B cell depletion with anti-CD20 promotes neuroprotection in a BAFF-dependent manner in mice and humans.

Anti-CD20 therapy to deplete B cells is highly efficacious in preventing new white matter lesions in patients with relapsing-remitting multiple sclerosis (RRMS), but its protective capacity against gray matter injury and axonal damage is unclear. In a passive experimental autoimmune encephalomyelitis (EAE) model whereby TH17 cells promote brain leptomeningeal immune cell aggregates, we found that anti-CD20 treatment effectively spared myelin content and prevented myeloid cell activation, oxidative damage, and mitochondrial stress in the subpial gray matter. Anti-CD20 treatment increased B cell survival factor (BAFF) in the serum, cerebrospinal fluid, and leptomeninges of mice with EAE. Although anti-CD20 prevented gray matter demyelination, axonal loss, and neuronal atrophy, co-treatment with anti-BAFF abrogated these benefits. Consistent with the murine studies, we observed that elevated BAFF concentrations after anti-CD20 treatment in patients with RRMS were associated with better clinical outcomes. Moreover, BAFF promoted survival of human neurons in vitro. Together, our data demonstrate that BAFF exerts beneficial functions in MS and EAE in the context of anti-CD20 treatment.

IL-4 shapes microglia-dependent pruning of the cerebellum during postnatal development.

Interleukin-4 (IL-4) is a type 2 cytokine with pleiotropic functions in adaptive immunity, allergies, and cognitive processes. Here, we show that low levels of IL-4 in the early postnatal stage delineate a critical period in which microglia extensively prune cerebellar neurons. Elevating the levels of this cytokine via peripheral injection, or using a mouse model of allergic asthma, leads to defective pruning, permanent increase in cerebellar granule cells, and circuit alterations. These animals also show a hyperkinetic and impulsive-like phenotype, reminiscent of attention-deficit hyperactivity disorder (ADHD). These alterations are blocked in Il4rαfl/fl::Cx3cr1-CreER mice, which are deficient in IL-4 receptor signaling in microglia. These findings demonstrate a previously unknown role for IL-4 during a neuroimmune critical period of cerebellar maturation and provide a first putative mechanism for the comorbidity between allergic disease and ADHD observed in humans.

Interleukin-4 receptor signaling modulates neuronal network activity.

Evidence is emerging that immune responses not only play a part in the central nervous system (CNS) in diseases but may also be relevant for healthy conditions. We discovered a major role for the interleukin-4 (IL-4)/IL-4 receptor alpha (IL-4Rα) signaling pathway in synaptic processes, as indicated by transcriptome analysis in IL-4Rα-deficient mice and human neurons with/without IL-4 treatment. Moreover, IL-4Rα is expressed presynaptically, and locally available IL-4 regulates synaptic transmission. We found reduced synaptic vesicle pools, altered postsynaptic currents, and a higher excitatory drive in cortical networks of IL-4Rα-deficient neurons. Acute effects of IL-4 treatment on postsynaptic currents in wild-type neurons were mediated via PKCγ signaling release and led to increased inhibitory activity supporting the findings in IL-4Rα-deficient neurons. In fact, the deficiency of IL-4Rα resulted in increased network activity in vivo, accompanied by altered exploration and anxiety-related learning behavior; general learning and memory was unchanged. In conclusion, neuronal IL-4Rα and its presynaptic prevalence appear relevant for maintaining homeostasis of CNS synaptic function.

Astrocytic potassium and calcium channels as integrators of the inflammatory and ischemic CNS microenvironment.

Astrocytes are key regulators of their surroundings by receiving and integrating stimuli from their local microenvironment, thereby regulating glial and neuronal homeostasis. Cumulating evidence supports a plethora of heterogenic astrocyte subpopulations that differ morphologically and in their expression patterns of receptors, transporters and ion channels, as well as in their functional specialisation. Astrocytic heterogeneity is especially relevant under pathological conditions. In experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis (MS), morphologically distinct astrocytic subtypes were identified and could be linked to transcriptome changes during different disease stages and regions. To allow for continuous awareness of changing stimuli across age and diseases, astrocytes are equipped with a variety of receptors and ion channels allowing the precise perception of environmental cues. Recent studies implicate the diverse repertoire of astrocytic ion channels - including transient receptor potential channels, voltage-gated calcium channels, inwardly rectifying K+ channels, and two-pore domain potassium channels - in sensing the brain state in physiology, inflammation and ischemia. Here, we review current evidence regarding astrocytic potassium and calcium channels and their functional contribution in homeostasis, neuroinflammation and stroke.

Growth-Promoting Treatment Screening for Corticospinal Neurons in Mouse and Man.

Neurons of the central nervous system (CNS) that project long axons into the spinal cord have a poor axon regenerative capacity compared to neurons of the peripheral nervous system. The corticospinal tract (CST) is particularly notorious for its poor regeneration. Because of this, traumatic spinal cord injury (SCI) is a devastating condition that remains as yet uncured. Based on our recent observations that direct neuronal interleukin-4 (IL-4) signaling leads to repair of axonal swellings and beneficial effects in neuroinflammation, we hypothesized that IL-4 acts directly on the CST. Here, we developed a tissue culture model for CST regeneration and found that IL-4 promoted new growth cone formation after axon transection. Most importantly, IL-4 directly increased the regenerative capacity of both murine and human CST axons, which corroborates its regenerative effects in CNS damage. Overall, these findings serve as proof-of-concept that our CST regeneration model is suitable for fast screening of new treatments for SCI.