Neuregulin-1 as a Context-Dependent Regulator of Neuroinflammation and Neural Repair: Mechanisms, Disease Relevance, and Therapeutic Challenges

Abstract

Highlights What are the main findings? NRG1 emerges as a context-dependent regulator of neuroinflammation that coordinates microglial, astrocytic, oligodendroglial, neuronal, and neurovascular responses through ErbB receptor signaling rather than functioning as a uniformly anti-inflammatory molecule. Across multiple preclinical models, NRG1 consistently demonstrates neuroprotective and immunomodulatory properties, although the strength of evidence and underlying mechanisms vary substantially by disease model. What are the implications of the main findings? Future NRG1 therapeutics should emphasize receptor-selective, isoform-specific, and anatomically targeted approaches to maximize neuroprotection. A deeper understanding of NRG1 isoform biology, receptor heterodimer composition, and cell-type-specific signaling networks will enable precision neuroimmune therapies capable of simultaneously limiting inflammation while promoting neural repair. Abstract Neuroinflammation is a coordinated response to central nervous system injury and disease involving resident glia, neurons, the neurovascular unit, and infiltrating immune cells. Although transient inflammatory signaling supports host defense, debris clearance, and repair, persistent activation contributes to synaptic dysfunction, demyelination, blood–brain barrier disruption, and neuronal loss. Neuregulin-1 (NRG1), a pleiotropic epidermal growth factor family ligand, has emerged as a potential regulator of this balance. Through ErbB receptor complexes, particularly ErbB4-containing dimers, NRG1 influences neural development, myelination, synaptic function, cell survival, and inflammatory signaling. Experimental evidence indicates that NRG1 can restrain NF-κB-dependent transcription, alter microglial activation states, enhance alpha7 nicotinic acetylcholine receptor-associated anti-inflammatory signaling, support oligodendroglial lineage cells, and stabilize neurovascular integrity. However, these actions are context-dependent; in spinal nociceptive circuits, ErbB2-linked signaling can promote microglial activation and pain hypersensitivity. This review examines NRG1 isoform biology, ErbB receptor architecture, cellular targets, and disease-specific evidence across demyelinating disease, stroke, traumatic brain injury, neurodegeneration, cerebral malaria, sickle cell disease, and neuropathic pain. Translation will require isoform-specific, receptor-biased, and anatomically targeted approaches supported by rigorous in vivo validation and verified biomarkers.