and peaked at 3 days (Figure 1). CCL2 recruits circulating mononuclear cells from the bone marrow, and the retinal pigment epithelial cells and microglial cells are the major sources of the CCL2 cells in the retina (Feng et al., 2017). Thus, the monocyte/macrophage recruiting signal, including CCL2, appears to be the first signal in the formation of CNVs.

It was reported that CCL2 is involved in the formation of retinal neovascularization (Sennlaub et al., 2013; Yoshida et al., 2003). However, the CCL2/CCR2 signals recruit a heterogeneous collection of monocyte/macrophage lineage cells and presumably do not determine their fate (Grochot-Przeczek et al., 2013; Pearson, 2010).

Bone marrow-derived cells and macrophages are critical contributors to retinal and choroidal neovascularization (Gao et al., 2016; Zhou et al., 2017). Higher levels of M1 than M2 type mRNAs were observed in advanced stage AMD patients (Cao et al., 2011). The M1 macrophages counteract the M2 type by the secretion of interferon-γ. Based on this, the M2 macrophages were considered to play a regulatory role in CNV formation. Consistent with this, Wu et al showed that the M2 type cytokine, IL-4, and conditioned macrophages become the regulatory phenotype to suppress the disease processes (Wu et al., 2015). However, the M1 types of IFNAR1+ macrophages have been reported to be protective in laser-induced CNV (Lückoff et al., 2016). Thus, the M1/M2 paradigm does not clearly explain how abnormal vessels are formed in AMD lesions or the CNVs of the model mice.

Wu et al also showed a contradictory role of IL-4 for CNV formation (Wu et al., 2015). This was shown using vitreous injection of IL-4 at very high concentration (600 ng/ml). This may cause toxic damage to endothelial cells or recruited cells which may not reflect physiological role of IL-4.

In the retina, vascular repair and neovascularization are performed largely by circulating EPCs because mature vascular endothelial cells for proliferation are limited (Caballero et al., 2007; Grant et al., 2002). EPCs are present in the bone marrow or are peripheral blood mononuclear cells (Rohde et al., 2006; Schatteman and Awad, 2003; Schmeisser et al., 2001), and they can differentiate into endothelial cells as late EPCs and be incorporated into the vasculature system. Alternatively, bone marrow cells will also differentiate into non-endothelial cell lineage and serve as providers of CNV-forming signals.

In the inductive phase of CNVs, a mobilization of circulating angiogenic cells and monocyte/macrophage lineage cells begins by the early recruitment of IL-4 secreting CD11b⁺ bone marrow cells (Figure 1). As a late phase phenomenon, the IL-4R⁺ bone marrow-derived cells are incorporated into the CNV presumably as late EPCs or non-endothelial lineage cells, together with the resident cell-derived endothelial cells. We propose that the bone marrow-derived cells contribute to both phases using IL-4 as the fate determinant.

We also noted that the IL-4/IL-4Rα axis is involved in pathologic angiogenesis. For example, IL-4 induces proinflammatory phenotypes and causes vascular leakage or increased turnover of endothelial cells (Kotowicz et al., 2004; Lee et al., 2010). IL-4 stimulates human umbilical vascular endothelial cells (HUVEC) cells to induce proinflammatory cytokines including CCL2, VCAM-1, and IL-6, as a signature of global transcriptional responses (Lee et al., 2004). These responses appear to be a general characteristics of vascular endothelial cells including coronary arterial endothelial cells (Skaria et al., 2016).

To identify an endothelial lineage, we used CD31 or isolectin staining because CD31 is highly expressed on endothelial cells and is commonly used as an endothelial cell marker. However, CD31 can also be expressed on other lineage cells including T cells, B cells, dendritic cells (DCs; Clement et al., 2014), neutrophils, monocytes, and macrophage (Merchand-Reyes et al., 2019).

Our data support the idea that bone marrow-derived cells may be able to differentiate into endothelial cells in the CNV lesions. However, whether the endothelial differentiation is complete or bone marrow cells serve as immature or of different lineage was not definitively determined. Importantly, bone marrow-derived cells do play pivotal roles in the CNV formation.

In conclusion, damages of the retina and choroidal tissue release signals to the bone marrow to repair the vascular damage. This signal induces a recruitment of the bone marrow-derived cells for differentiation into or establishment of new vessels. Calling and/or fate determining signals are governed by IL-4. IL-4 may serve as a therapeutic target to treat this visual disorder.

All data generated or analysed during this study are included in the manuscript. Source data files have been provided for Figure 1, 2, 3, Figure 3—figure supplement 1, 2, Figure 4, Figure 4—figure supplement 1 and Figure 5.

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Author details

1. Takashi Baba

   Division of Ophthalmology and Visual Science, Faculty of Medicine, Tottori University, Yonago, Japan

   Contribution

   Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Writing - original draft, Writing - review and editing

   For correspondence

   babatakashi8@gmail.com

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-7318-9420

2. Dai Miyazaki

   Division of Ophthalmology and Visual Science, Faculty of Medicine, Tottori University, Yonago, Japan

   Contribution

   Conceptualization, Data curation, Software, Formal analysis, Supervision, Writing - original draft, Project administration, Writing - review and editing

   For correspondence

   miyazaki-ttr@umin.ac.jp

   Competing interests

   No competing interests declared

3. Kodai Inata

   Division of Ophthalmology and Visual Science, Faculty of Medicine, Tottori University, Yonago, Japan

   Contribution

   Data curation, Formal analysis, Investigation

   Competing interests

   No competing interests declared

4. Ryu Uotani

   Division of Ophthalmology and Visual Science, Faculty of Medicine, Tottori University, Yonago, Japan

   Contribution

   Data curation, Formal analysis, Investigation

   Competing interests

   No competing interests declared

5. Hitomi Miyake

   Division of Ophthalmology and Visual Science, Faculty of Medicine, Tottori University, Yonago, Japan

   Contribution

   Data curation, Formal analysis, Investigation

   Competing interests

   No competing interests declared

6. Shin-ichi Sasaki

   Division of Ophthalmology and Visual Science, Faculty of Medicine, Tottori University, Yonago, Japan

   Contribution

   Data curation, Formal analysis, Investigation

   Competing interests

   No competing interests declared

7. Yumiko Shimizu

   Division of Ophthalmology and Visual Science, Faculty of Medicine, Tottori University, Yonago, Japan

   Contribution

   Data curation, Formal analysis, Investigation

   Competing interests

   No competing interests declared

8. Yoshitsugu Inoue

   Division of Ophthalmology and Visual Science, Faculty of Medicine, Tottori University, Yonago, Japan

   Contribution

   Supervision, Funding acquisition, Project administration, Writing - review and editing

   Competing interests

   medical advisor of Senju Pharmaceutical Company, Japan.

9. Kazuomi Nakamura

   Division of Pathological Biochemistry, Department of Biomedical Sciences, Faculty of Medicine, Tottori University, Tottori, Japan

   Contribution

   Resources, Formal analysis, Supervision, Methodology

   Competing interests

   No competing interests declared

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