Virus-Induced Host Chemokine CCL2 in COVID-19 Pathogenesis: Potential Prognostic Marker and Target of Anti-Inflammatory Strategy.

A wide variety of inflammatory mediators, mainly cytokines and chemokines, are induced during SARS CoV-2 infection. Among these proinflammatory mediators, chemokines tend to play a pivotal role in virus-mediated immunopathology. The C-C chemokine ligand 2 (CCL2), also known as monocyte chemoattractant protein-1 (MCP-1) is a potent proinflammatory cytokine and strong chemoattractant of monocytes, macrophages and CD4+ T cells bearing C-C chemokine receptor type-2 (CCR2). Besides controlling immune cell trafficking, CCL2 is also involved in multiple pathophysiological processes including systemic hyperinflammation associated cytokine release syndrome (CRS), organ fibrosis and blood coagulation. These pathological features are commonly manifested in severe and fatal cases of COVID-19. Given the crucial role of CCL2 in COVID-19 pathogenesis, the CCL2:CCR2 axis may constitute a potential therapeutic target to control virus-induced hyperinflammation and multi-organ dysfunction. Herein we describe recent advances on elucidating the role of CCL2 in COVID-19 pathogenesis, prognosis, and a potential target of anti-inflammatory interventions.

Emerging Role of the IL-36/IL-36R Axis in Multiple Inflammatory Skin Diseases.

IL-36 is a most recent member of the IL-1 cytokine family, primarily expressed at barrier sites of the body such as the skin, lungs, and intestine. It plays a vital role in inflammation and is implicated in the development of various cutaneous; intestinal; and pulmonary disorders, including psoriasis, inflammatory bowel disease, and chronic obstructive pulmonary disease. IL-36 comprises 4 isoforms: the proinflammatory IL-36α, IL-36ß, and IL-36γ and the anti-inflammatory IL-36R antagonist. An imbalance between proinflammatory and anti-inflammatory IL-36 isoforms can contribute to the inflammatory fate of cells and tissues. IL-36 cytokines signal through an IL-36R heterodimer mediating their function through canonical signaling cacade, including the NF-B pathway. Prominent for its role in psoriasis, IL-36 has recently been associated with disease mechanisms in atopic dermatitis, hidradenitis suppurativa, neutrophilic dermatoses, autoimmune blistering disease, and Netherton syndrome. The major cutaneous source of IL-36 cytokines is keratinocytes, pointing to its role in the communication between the epidermis, innate (neutrophils, dendritic cells) immune system, and adaptive (T helper [Th]1 cells, Th17) immune system. Thus, cutaneous IL-36 signaling is crucial for the immunopathological outcome of various skin diseases. Consequently, the IL-36/IL-36R axis has recently been recognized as a promising drug target for the treatment of inflammatory disorders beyond psoriasis. This review summarizes the current update on IL-36 cytokines in inflammatory skin diseases.

Non-coding RNAs in the epigenetic landscape of cutaneous T-cell lymphoma.

Cutaneous T-cell lymphoma (CTCL) is a type of cancer that affects skin, and is characterized by abnormal T-cells in the skin. Epigenetic changes have been found to play a significant role in the development and progression of CTCL. Recently, non-coding RNAs (ncRNAs), such as microRNAs and long non-coding RNAs, have been identified as key players in the regulation of gene expression in CTCL. These ncRNAs can alter the expression of genes involved in cell growth, differentiation, and apoptosis, leading to the development and progression of CTCL. In this review, we summarize the current understanding of the role of ncRNAs in CTCL, including their involvement in DNA methylation, and other biological processes. We also discuss the types of ncRNAs, their role as oncogenic or tumor suppressive, and their putative use as diagnostic and prognostic biomarkers, based on the emerging evidence from laboratory-based as well as patients-based studies. Moreover, we also present the potential targets and pathways affected by ncRNAs. A better understanding of the complex epigenetic landscape of CTCL, including the role of ncRNAs, has the potential to lead to the development of novel targeted therapies for this disease.

Azithromycin downregulates ICOS (CD278) and OX40 (CD134) expression and mTOR activity of TCR-activated T cells to inhibit proliferation.

The precise mechanism of macrolide antibiotic azithromycin (AZM) mediated CD4+ T cell suppression is not fully understood. Given the crucial role of co-stimulatory signaling in T-lymphocyte function, we tested in vitro effects of AZM on two of the most extensively investigated costimulatory molecules, ICOS and OX40 in context to CD4+ T cell proliferation. Using multi-color flow cytometry approach on TCR-activated healthy donor peripheral blood mononuclear cells, we observed a marked reduction in the frequencies and surface expression of ICOS and OX40 receptors following AZM treatment. Functionally, in contrast to ICOS- and OX40- CD3+ CD4+ T cells, AZM treated ICOS+ and OX40+ displayed profound reduction in cell proliferation. Furthermore, AZM treated T cells displaying reduced levels of ICOS and OX40 found to be associated with suppressed mTOR activity as detected by phosphorylation levels of S6 ribosomal protein. This study provides new insights on potential mechanism of AZM mediated inhibition of T cell proliferation by targeting costimulatory pathways.

Epigenetic programing of cancer stemness by transcription factors-non-coding RNAs interactions.

Cancer 'stemness' is fundamental to cancer existence. It defines the ability of cancer cells to indefinitely perpetuate as well as differentiate. Cancer stem cell populations within a growing tumor also help evade the inhibitory effects of chemo- as well as radiation-therapies, in addition to playing an important role in cancer metastases. NF-κB and STAT-3 are representative transcription factors (TFs) that have long been associated with cancer stemness, thus presenting as attractive targets for cancer therapy. The growing interest in non-coding RNAs (ncRNAs) in the recent years has provided further insight into the mechanisms by which TFs influence cancer stem cell characteristics. There is evidence for a direct regulation of TFs by ncRNAs, such as, microRNAs (miRNAs), long non-coding RNAs (lncRNAs) as well as circular RNAs (circRNAs), and vice versa. Additionally, the TF-ncRNAs regulations are often indirect, involving ncRNA-target genes or the sponging of other ncRNA species by individual ncRNAs. The information is rapidly evolving and this review provides a comprehensive review of TF-ncRNAs interactions with implications on cancer stemness and in response to therapies. Such knowledge will help uncover the many levels of tight regulations that control cancer stemness, providing novel opportunities and targets for therapy in the process.

Epigenetic regulation of CXCR4 signaling in cancer pathogenesis and progression.

Signaling involving chemokine receptor CXCR4 and its ligand SDF-1/CXL12 has been investigated for many years for its possible role in cancer progression and pathogenesis. Evidence emerging from clinical studies in recent years has further established diagnostic as well as prognostic importance of CXCR4 signaling. CXCR4 and SDF-1 are routinely reported to be elevated in tumors, distant metastases, which correlates with poor survival of patients. These findings have kindled interest in the mechanisms that regulate CXCR4/SDF-1 expression. Of note, there is a particular interest in the epigenetic regulation of CXCR4 signaling that may be responsible for upregulated CXCR4 in primary as well as metastatic cancers. This review first lists the clinical evidence supporting CXCR4 signaling as putative cancer diagnostic and/or prognostic biomarker, followed by a discussion on reported epigenetic mechanisms that affect CXCR4 expression. These mechanisms include regulation by non-coding RNAs, such as, microRNAs, long non-coding RNAs and circular RNAs. Additionally, we also discuss the regulation of CXCR4 expression through methylation and acetylation. Better understanding and appreciation of epigenetic regulation of CXCR4 signaling can invariably lead to identification of novel therapeutic targets as well as therapies to regulate this oncogenic signaling.

Long non-coding RNAs regulated NF-κB signaling in cancer metastasis: Micromanaging by not so small non-coding RNAs.

Cancer metastasis is a major reason for the cancer-associated deaths and a role of long non-coding RNAs (lncRNAs) in cancer metastasis is increasingly being realized. Among the many oncogenic pathways, NF-κB signalling's involvement in cancer metastasis as a key inflammation-regulatory transcription factor has been a subject of interest for long time. Accumulating data from in vitro as well as in vivo studies along with analysis of clinical cancer tissues points to regulation of NF-κB signalling by lncRNAs with implications toward the onset of cancer metastasis. LncRNAs FOXD2-AS1, KRT19P3 and the NF-κB interacting lncRNA (NKILA) associate with lymph node metastasis and poor prognosis of individual cancers. The role of epithelial-mesenchymal transition (EMT) in cancer metastasis is well known. EMT is regulated by NF-κB and regulation of NF-κB/EMT-induced metastasis by lncRNAs remains a hot topic of research with indications for such roles of lncRNAs MALAT1, SNHG15, CRNDE and AC007271.3. Among the many lncRNAs, NKILA stands out as the most investigated lncRNA for its regulation of NF-κB. This tumor suppressive lncRNA has been reported downregulated in clinical samples representing different human cancers. Mechanistically, NKILA has been consistently shown to inhibit NF-κB activation via inhibition of IκBα phosphorylation and the resulting suppression of EMT. NKILA is also a target of natural anticancer compounds. Given the importance of NF-κB as a master regulatory transcription factor, lncRNAs, as the modulators of NF-κB signaling, can provide alternate targets for metastatic cancers with constitutively active NF-κB.