Evolution, Expression and Functional Analysis of CXCR3 in Neuronal and Cardiovascular Diseases: A Narrative Review

Abstract

Chemokines form a sophisticated communication network wherein they maneuver the spatiotemporal migration of immune cells across a system. These chemical messengers are recognized by chemokine receptors, which can trigger a cascade of reactions upon binding to its respective ligand. CXC chemokine receptor 3 (CXCR3) is a transmembrane G protein-coupled receptor, which can selectively bind to CXCL9, CXCL10, and CXCL11. CXCR3 is predominantly expressed on immune cells, including activated T lymphocytes and natural killer cells. It thus plays a crucial role in immunological processes like homing of effector cells to infection sites and for pathogen clearance. Additionally, it is expressed on several cell types of the central nervous system and cardiovascular system, due to which it has been implicated in several central nervous system disorders, including Alzheimer’s disease, multiple sclerosis, dengue viral disease, and glioblastoma, as well as cardiovascular diseases like atherosclerosis, Chronic Chagas cardiomyopathy, and hypertension. This review provides a narrative description of the evolution, structure, function, and expression of CXCR3 and its corresponding ligands in mammals and zebrafish and the association of CXCR3 receptors with cardiovascular and neuronal disorders. Unraveling the mechanisms underlying the connection of CXCR3 and disease could help researchers investigate the potential of CXCR3 as a biomarker for early diagnosis and as a therapeutic target for pharmacological intervention, along with developing robust zebrafish disease models.

Level of CSF CXCL10 is highly elevated and decreased after steroid therapy in patients with autoimmune glial fibrillary acidic protein astrocytopathy

“…We estimated the predominant cascade of GFAP‐A and CNS‐irAE by examining the chemokine profile of CSF. In this study, the chemokine profile demonstrated the following: CNS‐irAE as Th1‐predominant diseases as reported previously 9–13,26 . GFAP‐A was the first to demonstrate a predominance of Th1 + Tfh/B cells, suggesting that cellular immunity is important in its pathogenesis.…”

“…Recent findings show that some neurological diseases are related to CXCR3 ligand interactions, which are pivotal in their pathogenesis. 9,12 Further evidence that CXCR3+ cells predominantly infiltrate the spinal fluid or CNS lesions in GFAP-A patients, with a trend toward elevated levels of Th1-dominant chemokines, may indicate that GFAP-A is a Th1-type cell-mediated inflammatory disease.…”

“…Chemokines can also identify the type of cells they recruit; thus, it is possible to classify chemokines as Th1‐dominant if, for example, CXCL9 and 10 are high, CCL20 as Th17‐dominant, and CCL17 and 22 as Th2‐dominant. Chemokines have been studied in neuroimmunological diseases, especially in MS, NMOSD, and HAM, and findings indicate that MS is Th1 and 17 predominant, 5–8 and HAM is Th1 predominant 9–13 …”

“…Chemokines have been studied in neuroimmunological diseases, especially in MS, NMOSD, and HAM, and findings indicate that MS is Th1 and 17 predominant, [5][6][7][8] and HAM is Th1 predominant. [9][10][11][12][13] Recently, new concepts of immune-related neurological diseases have emerged, such as autoimmune glial fibrillary acidic protein astrocytopathy (GFAP-A) [14][15][16] and central nervous system immune-related adverse events (CNS-irAE). [17][18][19] The main cytokine and chemokine cascade of these diseases remains unknown.…”

CXCL9, 10, 11/CXCR3 Axis Contributes to the Progress of Primary Sjogren’s Syndrome by Activating GRK2 to Promote T Lymphocyte Migration

“…CXCR3 is a 7-transmembrane domain G protein-coupled receptor, which is mainly expressed on immune cells, including T lymphocytes and natural killer cells [14,15]. CXCR3 plays an important role in T cell recruitment in various immune responses and autoimmune diseases [16,17].…”