Wesley Brandao and al.

Xenon (Xe) is a gas used in clinics as an anesthetic and a neuroprotective agent under conditions of traumatic brain injury. Here, the authors designed a Xe inhalation chamber and tested its therapeutic potential in murine models of Alzheimer’s disease (AD). In amyloidosis (APP/PS1 and 5xFAD) or tauopathy models (P301S), Xe treatment induced a "pre-neurodegenerative" microglial activation program exhibiting IFN-γ signaling signature. Such a phenotypic transition enhanced amyloid plaque compaction and reduced dystrophic neurites. Of note, Xe inhalation also reduced brain atrophy and neuroinflammation while improving nesting behavior in P301S mice.

Kristen C. Vogt and al.

CAR lymphocytes ("CAR-T cells") targeting the GD2 molecule induce rapid and fatal neurotoxicity due to the physiological expression of GD2 in brain tissue. To avoid such a neurotoxicity, the authors designed a synthetic Notch receptor that selectively expresses CAR upon binding to P-selectin, an adhesion protein overexpressed in tumoral neovessels. In this model, CAR-T cells are activated by the tumor microenvironment, the antitumoral effects are maintained and the  intracerebral T-cell infiltration is increased in the absence of neurotoxic effects.

Guiqin Chen and al.

Patients carrying the PSEN1 E280A mutation and the APOE3 Christchurch (R136S) variant are protected from Alzheimer’s disease (AD) symptoms and exhibit a distinct anatomical distribution of Tau-related pathology. However, the molecular mechanism underlying such a protective effect remains poorly understood. In this study, the authors show that the ApoE3 R136S variant binds Tau and reduces its internalization by neurons and microglia. This leads to a decreased fragmentation of Tau by asparagine endopeptidase (AEP) and a reduction of the pro-inflammatory reactions induced by Tau or amyloid-beta fibrils.

Henna Lehtonen and al.

The authors performed a molecular mapping of pituitary macrophages and revealed their heterogeneity and spatial specialization. Microglia-like macrophages are enriched in the posterior pituitary, while other macrophages in the anterior pituitary closely interact with hormone-secreting cells. All pituitary macrophages originate from early yolk sac-derived precursors and are maintained through self-renewal, independently of bone marrow-derived monocytes. Depletion experiments demonstrate the role of pituitary macrophages in regulating the intra-pituitary hormonal balance via extracellular ATP-mediated signaling.

Sarasa Yano and al.

In this study, the authors demonstrate that, in the developing mouse brain, neurons migrating through dense regions of the neocortex release "micronuclei" into the extracellular space. These neuronal micronuclei are phagocytosed by microglia and induce morphological changes (slow retraction of processes) that can be visualized in vivo using two-photon microscopy. The microglial KO of the cGAS gene attenuates the morphological effects induced by neuronal micronuclei. Furthermore, microglial cells that have phagocytosed these micronuclei display a specific transcriptomic signature.

Hongjie Chen and al.

Type 2 immunity in the lungs protects against pathogen infections, but its dysregulation is responsible for asthma. Although it has long been observed that asthma symptoms in patients can be exacerbated after a meal, the pathophysiological underlying this postprandial phenomenon remains poorly understood. In this study, the authors report that food intake induces, via the parasympathetic nervous system, an activation of type 2 immune responses in the lungs of mice. Importantly, the parasympathetic terminals in the lungs co-localize with type 2 innate lymphoid cells (ILC2s). Pharmacological or surgical blockade of parasympathetic signals reduced type 2 immunity in the lungs. Conversely, chemogenetic manipulation of parasympathetic inputs and their upstream neural circuits was ufficient to modulate these immune responses. Finally, the authors show that: i) ILC2s in the lungs of both mice and humans express Chrm4, a receptor for the parasympathetic neurotransmitter acetylcholine, and ii) deletion of Chrm4 attenuates ILC2-mediated pulmonary inflammation.

Marko Šestan and al.

This study shows that after forced fasting, mice lacking type 2 innate lymphoid cells (ILC2) exhibit impaired glucose homeostasis, altered pancreatic glucagon secretion, and ineffective hepatic gluconeogenesis. ILC2s originating from the intestines migrate to the pancreas through a mechanism dependent on β2-adrenergic receptor expression. Finally, the authors demonstrate that a targeted activation of intestinal catecholaminergic neurons promotes the accumulation of ILC2s in the pancreas.