Kimitoshi Kimura and al.

This study investigates the function of the immune-checkpoint molecule TIM-3 in microglia. The authors demonstrate that in mice, TGF-β signalling induces TIM-3 expression in microglia. In turn, TIM-3 interacts with SMAD2 and TGFBR2 through its carboxy-terminal tail, which enhances TGFβ signalling by promoting TGFBR-mediated SMAD2 phosphorylation. This process maintains microglial homeostasis. Genetic deletion of the TIM-3 encoding gene Havcr2 in microglia leads to increased phagocytic activity and a gene-expression profile consistent with the neurodegenerative microglial phenotype referred to as disease-associated microglia (DAM). Furthermore, microglia-targeted deletion of Havcr2 ameliorates cognitive impairment and reduces amyloid-β pathology in 5×FAD mice, a transgenic model of Alzheimer’s disease. Analyses by scRNA-seq show that microglia in Havcr2-deficient 5×FAD mice are characterized by increased pro-phagocytic and anti-inflammatory gene expression along with reduced pro-inflammatory gene expression.

Zhisheng Wub and al.

In this article, the authors show the existence of a peripharal nervous system (PNS)-resident macrophage population that shares transcriptomic and epigenetic profiles as well as an ontogenetic trajectory with microglia. This population, termed PNS microglia-like cells, enwraps the neuronal soma inside the satellite glial cell envelope, preferentially associates with larger neurons during PNS development, and is required for neuronal functions by regulating soma enlargement and axon growth. A phylogenetic survey of 24 vertebrates revealed an early origin of PNS microglia-like cells, whose presence is correlated with neuronal soma size (and body size) rather than evolutionary distance. Consistent with their requirement for soma enlargement, PNS microglia-like cells are maintained in vertebrates with large peripheral neuronal soma but absent when neurons evolve to have smaller soma.

Yunjin Lee and al.

Interleukin-17A (IL-17A) mediates protective immune responses by binding to IL-17 receptor A (IL-17RA) and IL-17RC subunits. IL-17A also modulates social interaction, yet the role of cytokine receptors in this process and their expression in the brain remains poorly characterized. Here, we mapped the brain-region-specific expression of all major IL-17R subunits and found that in addition to IL-17RA, IL-17RB—but not IL-17RC—plays a role in social behaviors through its expression in the cortex. We further showed that IL-17E, expressed in cortical neurons, enhances social interaction by acting on IL-17RA- and IL-17RB-expressing neurons. These findings highlight an IL-17 circuit within the cortex that modulates social behaviors. Thus, characterizing spatially restricted cytokine receptor expression can be leveraged to elucidate how cytokines function as critical messengers mediating neuroimmune interactions to shape animal behaviors.

Maike Becker and al.

The hypothalamus in the CNS has important functions in controlling systemic metabolism. A calorie-rich diet triggers CNS immune activation, impairing metabolic control and promoting obesity and type 2 diabetes, but the mechanisms driving hypothalamic immune activation remain unclear. Here, the authors identify regulatory T cells (Tregs) as key modulators of hypothalamic immune responses. In mice, calorie-rich environments activate hypothalamic CD4⁺ T cells, microglia and infiltrating macrophages while reducing hypothalamic Tregs. mRNA profiling of hypothalamic CD4⁺ T cells reveals a Th1-like activation state, with increased Tbx21, Cxcr3 and Cd226  but decreased Ccr7 and S1pr1. Importantly, results from Treg loss-of function and gain-of-function experiments show that Tregs limit hypothalamic immune activation and reverse metabolic impairments induced by hyper-caloric feeding.

Xiaoyue Aelita Zhu and al.

Cachexia, a severe wasting syndrome associated with inflammatory conditions, often leads to multiorgan failure and death. Patients with cachexia experience extreme fatigue, apathy, and clinical depression, yet the biological mechanisms underlying these behavioral symptoms and their relationship to the disease remain unclear. In a mouse cancer model, cachexia specifically induced increased effort-sensitivity, apathy-like symptoms through a cytokine-sensing brainstem-to-basal ganglia circuit. This neural circuit detects elevated interleukin-6 (IL-6) at cachexia onset and translates inflammatory signals into decreased mesolimbic dopamine, thereby increasing effort sensitivity. The authors alleviated these apathy-like symptoms by targeting key circuit nodes: administering an anti–IL-6 antibody treatment, ablating cytokine sensing in the brainstem, and optogenetically or pharmacologically boosting mesolimbic dopamine. These findings uncover a central neural circuit that senses systemic inflammation and orchestrates behavioral changes, providing mechanistic insights into the connection between chronic inflammation and depressive symptoms.