CXCL16 – Review

CXCL16 – Review

CXCL16/SR-POX gene has five exons, spans 6283 bp and is found on chromosome 17, position 17p13.2 (Huang et al., 2010) (genecards). CXCL16, also known as SR-PSOX, is a multi-functional molecule composed of four domains, a chemokine domain attached to a mucin stack fused to a transmembrane and cytoplasmic domain (Lehrke et al., 2007, Chandrasekar et al., 2003). It can be described as a scavenger receptor, adhesion molecule and soluble chemokine thus making it a triple threat in disease. Expression of CXCL16 has been reported on T-cells, dendritic cells, macrophages and cytokine stimulated ECs and SMCs (Zernecke et al., 2010) and B cells (Lougaris et al., 2012).

Soluble CXCL16

The disintegrin and metalloproteinase ADAM10 has the ability to cleave CXCL16 resulting in a soluble chemoattractant for CXCR6 associated cells. CXCR6 has been detected on a variety of cell types, interstitial lymphocytes, NK T cells, monocytes, dendritic cells, a subset of CD4+ or CD8+ T cells and CD4+ effector memory T cells, NK T cells, and a subset of Foxp3þ regulatory T cells in humans (Zernecke & Weber., 2009).CXCL16 as a chemokine signals via heterotrimeric G proteins/PI3K/PDK-1/Akt/IKK/I_B activating NF-ĸβ. In Human aortic smooth muscle cells (HASMC) CXCL16 increased NF- ĸβ binding activity resulting in up regulation of TNF-α, Iĸβ phosphorylation and degradation, cell to cell adhesion and ASMC proliferation (Chandrasekar et al., 2003).

Receptor CXCL16

CXCL16 is also a class G scavenger receptor which binds phosphatidyl-serine, oxidised lipoproteins, apoptotic cells and bacteria (Murphy at al., 2005, Lehrke et al., 2007). Pro-inflammatory cytokines associated with increased CXCL16 expression include IFN-γ, IL-18, LPS and to a lesser extent TNF-α, IL-12 and IL-15 (Wagsater et al., 2004).

CXCL16 & Atherosclerosis

Studies have shown CXCL16 to play a role in various steps of atheroma initiation and formation, including vascular cell proliferation (Lehrke et al., 2007), endocytosis of oxLDL, but not naïve LDL, leading to foam cell formation (Minami et al., 2001) and CD8+ t cell recruitment and IFN-γ production (Yamauchi et al., 2004). CXCL16 was also found to have an effect on IL-8 and MCP-1 release (Smith et al., 2008). The location of CXCL16 expression has been confirmed at sites pre-disposed to atheroma formation and has not been detected on the endothelium of healthy arteries. Increased expression has been reported in lesion prone areas with no visible plaque and in macrophage rich regions of advanced lesions (Hofnagel et al., 2011).Looking at the individual roles of the different forms of CXCL16 it appears to have a pro-atherogenic role. However, the role of CXCL16 in CAD has been controversial.

At present, more research needs to be invested into classifying this molecule as a biomarker, causative factor or therapeutic target (Sheikine and Sirsjo, 2008). Atherosclerosis is but one disease that CXCL16 and its receptor CXCR6 assist in inflammatory and therefore disease development. Other auto-immune and inflammatory related diseases have identified the chemokine/receptor duo as important biomarkers.

CXCL16 in Inflammatory Diseases

Sarcoidosis is an immunomediated disorder of unknown causes. It affects many organs including lungs, liver and heart. CXCR6 and CXCL16 play a pro-inflammatory role in the pathogenesis of T-cell Alveolitis in sarcoidsis. Sacrcoid CD4+ T cells in the bronchoalveolar express CXCR6 which then binds to CXCL16 on the epithelial/epithelioid cells and pulmonary macrophages (Agostini et al., 2005).

CXCL16 is also associated with Irritable Bowel Disease (IBD). The soluble form of the chemokine, which we know as an attractant for CXCR6– expressing T cells, significantly increases in patients with Ulcerative Colitis and Crohn’s Disease compared to healthy controls (Lehrke et al., 2007).Gout, an inflammatory arthritis, is also shows a correlation between increased CXCL16 expression and severity of the disease progression. It was also found to be correlated with renal function in the same cohort (Gong et al., 2012).

Precancerous lesions of proliferative inflammatory atrophy have been proposed to form prostatic intraepithelial neoplasia. A study revealed out of 37 chemokines associated with prostate cancer cell lines, CXCL16 had a significant positive correlation with the stage and grade of prostate cancer (Darash-Yahana et al., 2009). This chemokine enhances leukocyte recruitment enabling malignancy and CXCL16 and CXCR6 were also found on tumour-associated lymphocytes, proposing it as a tumour promoter. There is also a strong link between TNF-α and IL-1β levels and the expression level of CXCL16 in prostate epithelial cells (Lu et al., 2008). However, CXCL16 does not seem to be associated with a bad prognosis for all cancers, the increase in CXCL16 in colorectal cancerous tissue is an indicator of a better prognosis for colon rectal cancer (CRC). To date it is unclear to why CRC tumour cells upregulate CXCL16 (Hojo et al., 2007).

This multi-functional protein has proved itself to be a marker of importance in many diseases like TNF-α and IFN-γ, so investing research and time to uncover all its possible roles in disease will no doubt be beneficial to not one but multiple diseases.

Therapeutics Opportunities

Inhibition of chemokines is a potential approach to treating atherosclerosis. In current literature so far, receptor antagonists for RANTES, CCR5 and CXCR3 have reduced lesion development.

However, limitations exist using cytokine and chemokine blockers. Targeting the lesion site specifically while not affecting the rest of the hosts defence system is a major challenge (Braunersreuther et al., 2007).

5th Mar 2021 Seán Mac Fhearraigh PhD

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