Fast direct neuronal signaling via the IL-4 receptor as therapeutic target in neuroinflammation

Multiple sclerosis (MS) is a neuroinflammatory disorder, and current therapies focus on altering immune activity to reduce symptoms. Vogelaar and colleagues tested the ability of intrathecally applied IL-4, a cytokine typically associated with T helper type 2 responses, to treat established disease in several experimental autoimmune encephalomyelitis (EAE) models. IL-4 treatment led to reduced clinical scores, improved locomotor activity, and diminished axon damage. Somewhat surprisingly, the beneficial effects of IL-4 did not depend on T cell modulation in the chronic disease phase. The receptor for IL-4 was observed in postmortem brain histology of several MS patients, and they demonstrated that IL-4 could act directly on neurons in vitro. They also showed benefits of intranasal IL-4 administration in one of the EAE models, which could be a promising avenue to pursue in the clinic. Ongoing axonal degeneration is thought to underlie disability in chronic neuroinflammation, such as multiple sclerosis (MS), especially during its progressive phase. Upon inflammatory attack, axons undergo pathological swelling, which can be reversible. Because we had evidence for beneficial effects of T helper 2 lymphocytes in experimental neurotrauma and discovered interleukin-4 receptor (IL-4R) expressed on axons in MS lesions, we aimed at unraveling the effects of IL-4 on neuroinflammatory axon injury. We demonstrate that intrathecal IL-4 treatment during the chronic phase of several experimental autoimmune encephalomyelitis models reversed disease progression without affecting inflammation. Amelioration of disability was abrogated upon neuronal deletion of IL-4R. We discovered direct neuronal signaling via the IRS1-PI3K-PKC pathway underlying cytoskeletal remodeling and axonal repair. Nasal IL-4 application, suitable for clinical translation, was equally effective in improving clinical outcome. Targeting neuronal IL-4 signaling may offer new therapeutic strategies to halt disability progression in MS and possibly also neurodegenerative conditions

Maladaptive cortical hyperactivity upon recovery from experimental autoimmune encephalomyelitis

Multiple sclerosis (MS) patients exhibit neuropsychological symptoms in early disease despite the immune attack occurring predominantly in white matter and spinal cord. It is unclear why neurodegeneration may start early in the disease and is prominent in later stages. We assessed cortical microcircuit activity by employing spiking-specific two-photon Ca2+ imaging in proteolipid protein-immunized relapsing-remitting SJL/J mice in vivo. We identified the emergence of hyperactive cortical neurons in remission only, independent of direct immune-mediated damage and paralleled by elevated anxiety. High levels of neuronal activity were accompanied by increased caspase-3 expression. Cortical TNFα expression was mainly increased by excitatory neurons in remission; blockade with intraventricular infliximab restored AMPA spontaneous excitatory postsynaptic current frequencies, completely recovered normal neuronal network activity patterns and alleviated elevated anxiety. This suggests a dysregulation of cortical networks attempting to achieve functional compensation by synaptic plasticity mechanisms, indicating a link between immune attack and early start of neurodegeneration