Summary: Researchers have identified a microbiome-regulated, anti-inflammatory subset of astrocytes that helps control central nervous system inflammation and points toward new therapeutic possibilities.
Source: Brigham and Women’s Hospital
Astrocytes, the most abundant glial cells in the central nervous system (CNS), have long been thought to primarily support neurons. Over recent years, however, studies have shown that astrocytes can also drive neuroinflammation and contribute to neurological disease. New work from Brigham and Women’s Hospital reveals the opposite: a distinct subset of astrocytes that actively suppresses inflammation. These findings expand our understanding of how the brain’s immune environment is regulated and how the gut microbiome can shape CNS health.
Using advanced gene and protein analysis techniques, the research team identified an astrocyte population located near the meninges — the protective membranes that surround the brain — that expresses the lysosomal marker LAMP1 and the death receptor ligand TRAIL. Together, LAMP1 and TRAIL define a subset of astrocytes capable of limiting inflammation by inducing apoptosis in pro-inflammatory T cells, thereby reducing immune-driven damage in the CNS.
To understand what controls these LAMP1+TRAIL+ astrocytes, the investigators used CRISPR–Cas9 gene-editing and a series of functional experiments. They discovered that interferon-gamma (IFNγ), a signaling molecule produced by immune cells, drives astrocyte TRAIL expression. Importantly, the team found that IFNγ production in the relevant meningeal immune cells is regulated by the gut microbiome: microbes in the intestine influence peripheral immune cells that circulate through the body and reach the meninges, where they sustain astrocyte anti-inflammatory activity.
This gut–brain connection operates through meningeal natural killer (NK) cells that produce IFNγ. The microbiome helps “license” these IFNγ+ NK cells, supporting TRAIL expression in astrocytes and maintaining an anti-inflammatory environment in homeostatic conditions. Inflammatory signals from T cells and microglia can suppress TRAIL in astrocytes, tipping the balance toward inflammation during disease. The discovery of this pathway provides a clearer picture of how immune and microbial signals combine to regulate CNS inflammation.
Beyond expanding basic understanding, these results have practical implications. By revealing a microbiome-controlled mechanism that restrains harmful immune responses in the brain, the work points to new therapeutic directions for inflammatory neurological disorders such as multiple sclerosis. The researchers are exploring probiotic strategies and other approaches to modulate this pathway and enhance astrocytes’ anti-inflammatory activity as potential treatments.
The team also notes a potential relevance to cancer: their more recent data indicate that certain brain tumors may hijack this anti-inflammatory pathway to evade immune attack. In response, the investigators are pursuing cancer immunotherapy strategies aimed at blocking tumor exploitation of the LAMP1+TRAIL+ astrocyte axis and restoring effective anti-tumor immune responses.
“Identifying a microbiome-controlled, anti-inflammatory subset of astrocytes is an important advance in our understanding of CNS inflammation and its regulation,” said Francisco Quintana, PhD, corresponding author and leader of the study at the Ann Romney Center for Neurologic Diseases. He emphasized that earlier work tended to treat astrocytes as a single cell type, and that improved molecular resolution is revealing diverse astrocyte populations with distinct and sometimes opposing functions.
Quintana’s lab previously identified another gut-regulated astrocyte subset in 2016, and the investigators believe additional subsets remain to be characterized. They are systematically cataloguing astrocyte populations and investigating how gut microbes influence each group. This line of research highlights the broader importance of the gut microbiome in many diseases and underscores the potential for microbiome-informed interventions to modulate brain immunity.
Funding: This research received support from multiple sources, including the National Institutes of Health (awards listed by grant numbers), the National MS Society, the International Progressive MS Alliance, a Chan-Zuckerberg Initiative Ben Barres Early Career award, the Burroughs Wellcome Fund, Canadian funding agencies and institutional programs at Brigham and Women’s Hospital and Dana-Farber Cancer Institute, among others. Fellowship and foundation awards also contributed to the work.
About this neuroscience research news
Source: Brigham and Women’s Hospital
Contact: Haley Bridger – Brigham and Women’s Hospital
Image: The image is in the public domain
Original Research: Closed access. “Gut-licensed IFNγ+ NK cells drive LAMP1+TRAIL+ anti-inflammatory astrocytes” by Sanmarco, LM, et al. Nature
Abstract
Gut-licensed IFNγ+ NK cells drive LAMP1+TRAIL+ anti-inflammatory astrocytes
Astrocytes are abundant glial cells in the CNS that perform essential homeostatic functions and can also influence disease. Using high-throughput flow cytometry, single-cell RNA sequencing, and cell-specific in vivo CRISPR–Cas9 perturbations in mice, the authors identify an astrocyte subset marked by LAMP1 and TRAIL that limits CNS inflammation by inducing apoptosis of T cells through TRAIL–DR5 signaling. Under steady-state conditions, interferon-gamma produced by meningeal NK cells drives TRAIL expression in these astrocytes, and the gut microbiome modulates IFNγ expression in the NK cells. Inflammatory mediators from T cells and microglia suppress astrocyte TRAIL during disease. Together, the findings reveal a microbiome-dependent mechanism that maintains an anti-inflammatory astrocyte population and shapes CNS immune homeostasis.