Xiaodan Hu and al.

MEF2C is a crucial immune checkpoint that regulates microglial activation. In this paper, the authors found that microglia-like cells derived from MEF2C-deficient (MEF2C−/−) human pluripotent stem cells (hPSCs) exhibit overactivation following lipopolysaccharide stimulation, mimicking patterns observed in various neuroinflammatory disorders. High-throughput screening identified BMS265246, a CDK2 inhibitor, as being able to suppress such an overactivation process. Mechanistically, MEF2C transcriptionally upregulated p21 to inhibit CDK2-mediated degradation of retinoblastoma protein (RB), thereby preventing NFκB nuclear translocation and consequent microglial overactivation. In vivo, BMS265246 treatment substantially ameliorated microglial overactivation and ASD (autism spectrum disorder)-like behaviors in Mef2c-deficient mice.

Matija Zelic and al.

The authors performed scRNA-seq analyses of spinal cords from patients with amyotrophic lateral sclerosis (ALS) and identified altered glial cell states, including increased expression of inflammatory and glial activation markers. Many of these signals converged on RIPK1 and the necroptotic cell death pathway. In SOD1 G93A mice, blocking RIPK1 kinase activity delayed symptom onset and motor impairment and modulated glial responses. We used human iPSC-derived motor neuron, astrocyte, and microglia tri-cultures to identify potential biomarkers that are secreted upon RIPK1 activation in vitro and modulated by RIPK1 inhibition in the cerebrospinal fluid (CSF) of patients with ALS. These data suggest a deleterious role for neuroinflammatory signaling in ALS pathogenesis.

Zili Xie and al.

The enteric nervous system detects luminal pressure to regulate peristalsis independently of extrinsic input from the central and peripheral nervous systems. However, how the ∼500 million enteric neurons that reside in the GI tract sense and respond to force remains unknown. In this article, the authors establish that the mechanosensor Piezo1 is functionally expressed in cholinergic enteric neurons. Optogenetic stimulation of Piezo1+ cholinergic enteric neurons drives colonic motility, while Piezo1 deficiency reduces cholinergic neuronal activity and slows peristalsis. Additionally, Piezo1 deficiency in cholinergic enteric neurons abolishes exercise-induced acceleration of GI motility. Finally, we uncover that enteric neuronal Piezo1 function is required for motility alterations in colitis and acts to prevent aberrant inflammation and tissue damage.

Adam P. Jones and al.

Type II neurofibromatosis, also known as NF2-related schwannomatosis, is a rare disease characterised by the growth of multiple nervous system neoplasms, including bilateral vestibular schwannoma (VS). VS tumours are characterised by extensive leucocyte infiltration. However, the immunological landscape in VS and the spatial determinants within the tumour microenvironment that shape the trajectory of disease are presently unknown. In this study, to elucidate the complex immunological networks across VS, the authors performed imaging mass cytometry (IMC) on clinically annotated VS samples from NF2 SWN patients. This study reveals the heterogeneity in neoplastic cell, myeloid cell and T cell populations that co-exist within VS in distinct histomorphic niches. Together, the results point to niche-dependent modes of T-cell regulation in NF2 SWN VS, indicating the potential for microenvironment-altering therapies for VS.

Tyler P. Molitor and al.

GWAS have identified a protective hypomorphic TYK2 allele (P1104A) in multiple sclerosis (MS). The authors eployed brain-penetrant TYK2 inhibitors (cTYK2i) alongside the peripherally restricted TYK2 inhibitor (pTYK2i; BMS-986165) to untangle the contributions of central TYK2 inhibition in diverse models of neuroinflammation. While pTYK2i had little impact, cTYK2i reduced clinical score, lymphoid cell infiltration, and cytokines/chemokines in experimental autoimmune encephalomyelitis (EAE). Microglial activation was attenuated in cTYK2i-treated EAE spinal cords and circulating neurofilament light was reduced in plasma and cerebral spinal fluid. Additionally, cTYK2i was protective in an antibody-mediated mouse model of primary progressive MS (PPMS). Finally, the authors demonstrate TYK2 inhibition has a robust impact on a unique subset of activated astrocytes termed Interferon-Responsive-Reactive-Astrocytes. The data presented herein identify a key role for CNS TYK2 signaling in regulating neuroinflammation and solidify TYK2 as a potential therapeutic target for MS.