Neuronal apoptosis drives remodeling states of microglia and shifts in survival pathway dependence

Microglia are parenchymal innate immune cells and vital remodelers of the central nervous system (CNS) (Prinz et al., 2021). They have a myriad of critical functions during development, including elimination of viable or dying cells (Anderson and Vetter, 2019c; Anderson et al., 2019b). Similar to other macrophages, microglia are extremely attuned to changes in their neural niche (Lavin et al., 2014; Gosselin et al., 2017; Bennett et al., 2018) and rapidly respond by phagocytosis or secreting soluble factors. Recent single-cell RNA sequencing (scRNAseq) has demonstrated that microglia are particularly diverse during development (Hammond et al., 2019; Li et al., 2019a). However, we still lack an understanding of the drivers of this heterogeneity, including the impact of environmental cues or the act of phagocytosis itself. Therefore, connecting microglial states to specific developmental events and determining the pathways involved remains a central challenge.

One developmental process fundamental for nearly every organ in the body is apoptotic death of excess or dysfunctional cells (Jacobson et al., 1997). In the CNS, death of neurons and glia is an essential and well-documented feature of development (Oppenheim, 1991). Efferocytosis, or the phagocytosis of apoptotic cells, is a rapid and carefully orchestrated process designed to minimize damage to surrounding cells (Morioka et al., 2019; Boada-Romero et al., 2020). Largely mediated by microglia, efferocytosis is important for maintaining CNS homeostasis not only in development but in aging and disease as well (Galloway et al., 2019; VanRyzin, 2021). The developing mouse retina is an excellent CNS model system to link remodeling events such as efferocytosis and microglial state and function (Li et al., 2019b). During the postnatal period in the retina, as circuits are being established, waves of neuronal death occur (Braunger et al., 2014). For example, retinal ganglion cells (RGCs), the projection neurons connecting retina and brain, undergo a well-characterized culling during the first postnatal week which is dependent on pro-apoptotic factor, Bcl-2-associated X protein (Bax) (Péquignot et al., 2003). An estimated ~50% of RGCs will undergo apoptosis and need to be cleared (Farah and Easter, 2005; Farah, 2006). We previously found that neuronal death significantly influences microglia properties in postnatal retina, resulting in a majority of microglia expressing a distinct gene signature and showing altered dependence on CSF1R signaling for survival (Anderson et al., 2019a). Relative to adult microglia, homeostatic genes were reduced, while genes associated with phagocytosis and lipid metabolism were increased, similar to aging and disease-associated microglia (DAM) (Holtman et al., 2015; Keren-Shaul et al., 2017; Krasemann et al., 2017), and to developmental microglia residing in postnatal white matter tracts (PAM) (Li et al., 2019a) or (ATM) (Hammond et al., 2019) or CD11c microglia (Benmamar-Badel et al., 2020).

Consistent with either apoptotic cell recognition or phagocytosis playing a central role in driving this gene signature, microglia in disease states increase select DAM genes in response to apoptotic cells (Krasemann et al., 2017), and ATM/PAM populations in the white matter tract engulf oligodendrocyte precursor cells (Li et al., 2019a; Nemes-Baran et al., 2020). In disease, the TREM2 receptor is partially required for acquisition of the DAM signature (Keren-Shaul et al., 2017; Krasemann et al., 2017), but not for the developmental signature in retina (Anderson et al., 2019a) or brain (Li et al., 2019a). Thus, it remains unclear to what extent the process of phagocytosis is altering properties of developmental microglia or whether distinct recognition pathways are involved. Microglia, like other macrophages, can recognize and engulf apoptotic (or viable) cells via a variety of ligand-receptor systems including C1q/C3 to complement receptor 3 (CR3) and exposed phosphatidylserine (PtdSer) to TAM family of tyrosine kinase receptors Mer (gene Mertk) and Axl (Lemke, 2019), but how these pathways mediate changes in microglia properties and responses is an active area of research.

Here, we ask how neuronal apoptosis drives key properties of developmental microglia such as CSF1R dependence and expression of DAM/ATM/PAM-related genes, and test the role of phagocytosis and specific recognition pathways. Through scRNAseq on postnatal retinal microglia, we find considerable transcriptional heterogeneity, with multiple distinct microglial populations expressing DAM/ATM/PAM-related, lysosomal, and lipid metabolism genes. We further show, by analyzing microglia from Bax knockout (KO) retinas, that exposure to dying neurons drives several of these states and that most are more resistant to CSF1R inhibition. We find that CR3 and Mer are required for clearance of dying RGCs, but not for altering dependence on CSF1R signaling for survival. Conversely, Axl is not required for clearance of dying RGCs, but for augmenting microglial survival in the absence of CSF1R signaling. Loss of Mer did not have a widespread impact on expression of microglial remodeling genes, and neither did loss of Axl or Mertk/Axl double KO (dKO), suggesting that TAM receptor-mediated signaling or reduced clearance are not sufficient. Thus, we find that interactions with apoptotic neurons drives developmental microglial diversity, and that distinct recognition receptors mediate phagocytosis of dying cells versus specific microglial properties, including microglial survival.

scRNAseq has revealed that microglia in development and disease are transcriptionally diverse across the CNS (Masuda et al., 2020). Due to their remarkable plasticity, a major challenge is to determine the impact of local cues on microglial state and properties. Here, using the postnatal retina as a model system, we establish neuronal cell death as a key factor driving developmental microglia diversity. We show by scRNAseq that multiple microglial states coexist within this discrete CNS region, encompassing a spectrum from homeostatic to remodeling states with high lysosomal and lipid metabolism gene expression. We establish that multiple distinct remodeling states are driven by neuronal apoptosis, and further show that several of these remodeling states survive CSF1R inhibition, while more homeostatic microglia are susceptible. CR3 and Mer are important for clearance of apoptotic retinal neurons, while Axl facilitates microglial survival following inhibition CSF1R, but neither significantly regulates expression of microglial remodeling genes. Thus, we conclude that cell death is a critical cue for driving diverse microglial properties and that multiple pathways contribute.

We identify several states of remodeling microglia characterized by reduced homeostatic gene expression and elevated lipid metabolism and lysosomal genes, with more discrete expression of various genes including chemokines/cytokines. Many of the genes in these remodeling states are shared with microglia in developing white matter tracts of the brain (CD11c/ATM/PAM) (Wlodarczyk et al., 2017; Hammond et al., 2019; Li et al., 2019a) and disease (DAM) (Holtman et al., 2015; Keren-Shaul et al., 2017; Krasemann et al., 2017). Unlike in brain, we find they represent a majority of microglia in the early postnatal retina, with most of them dependent upon neuronal apoptosis. Due to the large proportion of microglia expressing these remodeling genes, we broaden our understanding of microglia subsets present during normal development. For example, we find genes such as Apoe and Ctsd are widely expressed at varying levels, while Fabp5 and Spp1 are confined to more discrete subsets, suggesting that regulation of these genes and microglial states is multifaceted.

While our previous work found that microglia expressing several of these remodeling genes were dynamically regulated over development, future work analyzing the localization of these populations would further inform understanding of function and population dynamics. At present, it remains unclear whether they transition from state to state. Since we find an increase in the proportion of homeostatic microglia in Bax KO retinas, this argues that microglia in the context of neuronal death shift from a homeostatic state to more remodeling ones. We found that loss of Bax had an effect on microglial density, consistent with zebrafish studies (Casano et al., 2016), suggesting that neuronal apoptosis is important for regulating other microglial properties. Whether this is due to a reduction in proliferation is unknown, however we did not see a change in the proportion of cycling cells by scRNAseq.

In other contexts, efferocytosis can have a major impact on the transcriptional profile and state of the phagocyte. For example, phagocytosis promotes distinct transcriptional states in macrophages in a tissue-specific manner throughout the body (A-Gonzalez et al., 2017), and tissue macrophages modify their repertoire of phagocytic machinery in response to phagocytosis (Zent and Elliott, 2017). In the CNS, there is much to learn about how phagocytosis impacts microglial state and function (Márquez-Ropero et al., 2020; VanRyzin, 2021). One study addressing this found engulfment of newborn neurons by microglia in adult neurogenic zones stimulates a microglial secretome that subsequently regulates neurogenesis (Diaz-Aparicio et al., 2020). Here, in the postnatal retina, phagocytosis and digestion appear to be a major aspect of microglial heterogeneity. We postulate that some remodeling states may even represent distinct stages of the clearance and digestion process. Our analysis also identified microglial states that did not change with loss of Bax. While perhaps they represent microglia that have not had the opportunity to interact with dying neurons, they may be involved in other important microglial functions during postnatal retinal development. For example, astrocytes are also pruned by microglia during this time period, which has been shown to be Bax-independent and also not require CR3, Mer, or CX3CR1 pathways (Puñal et al., 2019). Future studies could target these specific microglia subsets and try to link them to other important remodeling functions in the developing retina. Some clusters did have higher expression of ex vivo activation genes (Marsh et al., 2020) but the impact on developmental datasets has not been directly tested. exAM genes did not drive the formation of a single cluster and some genes were differentially expressed between samples, arguing against solely a technical effect. Further, we found exAM genes Ccl3 and Ccl4 were expressed in vivo, suggesting biological relevance (Figure 1—figure supplement 5 and data not shown).

Despite the fact that postnatal RGC death has been a well-characterized model of developmental cell death of the CNS (Péquignot et al., 2003), the recognition pathways required for the clearance of apoptotic RGCs was previously undefined. CR3 and Mer are well-known recognition receptors in the clearance of stressed or dying neurons in various contexts (Lemke, 2019). Here, we show that both receptors are important for clearance of apoptotic RGCs. Previous work has suggested that complement component C1q may get deposited on exposed PtdSer (Païdassi et al., 2008), suggesting the pathways might work together to signal for phagocytosis, but whether complement and TAM pathways are working redundantly or cooperatively is unknown in any context. It is also unclear whether other mechanisms can compensate for the loss of either receptor. We predict this is likely, since microglia express a broad array of phagocytic receptors, and other cell types such as astrocytes can phagocytose, particularly in contexts of deficient microglia (Puñal et al., 2019). Furthermore, since Mer and Axl are expressed in other cell types such as astrocytes (Fourgeaud et al., 2016), we cannot exclude the possibility of indirect effects. While receptors Mer and Axl are both members of the TAM receptor family of tyrosine kinases (Lemke, 2013), it has been appreciated that Mertk is more stably expressed in microglia, while Axl is more dynamic and upregulated with inflammation or disease (Fourgeaud et al., 2016). Both have previously been implicated in phagocytosis and in regulating inflammatory responses (Elliott et al., 2017), however this is cell type-dependent (Seitz et al., 2007). Here, we find Mertk/Axl dKO did not have an enhanced clearance deficit for apoptotic RGCs compared to Mertk KO, although this could be due to a ceiling effect since RBPMS likely gets downregulated as apoptotic programs continue (Elliott and Ravichandran, 2016).

Although Mer is important for clearance, we did not see a dramatic reduction in lysosomal or lipid metabolism genes in either Mertk or Axl KO microglia. These results are consistent with disease contexts where loss of Mertk and Axl did not have a profound effect on the DAM signature in mouse model of Alzheimer’s disease (Huang et al., 2021). This suggests that transcriptional changes in postnatal retinal microglia may depend upon other pathways, although Mer and Axl could still have essential roles in post-transcriptional regulation of microglial states. Additionally, Mertk KO microglia are likely still clearing, but at a reduced rate, since live-imaging has shown that loss of Mer results in delayed engagement with apoptotic cells but does not abolish phagocytosis completely (Damisah et al., 2020).

While in adulthood, retinal microglia can be ablated by blocking CSF1R signaling (MacDonald et al., 2010; Anderson et al., 2019a), we previously found that during the early postnatal period a large proportion of microglia expressing select remodeling genes are more resistant to inhibition or loss of this important survival pathway (Anderson et al., 2019a). One hypothesis is that specific microglial states, which are transient, have altered CSF1R dependence. Here, we identify specific remodeling states of microglia that persist following CSF1R inhibition showing reduced homeostatic gene expression. Other groups recently found small populations of CSF1R-independent or repopulating microglia in the brain, and we note similar patterns of gene expression, with reduced homeostatic genes such as Tmem119 and P2ry12, and increased expression of genes such as Lyz2 (Zhan et al., 2020; Hohsfield et al., 2021). In these microglia repopulation studies, it was proposed that more immature microglia survive CSF1R inhibition, but microglia maturation may not be a key factor in the context of development since we previously found greater dependence of retinal microglia on CSF1R at embryonic stages (Anderson et al., 2019b) than in postnatal retina (Anderson et al., 2019a). We find that most of these resistant microglia subsets are induced by neuronal apoptosis, consistent with our prior analysis showing increased microglial dependence on CSF1R in Bax KO retina (Anderson et al., 2019a). Interestingly, in culture, peritoneal and bone marrow macrophages that phagocytose apoptotic cells also survive in the absence of serum or survival factors (Reddy et al., 2002). In periods of elevated cell death and possible lack of extrinsic survival factors, such as neuronally expressed CSF1R ligand, IL-34 (Nandi et al., 2012), phagocytes such as microglia might have evolved strategies to survive in order to maintain homeostasis or reduce inflammation (Reddy et al., 2002). Importantly, cholesterol, along with CSF-1/IL-34 and TGF-ß2, has been shown to be an important survival factor for microglia in culture (Bohlen et al., 2017). However, other possibilities exist for the overlap between clusters dependent on neuronal apoptosis (0,3,4,5) and clusters more resistant to CSF1R inhibition (3,4,5,6,10). For example, PLX-treatment itself could be inducing transcriptional changes reminiscent of remodeling states. We did see an expansion of PLX-enriched (3) microglia with the lowest levels of homeostatic gene expression and high levels of lysosomal and lipid metabolism genes. Thus, CSF1R signaling may also be important for promoting microglial homeostasis (Hu et al., 2021). Consistent with this, mutations in CSF1R can lead to leukoencephalopathy, a neurodegenerative disorder that is associated with loss of homeostatic microglia phenotype (Kempthorne et al., 2020). PLX-enriched (3) microglia may also represent cells that are undergoing other changes, even progressing toward death. It will be valuable for future studies to explore the contributions of CSF1R signaling to microglial survival and homeostasis during development.

Here, we find that Axl expression, which is regulated by neuronal apoptosis, enhances microglial survival in the absence of CSF1R signaling. Since loss of Axl did not substantially alter expression of other candidate apoptotic pathways in microglia, one possibility is that signaling directly downstream of Axl is involved in promoting survival. Axl has been shown to inhibit apoptosis in a variety of cell types (Axelrod and Pienta, 2014) including fibroblasts (Goruppi et al., 1997), oligodendrocytes in contexts of growth factor withdrawal or TNF toxicity (Shankar et al., 2006), and in Gonadotropin-releasing hormone neurons in the brain (Pierce et al., 2008). Its role in various types of cancer has been well established for promoting tumor growth and metastasis in part due to its ability to inhibit apoptosis of cancer cells (Zhu et al., 2019). Axl has diverse downstream signaling cascades depending on context (Axelrod and Pienta, 2014), but one candidate signaling cascade is the PI3K-Akt-NfkB-Bcl2 pathway. Activation of PI3K and Akt has shown to be important for survival of cultured macrophages (Reddy et al., 2002), oligodendrocytes (Shankar et al., 2003; Shankar et al., 2006), neurons (Pierce et al., 2008) as well as cancer cells (Axelrod and Pienta, 2014). Another candidate pathway for regulating microglial survival is Spp1/osteopontin since we found it was significantly downregulated in Axl KO microglia. Spp1/osteopontin has been shown to promote survival of other cell types including peripheral immune cells (Denhardt et al., 2001) and cancer cells (Saleh et al., 2016). Furthermore, Spp1/osteopontin can influence aspects of microglial properties including enhancing survival under conditions of stress in culture (Yu et al., 2017).

Altogether, we show neuronal cell death is a key factor driving multiple states of microglia in developing retina, with distinct transcriptional profiles and altered dependence from CSF1R signaling for survival. Apoptotic cell recognition by microglia is thus a critical developmental event driving diverse effects on gene expression, clearance, and survival, with distinct pathways involved in mediating each of these responses.

Sequencing data have been deposited in GEO under the reference series GSE192602. https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE192602 Data generated or analyzed during this study are included in the manuscript.

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Author details

1. Sarah Rose Anderson

   Department of Neurobiology, University of Utah, Salt Lake City, United States

   Contribution

   Conceptualization, Formal analysis, Investigation, Methodology, Supervision, Validation, Visualization, Writing - original draft

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-7639-4064

2. Jacqueline M Roberts

   Department of Neurobiology, University of Utah, Salt Lake City, United States

   Contribution

   Data curation, Formal analysis, Investigation, Methodology, Software, Visualization, Writing – review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-1024-3976

3. Nathaniel Ghena

   1. Department of Neurobiology, University of Utah, Salt Lake City, United States
   2. Interdepartmental Program in Neuroscience, University of Utah, Salt Lake City, United States

   Contribution

   Formal analysis, Investigation, Visualization, Writing – review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-1890-8036

4. Emmalyn A Irvin

   Department of Neurobiology, University of Utah, Salt Lake City, United States

   Contribution

   Formal analysis, Investigation

   Competing interests

   No competing interests declared

5. Joon Schwakopf

   Department of Neurobiology, University of Utah, Salt Lake City, United States

   Contribution

   Formal analysis, Investigation

   Competing interests

   No competing interests declared

6. Isabelle B Cooperstein

   Department of Neurobiology, University of Utah, Salt Lake City, United States

   Contribution

   Formal analysis, Investigation

   Competing interests

   No competing interests declared

7. Alejandra Bosco

   Department of Neurobiology, University of Utah, Salt Lake City, United States

   Contribution

   Formal analysis, Investigation, Writing – review and editing

   Competing interests

   No competing interests declared

8. Monica L Vetter

   Department of Neurobiology, University of Utah, Salt Lake City, United States

   Contribution

   Conceptualization, Funding acquisition, Project administration, Supervision, Writing – review and editing

   For correspondence

   monica@neuro.utah.edu

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-6262-8504

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