Interplay Between Immunity and Fibrosis

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About this Research Topic

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Background

Fibrosis is the result of ongoing and uncontrolled tissue remodeling. There is growing evidence that fibrosis develops as the end-result of a chronic inflammatory process and that both innate and adaptive immune mechanisms are involved. Indeed, in various fibrotic diseases, including for example idiopathic pulmonary fibrosis and hepatic fibrosis, the roles of the innate and adaptive immune system are increasingly recognized. These observations are fueled by clear clinical and histological similarities between these diseases and auto-immune diseases with fibrotic complications, like rheumatoid arthritis and systemic sclerosis. In all these diseases, early events of fibrosis comprise inflammatory changes, including the proliferation of extracellular matrix (ECM)-producing cells and the occurrence of mononuclear inflammatory infiltrates. For example, macrophages have been implicated as important players in inflammatory processes leading to fibrosis. Activated macrophages regulate inflammatory ECM turnover through the release of chemokines, cytokines, and growth factors and can transdifferentiate in myofibroblast-like cells. ECM constituents have been found to activate mononuclear cells and fibroblasts, which in turn induce expression of various cytokines and chemokines, but also trigger the expression and secretion of macrophage-derived matrix metalloproteinases (MMP). Also, cells and cytokines of the adaptive immune system play a prominent role in the initiation and progression of fibrosis. Accumulating evidence supports a role for dendritic cells (DCs) in the pathogenesis of fibrosis, and in a few studies, a specific pathogenetic role of specific autoantibodies has been suggested. Traditionally, Th1 cells are thought to mediate tissue damage, whereas Th2 cells and their corresponding cytokines are linked with fibrogenesis and can directly stimulate both fibroblasts and macrophages.

Fibroblasts, which are traditionally recognized as quiescent cells responsible for ECM production, are more and more appreciated as key modulators of the immune system. This is underbuilt by the fact that the pathophysiology of fibrosis in many fibrotic disorders is similar regardless of the underlying primary disease or affected tissue. Various stimuli released in the course of the underlying diseases cause the secretion of certain cytokines, chemokines, and growth factors by inflammatory cells and activated resident cells that perpetuate inflammation, cause further cell injury and induce fibrotic events, e.g. activation, differentiation and proliferation of fibroblasts as well as increased production of collagen and other ECM proteins. Among the various pro- and anti-fibrotic cytokines, TGF-β isoforms seem to play a key role in the development of fibrosis with cellular actions ranging from anti-inflammatory, and fibroblast chemoattraction to regulation of ECM formation. However, there are still major knowledge gaps on how fibroblasts and immune cells reciprocally influence the pathogenesis of fibrosis. This includes on the one hand how fibroblasts are regulated by components of innate and adaptive immunity and on the other hand how fibroblasts modulate immune cell behavioral using direct cell-to-cell contacts or conditioning of cellular microenvironment by cytokines or other inter-cellular messenger systems.

More recently, the human microbiome has been considered as an important modulator of the immune system since it is directly involved in host defense and in the maturation of the immune system, and modulates the balance between inflammation and immune homeostasis. Recent techniques including high-throughput sequencing technology have enabled in-depth evaluation of the human microbiome. How the microbiome could be of influence in chronic inflammatory processes that consequently lead to fibrosis remains poorly understood.

Lastly, hypoxia is also known as a trigger of tissue fibrosis which can result in excessive scarring and compromised organ function. From this perspective, systemic sclerosis, a severe and incurable auto-immune disease, characterized by the triad of autoimmunity, micro-angiopathy, and fibrosis, can be seen as a paradigm disease to study the interplay between fibrosis and immunity. In this disease, both endothelial damage and immune activation including T cell infiltration in target organs, and induction of disease-related auto-antibodies are among the earliest disease features. There is also some evidence that microvascular endothelial cells themselves could transform into myofibroblasts after injury. The combination of microangiopathy and auto-immunity results in the activation of fibroblasts and uncontrolled fibrosis. How endothelial cell damage, autoimmunity and fibrosis interact is largely unknown.

In summary, a better understanding of the interplay between the immunity and fibrosis on multiple levels could lead to better insight into the mechanisms involved in tissue-specific fibrosis pathways that are modulated by the immune system. This could thereby facilitate the development of therapeutic approaches, including the design of new targeted strategies of immune intervention.

This Research Topic aims to provide an overview and discussions of the recent discoveries of the interplay between immune dysregulation and fibrosis with these main focuses:
1. Innate immunity and fibrosis.
2. Adaptive immunity and fibrosis.
3. Key players including soluble and cellular factors regulating immunity and fibrosis.
4. Fibrotic features in auto-immune diseases.
5. Interplay between microbiome, immune dysregulation and fibrosis.
6. Interplay between vasculopathy, immune dysregulation and fibrosis.

Topic Editor Prof. Oliver Distler received financial support from Actelion, Bayer, Boehringer Ingelheim, Mitsubishi Tanabe Pharma companies. All other Topic Editors declare no competing interests with regards to the Research Topic subject.

Important note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.

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