Role of the CXCL13/CXCR5 Axis in Autoimmune Diseases

Abstract

CXCL13 is a B-cell chemokine produced mainly by mesenchymal lymphoid tissue organizer cells, follicular dendritic cells, and human T follicular helper cells. By binding to its receptor, CXCR5, CXCL13 plays an important role in lymphoid neogenesis, lymphoid organization, and immune responses. Recent studies have found that CXCL13 and its receptor CXCR5 are implicated in the pathogenesis of several autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, primary Sjögren's syndrome, myasthenia gravis, and inflammatory bowel disease. In this review, we discuss the biological features of CXCL13 and CXCR5 and the recent findings on the pathogenic roles of the CXCL13/CXCR5 axis in autoimmune diseases. Furthermore, we discuss the potential role of CXCL13 as a disease biomarker and therapeutic target in autoimmune diseases.

Keywords: CXCL13; CXCR5; autoimmunity; chemokine; therapeutic target.

Figure 1

The CXCL13/CXCR5 axis in human diseases. The CXCL13/CXCR5 axis participates in the pathogenesis and progression of many human diseases, such as cancers, autoimmune diseases, infectious diseases, idiopathic pulmonary fibrosis, transplantation rejection, and neuropathic pain. COPD, chronic obstructive pulmonary disease; GVHD, graft versus host disease; SARS-CoV-2, severe acute respiratory syndrome coronavirus-2.

Figure 2

The complicated role of CXCL13-mediated immune responses in autoimmune diseases. CXCL13 can be produced by mLTo cells, FDC, Tfh cells, macrophages, DCs, epithelial cells, and Tph cells. In the fetal stage, CXCL13 promotes migration of LTi cells toward the parenchyma of the LNs anlagen, where LTi cells interact with mLTo cells to induce lymphoid neogenesis. CXCL13 is involved in the lymphoid organization by attracting B cells toward B-cell follicles. During an immune response, CXCL13 attracts B cells toward the light zones of GCs, where B cells undergo affinity selection and become long-lived plasma cells or memory B cells. Furthermore, CXCL13-mediated Tfh cells migration is essential in facilitating GCs response. In addition, CXCL13/CXCR5 axis is also implicated in B1 cell response through attracting B1 cell toward the body cavity. In autoimmune diseases, ectopic CXCL13 expression promotes ectopic lymphoid neogenesis and the production of disease-specific autoantibodies. In RA, CXCL13 drives EPC homing and VEGF expression, thus inducing angiogenesis in synovial tissue. In LN, CXCL13 promotes proliferation and TGF-β1 production of mesangial cells and induces podocyte secretion of proinflammatory cytokines/chemokines such as CXCL1, CXCL12, MIF, LIF, and soluble ICAM-1 and VCAM-1. DCs, dendritic cells; EPC, endothelial progenitor cells; FDC, follicular dendritic cells; GCs, germinal centers; IBD, inflammatory bowel disease; ICAM-1, intercellular adhesion molecule 1; LN, lupus nephritis; LIF, leucocyte inhibitory factor; LTi, lymphoid tissue inducer; MG, myasthenia gravis; MIF, macrophage inhibitory factor; mLTo, mesenchymal lymphoid tissue organizer; MS, multiple sclerosis; pSS, primary Sjögren’s syndrome; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; Tfh, T follicular helper; TGF-β1, transforming growth factor β1; Tph, T peripheral helper; VCAM-1, vascular cell adhesion molecule 1; VEGF, vascular endothelial growth factor.

Figure 3

Protein structures of CXCL13 and CXCR5. (A) The amino acid sequence of human CXCL13 precursor, mature CXCL13, Met CXCL13, Δ1L2M CXCL13, and two isoforms of human CXCR5. The human CXCL13 protein consists of 109 amino acids, including a signal peptide of 22 amino acids (marked in bold). The four conserved cysteine residues are marked in yellow. The human CXCR5 has two isoforms due to the alternatively spliced transcript variants. The difference between the two isoform of CXCR5 is additionally marked in bold. (B) The tertiary structure of Met CXCL13 [Protein Data Bank (PDB) ID: 7JNY]. The N-terminus of Met CXCL13 forms a β0-sheet, followed by a long N-loop ending in a short 3₁₀-helix, and the central three-stranded anti-parallel β-sheet, and a C-terminal α-helix. β-sheet is indicated by yellow arrows, and α-helix and 3₁₀-helix are indicated by red cylinders. (C) The tertiary structure of Δ1L2M CXCL13 monomer [PDB ID: 6VGJ]. In Δ1L2M CXCL13, the N-terminus folds into a β-strand (β-1), followed by a β0-sheet, and a canonical chemokine core domain. β-sheet is indicated by yellow arrows, and α-helix and 3₁₀-helix are indicated by red cylinders.

Figure 4

CXCL13/CXCR5-mediated signaling pathways. CXCL13 exerts its biological functions through activating CXCR5, a chemokine receptor coupled to G-protein heterotrimer. Upon activation, CXCR5 undergoes conformation change and induces the cycle of G-protein activation, leading to a cascade of downstream signal transduction pathways including: (1) activation of PLC leads to conversion of PIP2 to IP3 and DAG. IP3 can promote the release of Ca²⁺ from intracellular stores into the cytoplasm. On the other hand, DAG consistent with increased Ca²⁺ activate PKC, which contributes to the activation of transcription factor NF-κB to promote cell migration; (2) activation of PI3K can trigger the activation of Akt, thus stimulating downstream NF-κB, mTOR, and GSK-3β/β-catenin/TCF/LEF signaling, which play key roles in tumor cell growth, proliferation, invasion, and migration; (3) CXCR5 also activates MAPK pathways utilizing JNK, ERK, and p38 via G-protein, which may further stimulate AP-1 to promote cell proliferation and inflammation. AP-1, activating protein-1; DAG, diacylglicerol; ERK, extracellular signal-regulated kinase; GSK-3β, glycogen synthase kinase-3β; IP3, inositol triphosphate; JNK, c-Jun N-terminal kinase; mTOR, mammalian target of rapamycin; NF-κB, nuclear factor-κB; PI3K, phosphoinositide 3-kinase; PKC, protein kinase C, PLC, phospholipase C; PTEN, phosphatase and tensin homologue; TCF/LEF, T-cell factor/lymphoid enhancer-binding factor.