Targeting CXCL13 During Neuroinflammation

Huber, Amanda K.; Irani, David N.

doi:10.3233/nib-150101

Cited by 36 publications

(28 citation statements)

References 89 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Chemokine (C-X-C motif) ligand 13 (CXCL-13) is a member of small chemokines (8-10 kDa) [12], and it is a chemotactic protein targeting B lymphocytes, while its receptor, CXCR5, is expressed in specific T lymphocyte subsets [11]. In addition to the previous discovery that CXCL-13 is usually expressed by lymphoid organs, stromal cells and follicle dendritic cell, it also is secreted by some types of tumor cells, bone marrow endothelial cells, osteoblasts, myofibroblasts and CXCL-13-producing CD4 + follicular helper T cells [13][14][15]. So far, anecdotal evidence suggests that CXCL-13 together with CXCR5 might play increasingly vital roles in regulating tumor occurrence, progression, metastasis and prognosis in the microenvironment where the tumor is located [16][17][18][19].…”

Section: Introductionmentioning

confidence: 99%

CXCL-13 Regulates Resistance to 5-Fluorouracil in Colorectal Cancer

et al. 2020

View full text Add to dashboard Cite

Purpose5-Fluorouracil (5-Fu) is used as a conventional chemotherapy drug in chemotherapy for patients with advanced colorectal cancer, but many patients still suffer from treatment failure due to 5-Fu resistance. Emerging observations revealed the important role of chemokine (C-X-C motif) ligand 13 (CXCL-13) in tumor microenvironment and its relationship with prognosis in patients with colorectal cancer. This study is designed to reveal the important role of CXCL-13 in causing colorectal cancer resistance to 5-Fu.Materials and MethodsCXCL-13 levels of patient's serum or cell culture supernatants were measured separately by enzyme-linked immunosorbent assay. In cell assays, cell viability is detected by Cell Counting Kit-8. Therefore, the recombinant human CXCL-13 was used to simulate its high expression in cells while its antibody and siRNA were used to reduce CXCL-13 expression in cells.ResultsIn this study, we demonstrated that CXCL-13 is associated with 5-Fu resistance by culture medium exchange experiments and cytokine arrays of colorectal cancer resistant and nonresistant cells. Clinical studies showed that CXCL-13 is highly expressed in the serum of 5-Fu–resistant patients. High levels of serum CXCL-13 also predict a worse clinical outcome. The addition of recombinant CXCL-13 cytokine resulted in 5-Fu resistance, while its antibody overcame 5-Fu resistance, and knockdown of CXCL-13 expression by siRNA also reduced 5-Fu resistance, which can be saved by added recombination CXCL-13.ConclusionThese results not only identify a CXCL-13 mediated 5-Fu resistance mechanism but also provide a novel target for 5-Fu–resistant colorectal cancer in prevention and treatment strategies.

show abstract

Section: Introductionmentioning

confidence: 99%

CXCL-13 Regulates Resistance to 5-Fluorouracil in Colorectal Cancer

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Both innate and adaptive immunity participate in the pathogenesis of MS and its established model, experimental autoimmune encephalomyelitis (EAE), as indicated by the presence of activated lymphocytes and increased cytokine and chemokine production by macrophages, microglia and astrocytes (Gomez Perdiguero, Schulz, & Geissmann, ; Grebing et al, ; Hendriks, Teunissen, de Vries, & Dijkstra, ; Mayo, Quintana, & Weiner, ). Mechanisms of demyelination and ensuing neurodegeneration (axonal and neuronal damage) remain uncertain although inflammatory molecules including cytokines, chemokines, prostaglandins, reactive oxygen species (Caruso et al, ; Lassmann, ) and proteases have been implicated in demyelination and axonal/neuronal injury (Huber & Irani, ; Lam et al, ; Radbruch et al, ; Takahashi, Giuliani, Power, Imai, & Yong, ). Several mechanisms by which inflammatory mediators contribute to cytotoxicity have been identified, including exacerbation of glutamate excitotoxicity by proinflammatory cytokines, damage to DNA, lipids, and proteins by ROS, and induction of apoptosis by death‐receptors ligands (Kharel, McDonough, & Basu, ; Ohl, Tenbrock, & Kipp, ; Sulkowski, Dabrowska‐Bouta, Kwiatkowska‐Patzer, & Struzynska, ).…”

Section: Introductionmentioning

confidence: 99%

Suppressed oligodendrocyte steroidogenesis in multiple sclerosis: Implications for regulation of neuroinflammation

Boghozian

McKenzie

Saito

et al. 2017

Glia

View full text Add to dashboard Cite

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS). Neurosteroids are reported to exert anti-inflammatory effects in several neurological disorders. We investigated the expression and actions of the neurosteroid, dehydroepiandrosterone (DHEA), and its more stable 3β-sulphated ester, DHEA-S, in MS and associated experimental models. CNS tissues from patients with MS and animals with experimental autoimmune encephalomyelitis (EAE) displayed reduced DHEA concentrations, accompanied by diminished expression of the DHEA-synthesizing enzyme CYP17A1 in oligodendrocytes (ODCs), in association with increased expression of inflammatory genes including interferon (IFN)-γ and interleukin (IL)-1β. CYP17A1 was expressed variably in different human neural cell types but IFN-γ exposure selectively reduced CYP17A1 detection in ODCs. DHEA-S treatment reduced IL-1β and -6 release from activated human myeloid cells with minimal effect on lymphocyte viability. Animals with EAE receiving DHEA-S treatment showed reduced Il1b and Ifng transcript levels in spinal cord compared to vehicle-treated animals with EAE. DHEA-S treatment also preserved myelin basic protein immunoreactivity and reduced axonal loss in animals with EAE, relative to vehicle-treated EAE animals. Neurobehavioral deficits were reduced in DHEA-S-treated EAE animals compared with vehicle-treated animals with EAE. Thus, CYP17A1 expression in ODCs and its product DHEA were downregulated in the CNS during inflammatory demyelination while DHEA-S provision suppressed neuroinflammation, demyelination, and axonal injury that was evident as improved neurobehavioral performance. These findings indicate that DHEA production is an immunoregulatory pathway within the CNS and its restoration represents a novel treatment approach for neuroinflammatory diseases.

show abstract

“…The present study is important also from a clinical translational perspective since blocking CXCR5/CXCL13 signaling has been proposed as a therapeutic strategy in neuroinflammation. 45 Our findings raise the possibility that long-term inhibition of neuroinflammation by reducing CXCR5/CXCL13 signaling might compromise neurogenesis in older patients.…”

Section: Discussionmentioning

confidence: 76%

Loss of Cxcr5 alters neuroblast proliferation and migration in the aged brain

et al. 2020

View full text Add to dashboard Cite

Neurogenesis, the production of new neurons from neural stem cells, dramatically decreases during aging concomitantly with increased inflammation both systemically and in the brain. However, the precise role of inflammation and whether local or systemic factors drive the neurogenic decline during aging is poorly understood. Here, we identify CXCR5/5/CXCL13 signaling as a novel regulator of neurogenesis in the aged brain. The chemokine Cxcl13 was found to be upregulated in the brain during aging. Loss of its receptor, Cxcr5, led to increased proliferation and decreased numbers of neuroblasts in the aged subventricular zone (SVZ), together with accumulation of neuroblasts in the rostral migratory stream and olfactory bulb (OB), without increasing the amount of new mature neurons in the OB. The effect on proliferation and migration was specific to neuroblasts and likely mediated through increased levels of systemic IL‐6 and local Cxcl12 expression in the SVZ. Our study raises the possibility of a new mechanism by which interplay between systemic and local alterations in inflammation regulates neurogenesis during aging.

show abstract

Targeting CXCL13 During Neuroinflammation

Cited by 36 publications

References 89 publications

CXCL-13 Regulates Resistance to 5-Fluorouracil in Colorectal Cancer

CXCL-13 Regulates Resistance to 5-Fluorouracil in Colorectal Cancer

Suppressed oligodendrocyte steroidogenesis in multiple sclerosis: Implications for regulation of neuroinflammation

Loss of Cxcr5 alters neuroblast proliferation and migration in the aged brain

Contact Info

Product

Resources

About