Potential therapeutic manipulations of the CXCR3 chemokine axis for the treatment of inflammatory fibrosing diseases

Groover, Morgan K; Richmond, Julius B.

doi:10.12688/f1000research.26728.1

Cited by 16 publications

(5 citation statements)

References 95 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The CXCR3-axis has various functions, such as regulating immune cell migration, differentiation, and activation [ 25 , 26 ], and is expressed on numerous cells throughout the body, including leukocytes and endothelial cells [ 27 ].…”

Section: Discussionmentioning

confidence: 99%

Lower CXCR3 expression in both patients with neovascular AMD and advanced stages of chronic myeloproliferative blood cancers

et al. 2022

View full text Add to dashboard Cite

Purpose Peripheral T cell CXCR3 expression has been found uniquely lower in patients having neovascular age-related macular degeneration (nAMD) than in healthy individuals. The CXCR3-axis has been shown to have angiostatic and antifibrotic properties. We have recently investigated systemic markers in patients with myeloproliferative neoplasms (MPNs) because of their higher prevalence of AMD, and we have observed higher systemic chronic low-grade inflammation and immunosenescence signs in MPNs with drusen (MPNd) compared to those with normal retinas (MPNn). The MPNs evolve in a biological continuum from early cancer-stages (essential thrombocytosis, polycythemia vera) to the advanced myelofibrosis stage. Especially myelofibrosis is characterized by bone marrow angiogenesis and fibrosis, similarly to retinal observations in nAMD. We speculate if we can find lower CXCR3 expression in MPNs, particularly myelofibrosis and if differences are seen between MPNd and MPNn. We also wanted to compare expression in nAMD and intermediate (i)AMD. Methods Patients in this cross-sectional study were 29 nAMD, 28 iAMD, 35 MPNd, and 27 MPNn. We performed flowcytometry on blood to measure CXCR3 expression. Results CD8+CXCR3 expression in nAMD was 6,1%, significantly lower than in iAMD 16%, MPNd 11%, MPNn 12% (p-values<0.05). Similar results were seen for CD4+CXCR3 expression. We also found CXCR3 expression decreasing over the MPN-continuum. For instance, in myelofibrosis, intermediate monocytes expression was 6.2%, significantly lower than 18% in ET and 18% in PV (p-values<0.05). Conclusions We find CXCR3 downregulation on T-cells and some monocyte subset in nAMD compared to iAMD, MPNd, and MPNn, in line with previous nAMD studies. We also find CXCR3 downregulation in most monocyte subsets over the MPN continuum. Systemic leukocyte CXCR3 expression could both be involved in changes seen in the retina and the bone marrow. Further understanding the CXCR3-axis in AMD and MPNs may elucidate underlying pathogenic mechanisms and reveal new targets for treatment.

show abstract

Section: Discussionmentioning

confidence: 99%

Lower CXCR3 expression in both patients with neovascular AMD and advanced stages of chronic myeloproliferative blood cancers

et al. 2022

View full text Add to dashboard Cite

show abstract

“…We identified CXCL10 as a significantly upregulated biomarker at both protein and mRNA levels by multiple stimuli, including TNFα, IL-1β and IL-36 (S. Figure 2). Because modulation of CXCL10 and its receptor CXCR3 has been reported to be associated with inflammatory signaling-driven fibrogenesis 15, 16 , we chose it as a readout for efficacy in the ensuing screen. Though we did profile more conventional biomarkers of fibrosis, including ACTA2 and COL1A1, neither of them was induced by pro-fibrotic stimuli at either protein or mRNA level to yield an acceptable assay window for a high throughput screen (S. Figure 3).…”

Section: Resultsmentioning

confidence: 99%

Integrating inflammatory biomarker analysis and artificial intelligence-enabled image-based profiling to identify drug targets for intestinal fibrosis

Kalinin

Paraskevopoulou

et al. 2022

Preprint

View full text Add to dashboard Cite

Intestinal fibrosis is a common complication of several enteropathies with inflammatory bowel disease being the major cause. The progression of intestinal fibrosis may lead to intestinal stenosis and obstruction. Even with an increased understanding of tissue fibrogenesis, there are no approved treatments for intestinal fibrosis. Historically, drug discovery for diseases like intestinal fibrosis has been impeded by a lack of screenable cellular phenotypes. Here we applied Cell Painting, a scalable image-based morphology assay, augmented with machine learning algorithms to identify small molecules that were able to morphologically reverse the activated fibrotic phenotype of intestinal myofibroblasts under pro-fibrotic TNF? stimulus. In combination with measuring CXCL10, a common pro-inflammatory cytokine in intestinal fibrosis, we carried out a high-throughput small molecule chemogenomics screen of approximately 5000 compounds with known targets or mechanisms, which have achieved clinical stage or approval by the FDA. Through the use of two divergent analytical methods, we identified several compounds and target classes that are potentially able to treat intestinal fibrosis. The phenotypic screening platform described here represents significant improvements in identifying a wide range of drug targets over conventional methods by integrating morphological analyses and artificial intelligence using pathologically-relevant cells and disease-relevant stimuli.

show abstract

“…CXCL9 is a T cell type 1 chemokine detected in the blood that attracts CXCR3 + T cells in cGVHD target organs ( 20 , 35 ). Inhibitors of the CXCL9/CXCR3 axis are under development, such as the small molecule SCH546738 ( 36 ). This axis could also be targeted indirectly by molecules such as emapalumab — an anti-IFNγ — and JAK inhibitors that have shown to decrease CXCL9 levels as well as improvement of inflammatory diseases ( 37 , 38 ).…”

Section: Discussionmentioning

confidence: 99%

Validated graft-specific biomarkers identify patients at risk for chronic graft-versus-host disease and death

Logan,

Fu,

Howard

et al. 2023

Journal of Clinical Investigation

View full text Add to dashboard Cite

BACKGROUND Chronic graft-versus-host disease (cGVHD) is a serious complication of allogeneic hematopoietic cell transplantation (HCT). More accurate information regarding the risk of developing cGVHD is required. Bone marrow (BM) grafts contribute to lower cGVHD, which creates a dispute over whether risk biomarker scores should be used for peripheral blood (PB) and BM. METHODS Day 90 plasma proteomics from PB and BM recipients developing cGVHD revealed 5 risk markers that were added to 8 previous cGVHD markers to screen 982 HCT samples of 2 multicenter Blood and Marrow Transplant Clinical Trials Network (BMTCTN) cohorts. Each marker was tested for its association with cause-specific hazard ratios (HRs) of cGVHD using Cox-proportional-hazards models. We paired these clinical studies with biomarker measurements in a mouse model of cGVHD. RESULTS Spearman correlations between DKK3 and MMP3 were significant in both cohorts. In BMTCTN 0201 multivariate analyses, PB recipients with 1-log increase in CXCL9 and DKK3 were 1.3 times (95% CI: 1.1–1.4, P = 0.001) and 1.9 times (95%CI: 1.1–3.2, P = 0.019) and BM recipients with 1-log increase in CXCL10 and MMP3 were 1.3 times (95%CI: 1.0–1.6, P = 0.018 and P = 0.023) more likely to develop cGVHD. In BMTCTN 1202, PB patients with high CXCL9 and MMP3 were 1.1 times (95%CI: 1.0–1.2, P = 0.037) and 1.2 times (95%CI: 1.0–1.3, P = 0.009) more likely to develop cGVHD. PB patients with high biomarkers had increased likelihood to develop cGVHD in both cohorts (22%–32% versus 8%–12%, P = 0.002 and P < 0.001, respectively). Mice showed elevated circulating biomarkers before the signs of cGVHD. CONCLUSION Biomarker levels at 3 months after HCT identify patients at risk for cGVHD occurrence. FUNDING NIH grants R01CA168814, R21HL139934, P01CA158505, T32AI007313, and R01CA264921.

show abstract

Potential therapeutic manipulations of the CXCR3 chemokine axis for the treatment of inflammatory fibrosing diseases

Cited by 16 publications

References 95 publications

Lower CXCR3 expression in both patients with neovascular AMD and advanced stages of chronic myeloproliferative blood cancers

Lower CXCR3 expression in both patients with neovascular AMD and advanced stages of chronic myeloproliferative blood cancers

Integrating inflammatory biomarker analysis and artificial intelligence-enabled image-based profiling to identify drug targets for intestinal fibrosis

Validated graft-specific biomarkers identify patients at risk for chronic graft-versus-host disease and death

Contact Info

Product

Resources

About