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The development of immune checkpoint inhibitors (ICIs) has revolutionized cancer immunotherapy, but these agents carry a high risk of immune-related adverse events. Here, the authors introduce the mechanisms of action of ICIs and review their adverse effects on the CNS, which result in conditions such as paraneoplastic neurological syndromes and multiple sclerosis. Cancer treatment strategies based on immune stimulation have recently entered the clinical arena, with unprecedented success. Immune checkpoint inhibitors (ICIs) work by indiscriminately promoting immune responses, which target tumour-associated antigens or tumour-specific mutations. However, the augmented immune response, most notably the T cell response, can cause either direct neurotoxicity or, more commonly, indirect neurotoxic effects through systemic or local inflammatory mechanisms or autoimmune mechanisms. Consequently, patients treated with ICIs are susceptible to CNS disease, including paraneoplastic neurological syndromes, encephalitis, multiple sclerosis and hypophysitis. In this Opinion article, we introduce the mechanisms of action of ICIs and review their adverse effects on the CNS. We highlight the importance of early detection of these neurotoxic effects, which should be distinguished from brain metastasis, and the need for early detection of neurotoxicity. It is crucial that physicians are well informed of these neurological adverse effects, given the anticipated increase in the use of immunotherapies to treat cancer.

Paraneoplastic cerebellar degeneration (PCD) is a rare immune-mediated disease that develops mostly in the setting of neoplasia and offers a unique prospect to explore the interplay between tumor immunity and autoimmunity. In PCD, the deleterious adaptive immune response targets self-antigens aberrantly expressed by tumor cells, mostly gynecological cancers, and physiologically expressed by the Purkinje neurons of the cerebellum. Highly specific anti-neuronal antibodies in the serum and cerebrospinal fluid represent key diagnostic biomarkers of PCD. Some anti-neuronal antibodies such as anti-Yo autoantibodies (recognizing the CDR2/CDR2L proteins) are only associated with PCD. Other anti-neuronal antibodies, such as anti-Hu, anti-Ri, and anti-Ma2, are detected in patients with PCD or other types of paraneoplastic neurological manifestations. Importantly, these autoantibodies cannot transfer disease and evidence for a pathogenic role of autoreactive T cells is accumulating. However, the precise mechanisms responsible for disruption of self-tolerance to neuronal self-antigens in the cancer setting and the pathways involved in pathogenesis within the cerebellum remain to be fully deciphered. Although the occurrence of PCD is rare, the risk for such severe complication may increase with wider use of cancer immunotherapy, notably immune checkpoint blockade. Here, we review recent literature pertaining to the pathophysiology of PCD and propose an immune scheme underlying this disabling disease. Additionally, based on observations from patients' samples and on the pre-clinical model we recently developed, we discuss potential therapeutic strategies that could blunt this cerebellum-specific autoimmune disease.

Background Systemic bacterial infections often result in enduring cognitive impairment and are a risk factor for dementia. There are currently no effective treatments for infection-induced cognitive impairment. Previous studies have shown that intermittent fasting (IF) can increase the resistance of neurons to injury and disease by stimulating adaptive cellular stress responses. However, the impact of IF on the cognitive sequelae of systemic and brain inflammation is unknown. Methods Rats on IF for 30 days received 1 mg/kg of lipopolysaccharide (LPS) or saline intravenously. Half of the rats were subjected to behavioral tests and the other half were euthanized two hours after LPS administration and the hippocampus was dissected and frozen for analyses. Results Here, we report that IF ameliorates cognitive deficits in a rat model of sepsis by a mechanism involving NF-κB activation, suppression of the expression of pro-inflammatory cytokines, and enhancement of neurotrophic support. Treatment of rats with LPS resulted in deficits in cognitive performance in the Barnes maze and inhibitory avoidance tests, without changing locomotor activity, that were ameliorated in rats that had been maintained on the IF diet. IF also resulted in reduced levels of mRNAs encoding the LPS receptor TLR4 and inducible nitric oxide synthase (iNOS) in the hippocampus. Moreover, IF prevented LPS-induced elevation of IL-1α, IL-1β and TNF-α levels, and prevented the LPS-induced reduction of BDNF levels in the hippocampus. IF also significantly attenuated LPS-induced elevations of serum IL-1β, IFN-γ, RANTES, TNF-α and IL-6 levels. Conclusions Taken together, our results suggest that IF induces adaptive responses in the brain and periphery that can suppress inflammation and preserve cognitive function in an animal model of systemic bacterial infection.

The most common genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) is an intronic G 4 C 2 repeat expansion in C9orf72 . The repeats undergo bidirectional transcription to produce sense and antisense repeat RNA species, which are translated into dipeptide repeat proteins (DPRs). As toxicity has been associated with both sense and antisense repeat-derived RNA and DPRs, targeting both strands may provide the most effective therapeutic strategy. CRISPR-Cas13 systems mature their own guide arrays, allowing targeting of multiple RNA species from a single construct. We show CRISPR-Cas13d variant CasRx effectively reduces overexpressed C9orf72 sense and antisense repeat transcripts and DPRs in HEK cells. In C9orf72 patient-derived iPSC-neuron lines, CRISPR-CasRx reduces endogenous sense and antisense repeat RNAs and DPRs and protects against glutamate-induced excitotoxicity. AAV delivery of CRISPR-CasRx to two distinct C9orf72 repeat mouse models significantly reduced both sense and antisense repeat-containing transcripts. This highlights the potential of RNA-targeting CRISPR systems as therapeutics for C9orf72 ALS/FTD. CRISPR-CasRx effectively reduces ALS- and FTD-causing C9orf72 sense and antisense repeat derived RNAs and proteins in cell lines, patient iPSC-neurons and two independent mouse models of C9orf72 repeat expansion.

Cognitive decline is a common pathological outcome during aging, with an ill‐defined molecular and cellular basis. In recent years, the concept of inflammaging, defined as a low‐grade inflammation increasing with age, has emerged. Infiltrating T cells accumulate in the brain with age and may contribute to the amplification of inflammatory cascades and disruptions to the neurogenic niche observed with age. Recently, a small resident population of regulatory T cells has been identified in the brain, and the capacity of IL2‐mediated expansion of this population to counter neuroinflammatory disease has been demonstrated. Here, we test a brain‐specific IL2 delivery system for the prevention of neurological decline in aging mice. We identify the molecular hallmarks of aging in the brain glial compartments and identify partial restoration of this signature through IL2 treatment. At a behavioral level, brain IL2 delivery prevented the age‐induced defect in spatial learning, without improving the general decline in motor skill or arousal. These results identify immune modulation as a potential path to preserving cognitive function for healthy aging. Synopsis Delivery of interleukin 2 into the brain via a blood–brain barrier crossing AAV vector prevents cognitive decline in the aging mice. A gene delivery system uses an AAV‐based viral vector coupled with an astrocyte‐specific promoter to drive the expression of the anti‐inflammatory cytokine interleukin 2 in the brain of aged mice. At a molecular level, brain‐specific expression of IL2 in aged mice partially reverted the transcriptional signature of aged glial cells to the baseline state of young glial cells. At a cognitive level, brain‐specific expression of IL2 in aged mice partially restored the spatial learning decline, without improving the general decline in motor skill or arousal. Graphical Abstract Delivery of interleukin 2 into the brain via a blood–brain barrier crossing AAV vector prevents cognitive decline in the aging mice.

Single domain antibodies (VHHs) are potentially disruptive therapeutics, with important biological value for treatment of several diseases, including neurological disorders. However, VHHs have not been widely used in the central nervous system (CNS), largely because of their restricted blood–brain barrier (BBB) penetration. Here, we propose a gene transfer strategy based on BBB‐crossing adeno‐associated virus (AAV)‐based vectors to deliver VHH directly into the CNS. As a proof‐of‐concept, we explored the potential of AAV‐delivered VHH to inhibit BACE1, a well‐characterized target in Alzheimer’s disease. First, we generated a panel of VHHs targeting BACE1, one of which, VHH‐B9, shows high selectivity for BACE1 and efficacy in lowering BACE1 activity in vitro . We further demonstrate that a single systemic dose of AAV‐VHH‐B9 produces positive long‐term (12 months plus) effects on amyloid load, neuroinflammation, synaptic function, and cognitive performance, in the App NL‐G‐F Alzheimer’s mouse model. These results constitute a novel therapeutic approach for neurodegenerative diseases, which is applicable to a range of CNS disease targets. Synopsis VHH and blood‐brain‐barrier (BBB)‐crossing AAV‐based vectors are combined to achieve highly‐specific, long‐term BACE1 inhibition in a mouse model of Alzheimer's disease (AD). A gene transfer strategy based on BBB‐crossing AAV vectors is developed to deliver VHH single domain antibodies directly into the CNS. VHH‐B9 is generated to target BACE1, an enzyme critical to Aβ generation in AD, and incorporated into an AAV‐PHP.B‐based vector. A single dose of AAV‐VHH resulted in long‐term VHH expression in the App NL‐G‐F mouse model, with concomitant improvements in cognitive status, amyloidosis, neuroinflammation, and synaptic function. Graphical Abstract VHH and blood‐brain‐barrier (BBB)‐crossing AAV‐based vectors are combined to achieve highly‐specific, long‐term BACE1 inhibition in a mouse model of Alzheimer's disease (AD).

Ouabain (OUA) is a cardiac glycoside that binds to Na + ,K + -ATPase (NKA), a conserved membrane protein that controls cell transmembrane ionic concentrations and requires ATP hydrolysis. At nM concentrations, OUA activates signaling pathways that are not related to its typical inhibitory effect on the NKA pump. Activation of these signaling pathways protects against some types of injury of the kidneys and central nervous system. There are 4 isoforms of the alpha subunit of NKA, which are differentially distributed across tissues and may have different physiological roles. Glial cells are important regulators of injury and inflammation in the brain and express the α1 and α2 NKA isoforms. This study investigated the role of α2 NKA in OUA modulation of the neuroinflammatory response induced by lipopolysaccharide (LPS) in mouse primary glial cell cultures. LPS treatment increased lactate dehydrogenase release, while OUA did not decrease cell viability and blocked LPS-induced NF-κB activation. Silencing α2 NKA prevented ERK and NF-κB activation by LPS. α2 NKA also regulates TNF-α and IL-1β levels. The data reported here indicate a significant role of α2 NKA in regulating central LPS effects, with implications in the associated neuroinflammatory processes.

Aging is commonly associated with the loss of cognitive capacity driven by the degeneration of the brain. New research strengthens the links between CD8 + T cells and interferon-γ production in the brain, and neurodegeneration.

Baroreflex dysfunction, oxidative stress and inflammation, important hallmarks of hypertension, are attenuated by exercise training. In this study, we investigated the relationships and time-course changes of cardiovascular parameters, pro-inflammatory cytokines and pro-oxidant profiles within the hypothalamic paraventricular nucleus of the spontaneously hypertensive rats (SHR). Basal values and variability of arterial pressure and heart rate and baroreflex sensitivity were measured in trained (T, low-intensity treadmill training) and sedentary (S) SHR at weeks 0, 1, 2, 4 and 8. Paraventricular nucleus was used to determine reactive oxygen species (dihydroethidium oxidation products, HPLC), NADPH oxidase subunits and pro-inflammatory cytokines expression (Real time PCR), p38 MAPK and ERK1/2 expression (Western blotting), NF-κB content (electrophoretic mobility shift assay) and cytokines immunofluorescence. SHR-S vs. WKY-S (Wistar Kyoto rats as time control) showed increased mean arterial pressure (172±3 mmHg), pressure variability and heart rate (358±7 b/min), decreased baroreflex sensitivity and heart rate variability, increased p47phox and reactive oxygen species production, elevated NF-κB activity and increased TNF-α and IL-6 expression within the paraventricular nucleus of hypothalamus. Two weeks of training reversed all hypothalamic changes, reduced ERK1/2 phosphorylation and normalized baroreflex sensitivity (4.04±0.31 vs. 2.31±0.19 b/min/mmHg in SHR-S). These responses were followed by increased vagal component of heart rate variability (1.9-fold) and resting bradycardia (-13%) at the 4th week, and, by reduced vasomotor component of pressure variability (-28%) and decreased mean arterial pressure (-7%) only at the 8th week of training. Our findings indicate that independent of the high pressure levels in SHR, training promptly restores baroreflex function by disrupting the positive feedback between high oxidative stress and increased pro-inflammatory cytokines secretion within the hypothalamic paraventricular nucleus. These early adaptive responses precede the occurrence of training-induced resting bradycardia and blood pressure fall.

Recently, OTULIN haploinsufficiency was linked to enhanced susceptibility to Staphylococcus aureus infections accompanied by local necrosis and systemic inflammation. The pathogenesis observed in haploinsufficient patients differs from the hyperinflammation seen in classical OTULIN-related autoinflammatory syndrome (ORAS) patients and is characterized by increased susceptibility of dermal fibroblasts to S. aureus alpha toxin-inflicted cytotoxic damage. Immunological abnormalities were not observed in OTULIN haploinsufficient patients, suggesting a non-hematopoietic basis. In this research report, we investigated an Otulin +/− mouse model after in vivo provocation with lipopolysaccharide (LPS) to explore the potential role of hematopoietic-driven inflammation in OTULIN haploinsufficiency. We observed a hyperinflammatory signature in LPS-provoked Otulin +/− mice, which was driven by CD64 + monocytes and macrophages. Bone marrow-derived macrophages (BMDMs) of Otulin +/− mice demonstrated higher proinflammatory cytokine secretion after in vitro stimulation with LPS or polyinosinic:polycytidylic acid (Poly(I:C)). Our experiments in full and mixed bone marrow chimeric mice suggest that, in contrast to humans, the observed inflammation was mainly driven by the hematopoietic compartment with cell-extrinsic effects likely contributing to inflammatory outcomes. Using an OTULIN haploinsufficient mouse model, we validated the role of OTULIN in the regulation of environmentally directed inflammation.