Inflammatory responses, like all biological cascades, are shaped by a delicate balance between positive and negative feedback loops. It is now clear that in addition to positive and negative ...checkpoints, the inflammatory cascade rather unexpectedly boasts an additional checkpoint, a family of chemicals that actively promote resolution and tissue repair without compromising host defense. Indeed, the resolution phase of inflammation is just as actively orchestrated and carefully choreographed as its induction and inhibition. In this review, we explore the immunological consequences of omega-3-derived specialized proresolving mediators (SPMs) and discuss their place within what is currently understood of the role of the arachidonic acid-derived prostaglandins, lipoxins, and their natural C15-epimers. We propose that treatment of inflammation should not be restricted to the use of inhibitors of the acute cascade (antagonism) but broadened to take account of the enormous therapeutic potential of inducers (agonists) of the resolution phase of inflammation.
Cytokine-mediated pathways are central to the pathogenesis of rheumatoid arthritis (RA). The purpose of this short Opinion article is to briefly overview the roles of cytokine families in the various ...phases and tissue compartments of this disease. In particular, we consider the combinatorial role played by cytokines in mediating the overlapping innate and adaptive immune responses associated with disease onset and persistence, and also those cytokine pathways that, in turn, drive the stromal response that is critical for tissue localization and associated articular damage. The success of cytokine inhibition in the clinic is also considerable, not only in offering remarkable therapeutic advances, but also in defining the hierarchical position of distinct cytokines in RA pathogenesis, especially IL-6 and TNF. This hierarchy, in turn, promises to lead to the description of meaningful clinical endotypes and the consequent possibility of therapeutic stratification in future.
Fibroblasts are known for their ability to make and modify the extracellular matrix. However, there is more to them than meets the eye. It is now clear that they help define tissue microenvironments ...and support immune responses in organs. As technology advances, we have started to uncover the secrets of fibroblasts. In this Essay, we present fibroblasts as not only the builders and renovators of tissue environments but also the rheostat cells for immune circuits. Although they perform location-specific functions, they do not have badges of fixed identity. Instead, they display a spectrum of functional states and can swing between these states depending on the needs of the organ. As fibroblasts participate in a range of activities both in health and disease, finding the key factors that alter their development and functional states will be an important goal to restore homeostasis in maladapted tissues.
Cells called fibroblasts can boost health yet also drive disease. Cell-lineage analysis has unveiled the first comprehensive atlas of fibroblasts from various healthy and diseased tissues, a result ...that has major clinical implications.
In chronic infection, inflammation and cancer, the tissue microenvironment controls how local immune cells behave, with tissue-resident fibroblasts emerging as a key cell type in regulating ...activation or suppression of an immune response. Fibroblasts are heterogeneous cells, encompassing functionally distinct populations, the phenotypes of which differ according to their tissue of origin and type of inciting disease. Their immunological properties are also diverse, ranging from the maintenance of a potent inflammatory environment in chronic inflammation to promoting immunosuppression in malignancy, and encapsulating and incarcerating infectious agents within tissues. In this Review, we compare the mechanisms by which fibroblasts control local immune responses, as well as the factors regulating their inflammatory and suppressive profiles, in different tissues and pathological settings. This cross-disease perspective highlights the importance of tissue context in determining fibroblast-immune cell interactions, as well as potential therapeutic avenues to exploit this knowledge for the benefit of patients with chronic infection, inflammation and cancer.
The identification of lymphocyte subsets with non-overlapping effector functions has been pivotal to the development of targeted therapies in immune-mediated inflammatory diseases (IMIDs)
. However, ...it remains unclear whether fibroblast subclasses with non-overlapping functions also exist and are responsible for the wide variety of tissue-driven processes observed in IMIDs, such as inflammation and damage
. Here we identify and describe the biology of distinct subsets of fibroblasts responsible for mediating either inflammation or tissue damage in arthritis. We show that deletion of fibroblast activation protein-α (FAPα)
fibroblasts suppressed both inflammation and bone erosions in mouse models of resolving and persistent arthritis. Single-cell transcriptional analysis identified two distinct fibroblast subsets within the FAPα
population: FAPα
THY1
immune effector fibroblasts located in the synovial sub-lining, and FAPα
THY1
destructive fibroblasts restricted to the synovial lining layer. When adoptively transferred into the joint, FAPα
THY1
fibroblasts selectively mediate bone and cartilage damage with little effect on inflammation, whereas transfer of FAPα
THY1
fibroblasts resulted in a more severe and persistent inflammatory arthritis, with minimal effect on bone and cartilage. Our findings describing anatomically discrete, functionally distinct fibroblast subsets with non-overlapping functions have important implications for cell-based therapies aimed at modulating inflammation and tissue damage.
Metabolomic studies of body fluids show that immune‐mediated inflammatory diseases such as rheumatoid arthritis (RA) are associated with metabolic disruption. This is likely to reflect the increased ...bioenergetic and biosynthetic demands of sustained inflammation and changes in nutrient and oxygen availability in damaged tissue. The synovial membrane lining layer is the principal site of inflammation in RA. Here, the resident cells are fibroblast‐like synoviocytes (FLS) and synovial tissue macrophages, which are transformed toward overproduction of enzymes that degrade cartilage and bone and cytokines that promote immune cell infiltration. Recent studies have shown metabolic changes in both FLS and macrophages from RA patients, and these may be therapeutically targetable. However, because the origins and subset‐specific functions of synoviocytes are poorly understood, and the signaling modules that control metabolic deviation in RA synovial cells are yet to be explored, significant additional research is needed to translate these findings to clinical application. Furthermore, in many inflamed tissues, different cell types can forge metabolic collaborations through solute carriers in their membranes to meet a high demand for energy or biomolecules. Such relationships are likely to exist in the synovium and have not been studied. Finally, it is not yet known whether metabolic change is a consequence of disease or whether primary changes to cellular metabolism might underlie or contribute to the pathogenesis of early‐stage disease. In this review article, we collate what is known about metabolism in synovial tissue cells and highlight future directions of research in this area.
Immune-regulatory mechanisms of drug-free remission in rheumatoid arthritis (RA) are unknown. We hypothesized that synovial tissue macrophages (STM), which persist in remission, contribute to joint ...homeostasis. We used single-cell transcriptomics to profile 32,000 STMs and identified phenotypic changes in patients with early/active RA, treatment-refractory/active RA and RA in sustained remission. Each clinical state was characterized by different frequencies of nine discrete phenotypic clusters within four distinct STM subpopulations with diverse homeostatic, regulatory and inflammatory functions. This cellular atlas, combined with deep-phenotypic, spatial and functional analyses of synovial biopsy fluorescent activated cell sorted STMs, revealed two STM subpopulations (MerTK
TREM2
and MerTK
LYVE1
) with unique remission transcriptomic signatures enriched in negative regulators of inflammation. These STMs were potent producers of inflammation-resolving lipid mediators and induced the repair response of synovial fibroblasts in vitro. A low proportion of MerTK
STMs in remission was associated with increased risk of disease flare after treatment cessation. Therapeutic modulation of MerTK
STM subpopulations could therefore be a potential treatment strategy for RA.
Abstract One of the most important but as yet unanswered questions in inflammation research is not why inflammation occurs (we all get episodes of self limiting inflammation during the course of our ...lives) but why it does not resolve. Current models of inflammation stress the role of antigen-specific lymphocyte responses and attempt to address the causative agent. However, recent studies have begun to challenge the primacy of the leukocyte and have instead focused on an extended immune system in which stromal cells, such as fibroblasts play a role in the persistence of the inflammatory lesion. In this review I will illustrate how fibroblasts help regulate the switch from acute resolving to chronic persistent inflammation and provide positional memory during inflammatory responses. In chronic inflammation the normal physiological process of the removal of unwanted inflammatory effector cells becomes disordered, leading to the accumulation of leucocytes within lymphoid aggregates that resemble those seen in lymphoid tissue. I will describe how fibroblasts provide survival and retention signals for leukocytes leading to their inappropriate and persistent accumulation within inflamed tissue.
Inflammation and the repair of damaged tissues are regulated by immune cells called macrophages. The finding that they form a layer that shields mouse joints from damage has implications for the ...treatment of arthritis.
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