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Maternal health during pregnancy plays a major role in shaping health and disease risks in the offspring. The maternal immune activation hypothesis proposes that inflammatory perturbations in utero can affect fetal neurodevelopment, and evidence from human epidemiological studies supports an association between maternal inflammation during pregnancy and offspring neurodevelopmental disorders (NDDs). Diverse maternal inflammatory factors, including obesity, asthma, autoimmune disease, infection and psychosocial stress, are associated with an increased risk of NDDs in the offspring. In addition to inflammation, epigenetic factors are increasingly recognized to operate at the gene–environment interface during NDD pathogenesis. For example, integrated brain transcriptome and epigenetic analyses of individuals with NDDs demonstrate convergent dysregulated immune pathways. In this Review, we focus on the emerging human evidence for an association between maternal immune activation and childhood NDDs, including autism spectrum disorder, attention-deficit/hyperactivity disorder and Tourette syndrome. We refer to established pathophysiological concepts in animal models, including immune signalling across the placenta, epigenetic ‘priming’ of offspring microglia and postnatal immune–brain crosstalk. The increasing incidence of NDDs has created an urgent need to mitigate the risk and severity of these conditions through both preventive strategies in pregnancy and novel postnatal therapies targeting disease mechanisms.The maternal immune activation (MIA) hypothesis proposes that inflammatory perturbations in utero can affect fetal neurodevelopment. This Review examines the emerging human evidence for an association between MIA and childhood neurodevelopmental disorders, including autism spectrum disorder, attention-deficit/hyperactivity disorder and Tourette syndrome.

Background Neuroinflammation is one of the most important processes in secondary injury after traumatic brain injury (TBI). Triggering receptor expressed on myeloid cells 2 (TREM2) has been proven to exert neuroprotective effects in neurodegenerative diseases and stroke by modulating neuroinflammation, and promoting phagocytosis and cell survival. However, the role of TREM2 in TBI has not yet been elucidated. In this study, we are the first to use COG1410, an agonist of TREM2, to assess the effects of TREM2 activation in a murine TBI model. Methods Adult male wild-type (WT) C57BL/6 mice and adult male TREM2 KO mice were subjected to different treatments. TBI was established by the controlled cortical impact (CCI) method. COG1410 was delivered 1 h after CCI via tail vein injection. Western blot analysis, immunofluorescence, laser speckle contrast imaging (LSCI), neurological behaviour tests, brain electrophysiological monitoring, Evans blue assays, magnetic resonance imaging (MRI), and brain water content measurement were performed in this study. Results The expression of endogenous TREM2 peaked at 3 d after CCI, and it was mainly expressed on microglia and neurons. We found that COG1410 improved neurological functions within 3 d, as well as neurological functions and brain electrophysiological activity at 2 weeks after CCI. COG1410 exerted neuroprotective effects by inhibiting neutrophil infiltration and microglial activation, and suppressing neuroinflammation after CCI. In addition, COG1410 treatment alleviated blood brain barrier (BBB) disruption and brain oedema; furthermore, COG1410 promoted cerebral blood flow (CBF) recovery at traumatic injury sites after CCI. In addition, COG1410 suppressed neural apoptosis at 3 d after CCI. TREM2 activation upregulated p-Akt, p-CREB, BDNF, and Bcl-2 and suppressed TNF-α, IL-1β, Bax, and cleaved caspase-3 at 3 d after CCI. Moreover, TREM2 knockout abolished the effects of COG1410 on vascular phenotypes and microglial states. Finally, the neuroprotective effects of COG1410 were suppressed by TREM2 depletion. Conclusions Altogether, we are the first to demonstrate that TREM2 activation by COG1410 alleviated neural damage through activation of Akt/CREB/BDNF signalling axis in microglia after CCI. Finally, COG1410 treatment improved neurological behaviour and brain electrophysiological activity after CCI. Graphical Abstract

MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate gene expression at the post-transcriptional level and that play an important role in many cellular processes, including modulation of inflammation. MiRNAs are present in high concentrations in the central nervous system (CNS) and are spatially and temporally expressed in a specific way. Therefore, an imbalance in the expression pattern of these small molecules can be involved in the development of neurological diseases. Generally, CNS responds to damage or disease through the activation of an inflammatory response, but many neurological disorders are characterized by uncontrolled neuroinflammation. Many studies support the involvement of miRNAs in the activation or inhibition of inflammatory signaling and in the promotion of uncontrolled neuroinflammation with pathological consequences. MiR-155 is a pro-inflammatory mediator of the CNS and plays an important regulatory role. The purpose of this review is to summarize how miR-155 is regulated and the pathological consequences of its deregulation during neuroinflammatory disorders, including multiple sclerosis, Alzheimer’s disease and other neuroinflammatory disorders. Modulation of miRNAs’ expression could be used as a therapeutic strategy in the treatment of pathological neuroinflammation.

Multiple sclerosis (MS) is an autoimmune disease that affects the CNS, the pathophysiology of which remains unclear and for which there is no definitive cure. Antimicrobial peptides (AMPs) are immunomodulatory molecules expressed in various tissues, including the CNS. Here, we investigated whether the cathelicidin-related AMP (CRAMP) modulated the development of experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. We showed that, at an early stage, CNS-recruited neutrophils produced neutrophil extracellular traps (NETs) rich in CRAMP that were required for EAE initiation. NET-associated CRAMP stimulated IL-6 production by dendritic cells via the cGAS/STING pathway, thereby promoting encephalitogenic Th17 response. However, at a later disease stage, neurons also expressed CRAMP that reduced EAE severity. Camp knockdown in neurons led to disease exacerbation, while local injection of CRAMP 1–39 at the peak of EAE promoted disease remission. In vitro, CRAMP 1–39 regulated the activation of microglia and astrocytes through the formyl peptide receptor (FPR) 2. Finally, administration of butyrate, a gut microbiota-derived metabolite, stimulated the expression of neural CRAMP via the free fatty acids receptors 2/3 (FFAR2/3), and prevented EAE. This study shows that CRAMP produced by different cell types has opposing effects on neuroinflammation, offering therapeutic opportunities for MS and other neuroinflammatory disorders.

The cell‐to‐cell transfer of α‐synuclein (α‐Syn) greatly contributes to Parkinson's disease (PD) pathogenesis and underlies the spread of α‐Syn pathology. During this process, extracellular α‐Syn can activate microglia and neuroinflammation, which plays an important role in PD. However, the effect of extracellular α‐Syn on microglia autophagy is poorly understood. In the present study, we reported that extracellular α‐Syn inhibited the autophagy initiation, as indicated by LC3‐II reduction and p62 protein elevation in BV2 and cultured primary microglia. The in vitro findings were verified in microglia‐enriched population isolated from α‐Syn‐overexpressing mice induced by adeno‐associated virus (AAV2/9)‐encoded wildtype human α‐Syn injection into the substantia nigra (SN). Mechanistically, α‐Syn led to microglial autophagic impairment through activating toll‐like receptor 4 (Tlr4) and its downstream p38 and Akt‐mTOR signaling because Tlr4 knockout and inhibition of p38, Akt as well as mTOR prevented α‐Syn‐induced autophagy inhibition. Moreover, inhibition of Akt reversed the mTOR activation but failed to affect p38 phosphorylation triggered by α‐Syn. Functionally, the in vivo evidence showed that lysozyme 2 Cre (Lyz2cre)‐mediated depletion of autophagy‐related gene 5 (Atg5) in microglia aggravated the neuroinflammation and dopaminergic neuron losses in the SN and exacerbated the locomotor deficit in α‐Syn‐overexpressing mice. Taken together, the results suggest that extracellular α‐Syn, via Tlr4‐dependent p38 and Akt‐mTOR signaling cascades, disrupts microglial autophagy activity which synergistically contributes to neuroinflammation and PD development. Autophagy‐dependent and independent machinery synergistically contribute to hα‐Syn‐caused neuroinflammation in PD. The basal autophagy activity restricts microglia inflammation. Extracellular hα‐Syn interacts with and activates Tlr4, resulting in inflammatory responses, as well as autophagy suppression in microglia via Tlr4‐dependent p38 and Akt/mTOR signaling cascades. This impairs the inhibitory effect of autophagy on inflammation, and thus aggravating hα‐Syn‐induced inflammatory responses.

The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is a central mediator of cytosolic DNA-induced innate immune responses, driving the production of type I IFNs and pro-inflammatory cytokines. Beyond its canonical role in cytosolic DNA sensing, increasing attention has been directed toward the noncanonical functions of cGAS and STING, particularly within the nucleus. Recent studies implicate dysregulated cGAS-STING signaling in neurodegenerative diseases and brain aging, with a prominent contribution to glial activation-associated neuroinflammation, a hallmark of many neurological disorders. In this Review, we first summarize the molecular mechanisms underlying the canonical cGAS-STING pathway in DNA sensing and innate immune activation. We then discuss emerging noncanonical roles of cGAS in chromatin organization and RNA metabolism, drawing on insights from evolutionary conservation and protein interactome analyses. Finally, we outline the involvement of cGAS-STING signaling in diverse aspects of brain function, including glial state regulation, neuronal homeostasis, blood-brain barrier integrity, and peripheral immune surveillance, highlighting their contributions to neuroinflammation and neuropathology. We also summarize current pharmacological inhibitors targeting cGAS and STING and discuss their therapeutic potential for modulating cGAS-STING signaling to manage brain disorders.

Parkinson’s Disease (PD) is a highly prevalent neurodegenerative disease among older adults. PD neuropathology is marked by the progressive loss of the dopaminergic neurons of the substantia nigra pars compacta and the widespread accumulation of misfolded intracellular α-synuclein (α-syn). Genetic mutations and post-translational modifications, such as α-syn phosphorylation, have been identified among the multiple factors supporting α-syn accrual during PD. A decline in the clearance capacity of the ubiquitin-proteasome and the autophagy-lysosomal systems, together with mitochondrial dysfunction, have been indicated as major pathophysiological mechanisms of PD neurodegeneration. The accrual of misfolded α-syn aggregates into soluble oligomers, and the generation of insoluble fibrils composing the core of intraneuronal Lewy bodies and Lewy neurites observed during PD neurodegeneration, are ignited by the overproduction of reactive oxygen species (ROS). The ROS activate the α-syn aggregation cascade and, together with the Lewy bodies, promote neurodegeneration. However, the molecular pathways underlying the dynamic evolution of PD remain undeciphered. These gaps in knowledge, together with the clinical heterogeneity of PD, have hampered the identification of the biomarkers that may be used to assist in diagnosis, treatment monitoring, and prognostication. Herein, we illustrate the main pathways involved in PD pathogenesis and discuss their possible exploitation for biomarker discovery.

Neuroinflammation plays a key role in Alzheimer’s disease (AD) and many other neurodegenerative disorders. Chronic activation of astrocytes and microglia fuels neuronal damage via cytokine secretion, oxidative stress, and proteolysis, yet glial inflammatory regulation remains poorly understood. Using chemoproteomics, we identified CK2, particularly the brain-enriched catalytic subunit CK2α2, as a key driver of astrocytic inflammation. CK2 enhances NF-κB activity by phosphorylating NF-κB S529 and IκBα S32, promoting pro-inflammatory gene expression. Genetic or chemical CK2 inhibition dampens inflammation, including IL-6 and IL-8 expression in a TNFα acute neuroinflammation mouse model. CK2α2 is upregulated in AD postmortem tissues and patient-derived astrocytes. AD astrocytes exhibit a hyperinflammatory state that can be attenuated by CK2 inhibition. Overexpression of CK2α2 in cortical organoids mimics AD pathology, whereas CK2 inhibition using the potent, selective, and brain-penetrant probe TAL606 rescues inflammatory markers in AD APP/PS1 mice. These findings position CK2 as a central regulator of neuroinflammation and a promising therapeutic target for AD and related disorders. Chemoproteomics coupled with patient-derived and organoid models identify and validate brain-enriched CK2α2 as an inflammatory driver in Alzheimer's disease. Blocking CK2 (including with brain-penetrant TAL606) lowers inflammatory signals in AD mice.

As hippocampal neurons respond to diverse types of information 1 , a subset assembles into microcircuits representing a memory 2 . Those neurons typically undergo energy-intensive molecular adaptations, occasionally resulting in transient DNA damage 3 – 5 . Here we found discrete clusters of excitatory hippocampal CA1 neurons with persistent double-stranded DNA (dsDNA) breaks, nuclear envelope ruptures and perinuclear release of histone and dsDNA fragments hours after learning. Following these early events, some neurons acquired an inflammatory phenotype involving activation of TLR9 signalling and accumulation of centrosomal DNA damage repair complexes 6 . Neuron-specific knockdown of Tlr9 impaired memory while blunting contextual fear conditioning-induced changes of gene expression in specific clusters of excitatory CA1 neurons. Notably, TLR9 had an essential role in centrosome function, including DNA damage repair, ciliogenesis and build-up of perineuronal nets. We demonstrate a novel cascade of learning-induced molecular events in discrete neuronal clusters undergoing dsDNA damage and TLR9-mediated repair, resulting in their recruitment to memory circuits. With compromised TLR9 function, this fundamental memory mechanism becomes a gateway to genomic instability and cognitive impairments implicated in accelerated senescence, psychiatric disorders and neurodegenerative disorders. Maintaining the integrity of TLR9 inflammatory signalling thus emerges as a promising preventive strategy for neurocognitive deficits. Learning results in persistent double-stranded DNA breaks, nuclear rupture and release of DNA fragments and histones within hippocampal CA1 neurons that, following TLR9-mediated DNA damage repair, results in their recruitment to memory circuits.

Acute neuroinflammation rapidly activates brain immune responses, but its lasting effects on microglia are unclear. Using systemic LPS administration and LCMV-Armstrong infection, we found that blood–brain barrier disruption and cytokine shifts resolved within 30 days, yet microglial recovery was incomplete—marked by persistent numerical loss and an IFN-γ–low phenotype in the LPS model and reduced relative abundance in the LCMV model. Single-cell RNA sequencing revealed sustained transcriptional alterations, including disease-associated microglia (DAM) features and a distinct recovery-biased population. These acute signatures overlapped with profiles from Alzheimer’s model mice and were enriched in human microglia from multiple sclerosis, Alzheimer’s disease, and other neuroinflammatory conditions. Although our observation period was shorter than the chronic course of these diseases, the persistence of disease-like microglial states suggests that transient inflammation can prime the brain for long-term vulnerability. Targeting this primed state may offer new strategies to prevent or mitigate neurodegenerative pathology.