Neurotensin – B Cells
A new study in Journal of Immunology by Sofiane Saada and colleagues from the Department of Immunology, University of Limoges, Limoges, France is the first to report the expression of neurotensin and its high NTSR1 and low NTSR2-affinity receptors in human B cell lines, primary malignant B cells from chronic B cell lymphocytic leukemia (CLL) patients and healthy peripheral B cells.
Neurotensin is a 13-amino acid peptide discovered and isolated in 1973, from extracts of bovine hypothalamus by Robert Carraway and Susan Leeman.
The peptide is widely distributed throughout the brain, predominantly in the hypothalamus, amygdala and nucleus accumbens. Neurotensin acts as a neurotransmitter or neuromodulator mostly of dopamine neurotransmission and the anterior pituitary hormone secretion. High concentrations of neurotensin are also found in the neuroendocrine cells and mucosa of the distal small intestine, where it exerts endocrine and paracrine actions.
Three neurotensin receptors (NTSRs) have been identified: two are G protein–coupled receptors – the high-affinity receptor (NTSR1) and the low-affinity receptor (NTSR2). The 3rd neurotensin receptor (NTSR3), also referred to as sortilin, is not a G protein–coupled receptor, is common to neurotrophins and neurotensin and belongs to the Vps10p intracellular protein family, which is predominantly located in endoplasmic reticulum/Golgi compartment.
Neurotensin has been implicated in regulation of immunity and inflammation. Neurotensin and its receptors are expressed by T lymphocytes, macrophages and dendritic cells. The peptide is involved in regulation of cytokine production, neutrophil chemotaxis, nitric oxide (NO) generation and mast cell activation.
Interestingly, a recent study indicates that the exit of interferon-gamma from the Golgi apparatus requires the presence of sortilin (Herda S. et al., Immunity, 2012, 37:854). Sortilin and brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, might also be implicated in the survival and activation of normal B cells (Anne-Laure Fauchais et al., J. Immunol., 2008, 181: 3027). In addition, neurotensin increases in the skin following acute stress, stimulates skin mast cells and increases vascular permeability through mast cell activation.
Neurotensin triggers mast cells to release histamine and elevates plasma levels of histamine through NTSR. Unique interactions among neurotensin, corticotropin-releasing hormone (CRH) and mast cells may contribute to allergic or inflammatory/autoimmune diseases (cf. Alysandratos K–D et al., PLoS ONE, 2012, 7: e48934. doi:10.1371/journal.pone.0048934).
Neurotensin also stimulates cancer cell growth and metastatic spread, mainly through binding to NTSR1 that is over-expressed in many cancer cell lines. Neurotensin receptor 1 (NTSR1) was recently suggested as a prognosis marker in breast, lung, and head and neck squamous carcinomas. This indicates that the neurotensin/NTSR1 complex may play an important role in cancer progression.
According to Saada et al., the authors of the study in Journal of Immunology, NTSR2 transcripts were over-expressed exclusively in CLL, whereas NTSR1 expression was lower than in resting or activated human normal B lymphocytes.
The over-expression in CLL B cells supports the hypothesis that NTSR2 could be involved in the apoptotic defect characteristic of the disease.
Previous research indicates that NTSR2 and NTSR3 neurotensin receptors are crucial for the anti-apoptotic effect of neurotensin on pancreatic beta-TC3 cells. Thus, the study by Saada et al. suggests that the role of neurotensin and its receptors in chronic B cell leukemia warrant further investigation and this may point to new therapeutic targets and approaches in this disease.
SOURCE: J Immunol. 2012, 189:5293.
Updates
A 2017 study published in the journal Oncogene identified neurotensin receptor 2 (NTSR2) as an essential driver of apoptosis resistance in B-CLL. NTSR2 was highly expressed in B-CLL cells, whereas expression of its natural ligand, neurotensin (NTS), was minimal in both B-CLL cells and patient plasma. Surprisingly, NTSR2 remained in a constitutively active phosphorylated state, caused not by a mutation-induced gain-of-function but rather by an interaction with the oncogenic tyrosine kinase receptor TrkB.
Functional and biochemical characterization revealed that the NTSR2–TrkB interaction acts as a conditional oncogenic driver requiring the TrkB ligand brain-derived neurotrophic factor (BDNF), which unlike NTS is highly expressed in B-CLL cells. Together, NTSR2, TrkB and BDNF induce autocrine and/or paracrine survival pathways that are independent of mutation status and indolent or progressive disease course.
A 2024 study published in the journal Scientific Reports explored the targeting of an unexplored pathway in chronic lymphocytic leukemia (CLL), with the aim of demonstrating its therapeutic potential.
Previous research found that NTSR2 (neurotensin receptor 2), through the recruitment of TRKB (tropomyosin related kinase B), induces survival pathways in leukemic B cells. Previous work by this research team evidenced the interaction of these two surface receptors, NTSR2 and TRKB, and their involvement in the activation of survival pathways in CLL-B cells, notably through the activation of kinases SRC and AKT and the overexpression of anti-apoptotic proteins BCL-2 and BCL-XL.
Together, these findings demonstrated that the NTSR2–TRKB interaction plays a crucial role in CLL-B cell survival, suggesting that its inhibition represents a promising strategy for treating CLL.
The present study validated the therapeutic value of targeting this oncogenic interaction. The authors determined the binding domain of these two proteins and formulated a peptide targeting it, to evaluate the therapeutic interest of this pathway in the treatment of CLL.
The designed peptide proved to be cytotoxic to CLL-B cells but not to healthy donors’ PBMCs, indicating its specificity for cancer cells which could suggest a potentially low toxicity. Moreover, following peptide treatment, a decrease in SRC and LYN activation as well as a decrease in the amount of anti-apoptotic proteins BCL-2, BCL-XL and MCL-1 and their transcripts was observable in CLL-B cells, thus confirming some of the molecular actors described in previous published work and evidencing new actors at play.