Immune cells in cerebral small vessel disease: Emerging roles and potential targeting therapies

Cerebral small vessel disease is an age-related condition that severely affects the quality of life of older adults; however, there are currently no definitive treatments or preventive measures. Cells from both the peripheral and central immune systems significantly impact the development of cerebral small vessel disease. By analyzing the effects of different immune cells on brain dysfunction associated with this disease, we aim to explore the various mechanisms through which autoimmune and acquired immune cells in peripheral circulation and the central nervous system contribute to disease development. Additionally, we seek to identify potential therapeutic modalities targeting these immune cells. In innate immunity, treatment targeting different monocyte loci includes four main modalities: cytokines (CSF1R, MIF, P2X7, CX3CR1, and CCL2), signaling pathways (DAP12/TREM, PI3K/AKT, and Wnt/β-catenin), tissue engineering (mitochondrial transplantation and exosomes), and traditional Chinese medicines. Treatment targeting different dendritic cell loci encompasses two modalities: signaling pathway (cGAS/STING/NF-κB) and tissue engineering (tolerogenic dendritic cells and engineered probiotics). For natural killer cells, treatment targeting different loci includes two modalities: tissue engineering (natural killer cell-based immunotherapies) and traditional Chinese medicines ( Tongxinluo capsule). In adaptive immunity, treatment targeting different T cell loci includes four modalities: cytokines (S1PR and RXR), signaling pathway (Nrf2/GPX4 and Notch-ITGB1), tissue engineering (elimination of senescent T cells, monoclonal antibodies targeting amyloid-beta protofibrils, nanovaccines, and nanomedicines), and traditional Chinese medicines (traditional herbal remedies and microneedle therapy). Treatment targeting different B cell loci includes three modalities: monoclonal antibodies (targeting CD49d and CD20), purine glycoside analogs (Cladribine), and plasma exchange. This review explores the relationship between nerve regeneration, immune cells, and cerebral small vessel disease. The disease is characterized by the crucial role played by signaling and interactions between immune cells and components of the neurovascular unit, which is a functional complex composed of neurons, glial cells, and microvessels that regulate inflammatory responses and tissue repair. The central nervous system lacks intrinsic regenerative capacity, and currently, there is no effective method to fully restore its function. The primary focus of current research is on utilizing tissue engineering and regenerative medicine to create environments that facilitate cell proliferation and tissue regeneration. Hydrogels, induced pluripotent stem cells, exosomes, regulatory T cell transplants, and gene modification are key areas of focus in neural regeneration research. In the future, immune rejuvenation and other emerging therapies may offer potential treatment strategies for cerebral small vessel disease. This review analyzes the functions of various immune cells in cerebral small vessel disease, explores the relationship between nerve regeneration and these immune cells, and discusses potential therapeutic avenues that target immune cells for future treatments and neural regeneration related to cerebral small vessel disease.