Peptide Targeting of PDZ-Dependent Interactions as Pharmacological Intervention in Immune-Related Diseases.

PDZ (postsynaptic density (PSD95), discs large (Dlg), and zonula occludens (ZO-1)-dependent interactions are widely distributed within different cell types and regulate a variety of cellular processes. To date, some of these interactions have been identified as targets of small molecules or peptides, mainly related to central nervous system disorders and cancer. Recently, the knowledge of PDZ proteins and their interactions has been extended to various cell types of the immune system, suggesting that their targeting by viral pathogens may constitute an immune evasion mechanism that favors viral replication and dissemination. Thus, the pharmacological modulation of these interactions, either with small molecules or peptides, could help in the control of some immune-related diseases. Deeper structural and functional knowledge of this kind of protein-protein interactions, especially in immune cells, will uncover novel pharmacological targets for a diversity of clinical conditions.

CX3CL1 and CX3CR1 could be a relevant molecular axis in the pathophysiology of idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis is a chronic and progressive disease of unknown cause. It is characterized by the aberrant activation of the bronchioalveolar epithelium, the formation of fibroblast foci and the excessive production extracellular matrix. The cellular and molecular mechanisms that contribute to the pathobiology of the disease are unclear. The CX3CL1-CX3CR1 axis regulates cellular responses that are known to be relevant in IPF, such as proliferation and collagen production. In this study, we characterize for the first time the expression of CX3CL1 and its receptor in lung tissue from patients with IPF; and its effect on collagen production in IPF fibroblasts. We found that CX3CL1-CX3CR1 axis has a modified expression in the lung tissue, importantly this axis is expressed on fibroblasts, and CX3CL1 decreased the collagen production in pulmonary fibroblasts derived from IPF patients.

Layered Double Hydroxide as a Vehicle to Increase Toxicity of Gallate Ions against Adenocarcinoma Cells.

The antineoplasic activity of gallic acid has been reported. This compound induces apoptosis and inhibits the growth of several neoplasic cells. However, this molecule is easily oxidized and degraded in the body. The aim of this work was to intercalate gallate ions into layered double hydroxide (LDH) nanoparticles under controlled conditions to reduce oxidation of gallate and to evaluate its toxicity against the A549 adenocarcinoma cell line. An isopropanol medium under nitrogen atmosphere was adequate to intercalate gallate ions with a lesser oxidation degree as detected by electron spin resonance spectroscopy. Concentrations of the hybrid LDH-gallate nanoparticles between 0.39 and 25 µg/mL reduced the cell viability to 67%, while the value reached with the pure gallic acid and LDH was 90% and 78%, respectively, thus proving that the combination of gallate ions with the inorganic nanoparticles increases the toxicity potential within this dose range.

A putative role for lactate in the crosstalk between chemokines and glycolysis in solid cancer.

Chemokines are very important for carcinogenesis and the development of a malignant phenotype. Lactate is a small molecule produced during glycolysis; recently it has emerged as an immunomodulator that could impact tumor cell behavior. In this paper we explore the interplay between chemokines, glycolysis, and lactate in cancer progression, and propose the existence of a pro-tumoral lactate-chemokine-glycolysis loop driven by high glucose levels.

Regulation and biological functions of the CX3CL1-CX3CR1 axis and its relevance in solid cancer: A mini-review.

CX3CL1 is a transmembrane protein from which a soluble form can be generated by proteolytic shedding. Membranal and soluble forms of CX3CL1 exhibit different functions, although both bind to the CX3CR1 chemokine receptor. The CX3CL1-CX3CR1 axis mediates the adhesion of leukocytes and is also involved in cell survival and recruitment of immune cell subpopulations. The function of CX3CL1 is finely tuned by cytokines and transcription factors regulating its expression and post-translational modifications. On homeostasis, the CX3CL1-CX3CR1 axis participates in the removal of damaged neurons and neurogenesis, and it is also involved on several pathological contexts. The CX3CL1-CX3CR1 axis induces several cellular responses relevant to cancer such as proliferation, migration, invasion and apoptosis resistance. In this review, we address biological aspects of this molecular axis with important therapeutic potential, emphasizing its role in cancer, one of the most prevalent chronic diseases which significantly affect the quality of life and life expectancy of patients.

Could SARS-CoV-2 blocking of ACE2 in endothelial cells result in upregulation of CX3CL1, promoting thrombosis in COVID-19 patients?

SARS-CoV-2 is the causal agent of COVID-19 disease. Currently, infection with SARS-CoV-2 has been the cause of death of over 2.5 million people globally, and there is still no effective curative treatment. Clinically, the severe symptoms caused by COVID-19, in addition to pneumonia, are associated with the development of hyperinflammatory syndrome and thrombosis. It is urgent to expand our understanding of the molecular mechanisms involved in the pathophysiology of COVID-19. This article discusses the potential role that the chemokine CX3CL1 could have in the development of COVID-19-associated thrombosis. CX3CL1 is abundantly expressed by activated endothelium and is an important regulator of many aspects of endothelial function and dysfunction, including thrombosis. The generation of hypotheses about molecules that could be relevant in well-defined aspects of the pathophysiology of COVID-19 encourages the development of basic and clinical studies, that could help find effective and much needed treatments.

Fcgamma receptors exhibit different phagocytosis potential in human neutrophils.

In neutrophils, two receptors for IgG antibodies, namely FcgammaRIIA and FcgammaRIIIB are constitutively expressed, and a third one, FcgammaRI, can be upregulated by interferon-gamma. Whether FcgammaRIIIB is capable of triggering phagocytosis by itself is still controversial. The main role of FcgammaRI has not been clearly established in these cells. To address this problem, neutrophils were treated with interferon-gamma, and then phagocytosis mediated by each type of Fcgamma receptor was evaluated by flow cytometry. FcgammaRIIA was the most efficient receptor for phagocytosis. FcgammaRIIIB could mediate phagocytosis but much less efficiently than FcgammaRIIA. Both FcgammaRIIA- and FcgammaRIIIB-mediated phagocytosis were blocked by inhibitors of Src family kinases, Syk, PI 3-K, and ERK. In contrast, interferon-gamma-induced FcgammaRI was not able to mediate phagocytosis. Also, FcgammaRI did not activate ERK in the nucleus, but was however able to stimulate an efficient calcium rise. These data show that different neutrophil Fcgamma receptors possess different phagocytosis capabilities: FcgammaRIIA and FcgammaRIIIB, but not FcgammaRI, promote phagocytosis.

Restoration of Peripheral Intermediate and Classical Monocytes Expressing HLA-DR in Patients With Lung Adenocarcinoma After Platinum-Based Chemotherapy.

Lung adenocarcinoma represents one of the lung cancer subtypes with major prevalence. Accumulating evidence indicates that the immune system plays an important role in the evolution of the neoplastic process; additionally, several reports suggest that chemotherapy has an immunomodulatory effect. In order to identify the peripheral subpopulations of leukocytes that may change after chemotherapy, we evaluated several peripheral immune subpopulations of monocytes and lymphocytes by multicolor flow cytometry. In addition, we also measured cytokines and growth factors on plasma in order to evaluate the pro-inflammatory context in patients with lung adenocarcinoma after chemotherapy. We found that HLA-DR+ classical and intermediate monocytes were decreased in patients before chemotherapy, compared to controls. After chemotherapy, the relative percentage of those subpopulations was restored. In addition, interleukin 1ß, interleukin 12, and interleukin 5 were increased after chemotherapy compared to prechemotherapy levels, while MIP-1ß was decreased.

Role of Chemokines in Non-Small Cell Lung Cancer: Angiogenesis and Inflammation.

Non-small cell lung cancer (NSCLC) is one of the most common types of aggressive cancer. The tumor tissue, which shows an active angiogenesis, is composed of neoplastic and stromal cells, and an abundant inflammatory infiltrate. Angiogenesis is important to support tumor growth, while infiltrating cells contribute to the tumor microenvironment through the secretion of growth factors, cytokines and chemokines, important molecules in the progression of the disease. Chemokines are important in development, activation of the immune response, and physiological angiogenesis. Chemokines have emerged as important regulators in the pathophysiology of cancer. These molecules are involved in the angiogenesis/angiostasis balance and in the recruitment of tumor infiltrating hematopoietic cells. In addition, chemokines promote tumor cell survival, as well as the directing and establishment of tumor cells to metastasis sites. The findings summarized here emphasize the central role of chemokines as modulators of tumor angiogenesis and their potential role as therapeutic targets in the inflammatory process of NSCLC angiogenesis.

Polymorphisms in chemokine and chemokine receptor genes and the development of coal workers' pneumoconiosis.

Chemokines and their receptors are key regulators of inflammation and may participate in the lung fibrotic process. Associations of polymorphisms in CCL5 (G-403A) and its receptor CCR5 (Delta32), CCL2 (A-2578G) and CCR2 (V64I), and CX3CR1 V249I and T280M with coal worker's pneumoconiosis (CWP) were investigated in 209 miners examined in 1990, 1994 and 1999. Coal dust exposure was assessed by job history and ambient measures. The main health outcome was lung computed tomography (CT) score in 1990. Internal coherence was assessed by studying CT score in 1994, 4-year change in CT score, and CWP prevalence in 1999. CCR5 Delta32 carriers had significantly higher CT score in 1990 and 1994 (2.15 vs. 1.28, p=0.01; 3.04 vs. 1.80, p=0.04). The CX3CR1 I249 allele was significantly associated with lower 1990 CT score and lower progression in 4-year change in CT score in CCR5 Delta32 carriers only (p for interaction=0.03 and 0.02). CX3CR1 V249I was associated with lower 1999 CWP prevalence (16.7%, 13.2%, 0.0% for VV, VI and II); the effect was most evident in miners with high dust exposure (31.6%, 21.7%, 0.0%). Our findings indicate that chemokine receptors CCR5 and CX3CR1 may be involved in the development of pneumoconiosis.