NR3C1 limits the imprinting of astrocyte epigenetic inflammatory memory early in life

Abstract

In a recent study, Park et al. show that early-life loss of NR3C1 in astrocytes establishes a long-lasting epigenetic memory that heightens neuroinflammation and worsens pathology in the central nervous system (CNS) later in life. These findings highlight the potential roles of astrocyte inflammatory memory in CNS pathology, as well as potential targets for its modulation.

Astrocytes, the most abundant glial cells in the central nervous system (CNS), are increasingly recognized as key regulators of neuroinflammation. Beyond their classical roles in development and homeostasis, astrocyte subsets have been shown to play important roles in the control of adaptive and innate immune responses in the CNS, with significant implications for neurodegeneration and other forms of pathology^1,2. For instance, in multiple sclerosis (MS) astrocytes subsets promote disease progression through an extensive bi-directional crosstalk with CNS-resident and -recruited immune cells that modifies the activity of both, astrocytes and interacting immune cells³. In this context, it was recently reported that astrocytes retain an epigenetic memory of prior immunostimulatory experiences, which shapes astrocyte long-term responses to subsequent challenges^4,5. However, the mechanisms regulating this process, and whether inflammatory memories are acquired during development, is still unknown.

In a recent study, Park et al.⁶ addressed this question through the longitudinal multi-omics profiling of cortical astrocytes from embryonic to postnatal stages in mice, uncovering stage-specific transcriptional and epigenetic programs, and identifying the glucocorticoid receptor NR3C1 as a key regulator. Conditional deletion of NR3C1 in astrocytes at P17 resulted in widespread transcriptional alterations but no overt baseline abnormalities. However, upon immune challenge these mice displayed a worsening of experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, showing exacerbated demyelination, elevated astrocyte and microglial activation, and increased CD4 + T-cell infiltration. Interestingly, NR3C1 target genes were associated with MS, providing a mechanistic link between early astrocyte programming and CNS inflammatory disorders later in life. These findings highlight the long-term implications of astrocyte epigenetic inflammatory memory, while also underscoring the importance of mechanisms limiting the acquisition of these pro-inflammatory epigenetic programs early in life.

Single-nucleus RNA-sequencing analyses of NR3C1-deficient astrocytes at the peak of EAE detected the upregulation of signaling associated with immune pathways, including those linked to type II interferon, IL-2/STAT5, and IL-6. Importantly, these transcriptional alterations overlapped with gene signatures associated with active MS lesions, suggesting that the exacerbated CNS inflammation in EAE mice harboring NR3C1-deficient astrocytes arise from the loss of mechanisms limiting modules of astrocyte inflammatory memory established early in life and relevant for MS pathology. Indeed, chromatin accessibility analyses further revealed that pro-inflammatory cis-regulatory elements were already accessible in NR3C1-deficient astrocytes by postnatal day 17 and persisted into adulthood, well before immune challenge. Notably, the restraining effects of NR3C1 on astrocyte immune memory seem to be physiologically relevant early in life, as NR3C1 inactivation in adulthood failed to reproduce enduring epigenetic and transcriptional alterations. Thus, NR3C1 specifically limits the establishment of epigenetically-driven astrocyte pro-inflammatory memory early in life (Fig. 1). These findings also suggest that other mechanisms operate later in life to control astrocyte inflammatory memory.

Fig. 1. Early-life NR3C1 inactivation establishes long-term astrocyte epigenetic inflammatory memory.

Conditional deletion in astrocytes of the glucocorticoid receptor NR3C1 during early postnatal development imprints long-lasting astrocyte epigenetic inflammatory memory. Following astrocyte-specific NR3C1 genetic inactivation, chromatin accessibility profiling revealed that pro-inflammatory cis-regulatory elements became prematurely open during the postnatal stage and remained persistently accessible into adulthood. Although NR3C1-deficient astrocytes appear phenotypically normal at baseline, upon immune stimulation, they display hyperactivation of type II interferon, IL-2/STAT5, and IL-6 pathways, worsening experimental autoimmune encephalomyelitis (EAE). These transcriptional changes overlap with those detected in active multiple sclerosis (MS) lesions, suggesting that astrocyte epigenetic memories imprinted early in life may contribute to the development of MS and other neurologic diseases in adulthood. Created in BioRender. Kim, D. (2025) https://BioRender.com/rbh4jhp.

These findings align with accumulating evidence showing that astrocytes, following activation by inflammatory stimuli, develop a long-term epigenetic inflammatory memory that modifies their responses upon subsequent activation^4,5. In MS, for example, chromatin remodeling induced by pro-inflammatory cytokines amplifies astrocyte responses and exacerbates CNS pathology⁴. Similarly, epigenetically controlled astrocyte immune memory boosts astrocyte pro-inflammatory responses and enhances microglial Aβ clearance⁵. Interestingly, this inflammatory memory is controlled by the disease-related genes CLEC16A in MS and the Alzheimer’s Disease (AD)-related allele APOE4^5,7. Taken together, these studies suggest potential contributions of epigenetically driven astrocyte immune memory to CNS pathology. In this context, the work by Park et al. suggests that compensatory mechanisms such as those driven by NR3C1 limit the acquisition of pro-inflammatory memory in astrocytes. Such mechanisms may prevent long-term deleterious effects of inflammation early in life, which could otherwise contribute to the development of neurologic disorders in adulthood. For instance, NR3C1-dependent mechanisms may prevent the establishment of inflammatory memories triggered by the acquisition of the gut microbiome, as well as changes in the permeability of the intestinal barrier, during development, or triggered by infections in the pregnant mother or the newborn^8–10. Similar mechanisms may operate to limit the acquisition of inflammatory memory in other CNS^11,12 and peripheral^13,14 cell types.

Conclusions

In summary, this study identifies NR3C1 as a key regulator of astrocyte epigenetic inflammatory programming in early life, revealing a critical developmental window during which astrocytes acquire lasting inflammatory potential. More broadly, these findings illustrate how glial cells integrate developmental and environmental cues into epigenetic states that shape lifelong CNS immunity and neurodegeneration. This study also raises important questions. How do developmental and environmental factors such as perinatal stress, infections, or glucocorticoid exposure intersect with NR3C1-dependent pathways to shape astrocyte inflammatory memory, and what are the mechanisms involved? Moreover, as glucocorticoids are widely used in the clinic, an important question is whether their administration at defined developmental windows could regulate long-term reactivity in astrocytes and other cell types. More broadly, how inflammatory memory is coordinated across different cell types to influence development, physiology, and pathology remains unknown. Addressing these questions is essential to develop approaches for the therapeutic modulation of inflammatory memory.

Author contributions

H-G.L. and F.J.Q. conceived and wrote this commentary.

Competing interests

The authors declare no competing interests.