Persistent and excessive cytokine production is a hallmark of autoimmune diseases and may play a role in disease pathogenesis and amplification. Therefore, cytokine neutralization is a useful ...therapeutic strategy to treat immune-mediated conditions. MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate gene expression in diverse biological processes. Altered miRNA levels are observed in most autoimmune diseases and are recognized to influence autoimmunity through different mechanisms. Here, we review the impact of altered miRNA levels on the expression of cytokines that play a relevant pathogenic role in autoimmunity, namely primary pro-inflammatory cytokines, the IL-17/IL-23 axis, type I interferons and IL-10. Regulation can be either "direct" on the target cytokine, or "indirect," meaning that one given miRNA post-transcriptionally regulates the expression of a protein that in turn influences the level of the cytokine. In addition, miRNAs associated with extracellular vesicles can regulate cytokine production in neighboring cells, either post-transcriptionally or via the stimulation of innate immune RNA-sensors, such as Toll-like receptors. Because of their tremendous potential as physiological and pathological regulators, miRNAs are in the limelight as promising future biopharmaceuticals. Thus, these studies may lead in the near future to the design and testing of therapeutic miRNAs as next generation drugs to target pathogenic cytokines in autoimmunity.
Dendritic cells (DCs) are professional antigen-presenting cells responsible for the activation of specific T-cell responses and for the development of immune tolerance. Immature DCs reside in ...peripheral tissues and specialize in antigen capture, whereas mature DCs reside mostly in the secondary lymphoid organs where they act as antigen-presenting cells. The correct localization of DCs is strictly regulated by a large variety of chemotactic and nonchemotactic signals that include bacterial products, DAMPs (danger-associated molecular patterns), complement proteins, lipids, and chemokines. These signals function both individually and in concert, generating a complex regulatory network. This network is regulated at multiple levels through different strategies, such as synergistic interactions, proteolytic processing, and the actions of atypical chemokine receptors. Understanding this complex scenario will help to clarify the role of DCs in different pathological conditions, such as autoimmune diseases and cancers and will uncover new molecular targets for therapeutic interventions.
Monocytes and cells of the dendritic cell lineage circulate in blood and eventually migrate into tissue where they further mature and serve various functions, most notably in immune defense. Over ...recent years these cells have been characterized in detail with the use of cell surface markers and flow cytometry, and subpopulations have been described. The present document proposes a nomenclature for these cells and defines 3 types of monocytes (classical, intermediate, and nonclassical monocytes) and 3 types of dendritic cells (plasmacytoid and 2 types of myeloid dendritic cells) in human and in mouse blood. This classification has been approved by the Nomenclature Committee of the International Union of Immunological Societies, and we are convinced that it will facilitate communication among experts and in the wider scientific community.
Chemokine (C–C motif) receptor‐like 2 (CCRL2), is a seven transmembrane receptor closely related to the chemokine receptors CCR1, CCR2, CCR3, and CCR5. Nevertheless, CCRL2 is unable to activate ...conventional G‐protein dependent signaling and to induce cell directional migration. The only commonly accepted CCRL2 ligand is the nonchemokine chemotactic protein chemerin (RARRES2). The chemerin binding to CCLR2 does induce leukocyte chemotaxis, yet, genetic targeting of CCRL2 was shown to modulate the inflammatory response in different experimental models. This mechanism was shown to be crucial for lung dendritic cell migration, neutrophil recruitment, and Natural Killer cell‐dependent immune surveillance in lung cancer. To gain more insight in the interactions involved in the CCRL2‐chemerin, the binding complexes were generated by protein–protein docking, then submitted to accelerated molecular dynamics. The obtained trajectories were inspected by principal component analyses followed by kernel density estimation to identify the ligand‐receptor regions most frequently involved in the binding. To conclude, the reported analyses led to the identification of the putative hot‐spot residues involved in CCRL2‐chemerin binding.
Cancer progression is continuously controlled by the immune system which can identify and destroy nascent tumor cells or inhibit metastatic spreading. However, the immune system and its deregulated ...activity in the tumor microenvironment can also promote tumor progression favoring the outgrowth of cancers capable of escaping immune control, in a process termed cancer immunoediting. This process, which has been classified into three phases, i.e. "elimination", "equilibrium" and "escape", is influenced by several cancer- and microenvironment-dependent factors. Senescence is a cellular program primed by cells in response to different pathophysiological stimuli, which is based on long-lasting cell cycle arrest and the secretion of numerous bioactive and inflammatory molecules. Because of this, cellular senescence is a potent immunomodulatory factor promptly recruiting immune cells and actively promoting tissue remodeling. In the context of cancer, these functions can lead to both cancer immunosurveillance and immunosuppression. In this review, the authors will discuss the role of senescence in cancer immunoediting, highlighting its context- and timing-dependent effects on the different three phases, describing how senescent cells promote immune cell recruitment for cancer cell elimination or sustain tumor microenvironment inflammation for immune escape. A potential contribution of senescent cells in cancer dormancy, as a mechanism of therapy resistance and cancer relapse, will be discussed with the final objective to unravel the immunotherapeutic implications of senescence modulation in cancer.
Plasmacytoid dendritic cells (PDCs) represent a subset of circulating leukocytes characterized by the ability to release high levels of type I interferon (IFN). Under homeostatic conditions PDCs are ...confined to primary and secondary lymphoid organs. This is consistent with the restricted profile of functional chemotactic receptors expressed by circulating PDCs (i.e. CXCR4 and ChemR23). Accumulation of PDCs in non-lymphoid tissue is, however, observed in certain autoimmune diseases, allergic reactions and tumors. Indeed, PDCs are now considered to be involved in the pathogenesis of diseases characterized by a type I IFN-signature and are considered as a promising target for new intervention strategies. Here, current knowledge of the molecular mechanisms involved in the recruitment of PDCs under homeostatic and pathological conditions are summarized.
Oxysterols are involved in maintaining cellular cholesterol levels. Recently, oxysterols have been demonstrated to modulate the function of immune cells and tumor growth. These effects can be ...dependent on the activation of the oxysterol‐binding liver X receptors (LXRs) or, as recently demonstrated for T and B cells, DCs and neutrophils, can be independent of LXR activation. LXR‐dependent oxysterol effects can be ascribed to the activation of LXRα, LXRβ or LXRαβ isoforms, which induces transcriptional activation or trans‐repression of target genes. The prevalent activation of one isoform seems to be cell‐, tissue‐, or context‐specific, as shown in some pathologic processes, i.e., infectious diseases, atherosclerosis, and autoimmunity. Oxysterol‐LXR signaling has recently been shown to inhibit antitumor immune responses, as well as to modulate tumor cell growth. Here, we review the mechanisms that link oxysterols to tumor growth, and discuss possible networks at the basis of LXR‐dependent and ‐independent oxysterol effects on immune cells and tumor development.
CCRL2 is a 7-transmembrane domain receptor that shares structural and functional similarities with the family of atypical chemokine receptors (ACKRs). CCRL2 is upregulated by inflammatory signals ...and, unlike other ACKRs, it is not a chemoattractant-scavenging receptor, does not activate β-arrestins, and is widely expressed by many leukocyte subsets. Therefore, the biological role of CCRL2 in immunity is still unclear. We report that CCRL2-deficient mice have a defect in neutrophil recruitment and are protected in 2 models of inflammatory arthritis. In vitro, CCRL2 was found to constitutively form homodimers and heterodimers with CXCR2, a main neutrophil chemotactic receptor. By heterodimerization, CCRL2 could regulate membrane expression and promote CXCR2 functions, including the activation of β2-integrins. Therefore, upregulation of CCRL2 observed under inflammatory conditions is functional to finely tune CXCR2-mediated neutrophil recruitment at sites of inflammation.
•CCRL2 is required for CXCR2-dependent neutrophil recruitment.•CCRL2 forms heterodimers with CXCR2 and regulates CXCR2 signaling.
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