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Innate lymphoid cells (ILCs) are innate immune cells that do not possess B or T cell receptors but belong to the lymphoid lineage. While these cells have not yet been extensively investigated since their classification as a homogenous group, emerging evidence suggests that they exert significant regulatory roles in both tissue remodelling and inflammation, and are therefore, also involved in fibrotic regulation. The following review will serve to outline the transcription factors, surface markers, and cytokines that define each subgroup, and the process by which these cells differentiate. Furthermore, the diverse functions of these cells in non-pathogenic states will be discussed, in addition to the interactions between ILCs and other cells of the immune system, both innate and adaptive, and how these pathways can elicit both pro- and anti-inflammatory and -fibrotic effects in varying tissues., (Copyright © 2017 European Federation of Immunological Societies. All rights reserved.)

Pattern Recognition Receptors are critical receptors that elicit an immune response upon their activation that culminates in activation of NF-KB and cytokine secretion. Key among these receptors are the Toll-Like Receptors (TLRs). These evolutionary conserved receptors form a key part in the defence against various pathogens and comprise a key part of the innate immune system. Systemic sclerosis is an autoimmune disease in which a breach of tolerance has occurred and leads to fulminant autoimmunity, dysregulated cytokines, pro-fibrotic mediators and activation of fibroblasts leading to fibrosis via collagen deposition. It has become apparent in recent years that the innate immune system and specifically TLRs are important in disease pathogenesis; responding to internal ligands to initiate an innate immune response ultimately leading to release of a variety of factors that initiate and perpetuate fibrosis. This review will examine the recent evidence of TLR signalling in systemic sclerosis and the internal danger associated molecules that may mediate the fibrotic cascade. Evaluation of their contribution to disease in systemic sclerosis and possible therapeutic targeting will be discussed., (Copyright © 2017 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.)

Summary: Interleukin-11 is a cytokine from the IL-6 family of cytokines that includes IL-6 and oncostatin-M. Initially described for its role in platelet generation, it is now appreciated that this cytokine has multiple functions. Recently it has been found that IL-11 is critical in fibrosis in multiple different organ systems and systemically as in the autoimmune disease systemic sclerosis. Animal models of fibrosis have determined that animals with IL-11 receptor deletions have retarded fibrosis and that in wild-type animals IL-11 is found at the organ of fibrosis. Recent evidence suggests that IL-11 may be a master regulator of fibrosis regardless of end target organ. With the development of neutralizing antibodies targeting the cytokine in pre-clinical models this could be a possible therapeutic, in a disease in which no specific therapies exist. This review appraises the evidence of the role of IL-11 in tissue fibrosis, its signalling properties, and therapeutic targeting. The review ends with an appraisal of indications for which IL-11 modulation is targeted. IL-11 is a key IL-6 family cytokine that has recently been associated with tissue fibrosis. [ABSTRACT FROM AUTHOR]

SSc is an autoimmune disease that has features of vascular abnormalities, inflammation and skin and lung fibrosis. Toll-like receptors (TLRs) are sentinel receptors that serve to recognize pathogens or internal danger signals leading to downstream signalling pathways that ultimately lead to inflammation and modification of adaptive immunity. Inflammation and fibrosis appear intricately connected in this disease and TLR ligation on fibroblasts can directly activate these cells to produce copious amounts of collagen, a hallmark of disease. The presence of damage-associated molecular patterns in association with fibrosis has been highlighted. Given their prominent role in disease, this review discusses the evidence of their expression and role in disease pathogenesis and possible therapeutic intervention to mitigate fibrosis. [ABSTRACT FROM AUTHOR]

Objective: In systemic sclerosis (SSc), a persistent tissue repair process leads to progressive fibrosis of the skin and internal organs. The role of mesenchymal stem cells (MSCs), which characteristically initiate and regulate tissue repair, has not been fully evaluated. We undertook this study to investigate whether dividing metakaryotic MSCs are present in SSc skin and to examine whether exposure to the disease microenvironment activates MSCs and leads to transdifferentiation. Methods: Skin biopsy material from patients with recent‐onset diffuse SSc was examined by collagenase spread of 1‐mm–thick surface‐parallel sections, in order to identify dividing metakaryotic stem cells in each tissue plane. Adipose‐derived MSCs from healthy controls were treated with dermal blister fluid (BF) from patients with diffuse SSc and profiled by next‐generation sequencing, or they were evaluated for phenotypic changes relevant to SSc. Differential responses of dermal fibroblasts were studied in parallel. Results: MSC‐like cells undergoing active metakaryotic division were identified in SSc sections (but not control sections) most prominently in the deep dermis and adjacent to damaged microvessels, in both clinically involved and uninvolved skin. Furthermore, exposure to SSc BF caused selective MSC activation, inducing a myofibroblast signature, while reducing signatures of vascular repair and adipogenesis and enhancing migration and contractility. Microenvironmental factors implicated in inducing transdifferentiation included the profibrotic transforming growth factor β, the presence of lactate, and mechanosensing, while the microenvironment Th2 cytokine, interleukin‐31, enhanced osteogenic commitment (calcinosis). Conclusion: Dividing MSC‐like cells are present in the SSc disease microenvironment where multiple factors, likely acting in concert, promote transdifferentiation and lead to a complex and resistant disease state. [ABSTRACT FROM AUTHOR]

SSc is an autoimmune idiopathic disease in which there is an inflammatory component driving fibrosis. The chief cell involved is the myofibroblast, which when activated secretes copious amounts of extracellular matrix that forms deposits, leading to stiffness and fibrosis. The fibrosis is most prevalent in the skin and lungs. In recent years epigenetic modifications have been uncovered that positively and negatively regulate the genesis of the myofibroblasts and that can be activated and regulated by a variety of cytokines and hormones. The epigenetic contribution to these cells and to SSc is only now really coming to light, and this opens up a new therapeutic target for the disease for which many epigenetic drugs, such as miRNA replacements, are beginning to be developed. This review will examine the epigenetic regulators in the disease and possible targeting of these. [ABSTRACT FROM AUTHOR]

Pattern Recognition Receptors are critical receptors that elicit an immune response upon their activation that culminates in activation of NF-KB and cytokine secretion. Key among these receptors are the Toll-Like Receptors (TLRs). These evolutionary conserved receptors form a key part in the defence against various pathogens and comprise a key part of the innate immune system. Systemic sclerosis is an autoimmune disease in which a breach of tolerance has occurred and leads to fulminant autoimmunity, dysregulated cytokines, pro-fibrotic mediators and activation of fibroblasts leading to fibrosis via collagen deposition. It has become apparent in recent years that the innate immune system and specifically TLRs are important in disease pathogenesis; responding to internal ligands to initiate an innate immune response ultimately leading to release of a variety of factors that initiate and perpetuate fibrosis. This review will examine the recent evidence of TLR signalling in systemic sclerosis and the internal danger associated molecules that may mediate the fibrotic cascade. Evaluation of their contribution to disease in systemic sclerosis and possible therapeutic targeting will be discussed. [ABSTRACT FROM AUTHOR]

Chronic inflammation can lead to altered extracellular matrix deposition and ultimately fibrosis. Interleukin-13 (IL-13) is a cytokine that was found to promote IgE class switching and inhibit proinflammatory cytokines. However, it is now recognized as an important mediator in allergy and most importantly fibrosis. Indeed, animal studies with genetically deleted mice have demonstrated its critical role in fibrosis and although it shares over lapping functions with IL-4 it is the dominant cytokine in fibrosis. Systemic sclerosis is an autoimmune disease in which there is chronic inflammation and fibrosis. The disease is associated with a Th2 polarization and IL-13 levels are elevated both in the blood and in the skin of patients. This review will examine the role of IL-13 in driving fibrosis with a particular emphasis on systemic sclerosis as a prototypical fibrotic disease. It will highlight recent research into the role of IL-13 and how this cytokine may be targeted in systemic sclerosis. © 2013 BioFactors, 39(6):593-596, 2013 [ABSTRACT FROM AUTHOR]

Abstract: Interleukin-6 is a classic pro-inflammatory cytokine needed to mount an effective immune response. It is secreted by a wide array of cell types, however, its target cells are more restricted, due to the fact that very few cells, except lymphocytes and hepatocytes, express the functional membrane IL-6 receptor. This therefore limits the amount of cells that can respond to IL-6. Transsignalling, the shedding of the membrane bound form of the IL-6 receptor (sIL-6R) into the local microenvironment, greatly increases the range of cells that can respond e.g. as part of a wound healing response necessary to restore the homeostatic balance. Therefore, tight regulation of IL-6 signalling must occur to stop an inappropriate wound healing response occurring. This review focusses on the role of IL-6 in inflammation and fibrosing conditions, with a particular emphasis on systemic sclerosis (SSc), a chronic autoimmune disease in which a classical hallmark of fibrosis occurs. This fibrosis, in particular the skin and internal organs, leads to contractures and internal organ failure respectively with potential fatal consequences. In this review we will discuss the biology of IL-6 in the context of fibrosing conditions such as SSc and argue why molecular targeting of IL-6 is a promising therapeutic target. [Copyright &y& Elsevier]

The authors criticize the study by Y. Chen and colleagues regarding the role played by the miR-146a-5p RNA sequences in the activation of hepatic stellate cells (HSC) mediated by Lipopolysaccharide (LPS)/Toll-Like Receptor 4 (TLR4). Topics discussed include the functional significance of miR146a-5p, the benefit of the use of mimic miR-146-5p in liver fibrosis, and the altered levels of chemokines and inflammatory cytokines.

Abstract Systemic sclerosis (SSc) is an idiopathic autoimmune disease characterised by inflammation, vascular problems, cytokine dysregulation and ultimately fibrosis, which accounts for poor prognosis and eventual mortality. At present no curative treatments exist, hence there is an urgent need to better understand the aetiology and develop improved therapies accordingly. Although still widely debated, significant evidence points to upregulation of the innate immune response via the activity of Toll-like receptors (TLRs) and the NLRP3 inflammasome as the start points in a cascade of signaling events which drives excessive extracellular matrix protein production, causing fibrosis. Herein the recent breakthroughs which have implicated TLR signaling and the NLRP3 inflammasome in SSc and the novel therapeutic possibilities this introduces to the field will be discussed. [ABSTRACT FROM AUTHOR]