The Role of Fibroblast Subsets in Immune-mediated Inflammatory and Fibrotic Diseases

Immune-mediated inflammatory diseases (IMIDs) encapsulate a range of disorders with varied tissue tropism such as rheumatoid arthritis (RA), primary Sjögren’s syndrome, Inflammatory bowel disease(IBD), and psoriasis. Despite the diverse presentation of IMIDs, immune dysfunction and erroneous inflammation are common features of this grouping, exemplified by the utilization of cytokine signaling pathways, or cytokine hubs. TNFα is a cytokine common to the pathology of many IMIDs, the targeting of which has shown therapeutic efficacy in RA, IBD (ulcerative colitis and Crohn’s disease), psoriasis and psoriatic arthritis. However, not all pathways are shared: targeting IL-17, IL-23, and IL-6 has shown therapeutic effect in psoriatic arthritis/axial spondylitis, IBD, and RA respectively. The prominent involvement of cytokines emphasizes the immune aspect of IMIDs and the involvement of leukocytes. However, stromal cells have also been shown to drive the pathogenesis and persistence of IMIDs, with the role of fibroblasts coming to prominence as the diversity of fibroblast populations has been uncovered using single-cell sequencing technologies. In synovitis, discrete fibroblast subsets mediate distinct functions with joint damage and inflammation elicited by distinct populations. Fibrotic diseases, such as systemic sclerosis (SSc) and group of interstitial lung diseases (ILD), exhibit variable immune cell dysfunctions while being characterized by a global dysregulation of the stromal cell compartment (fibroblasts, myofibroblasts) leading to tissue fibrosis. Fibrotic diseases can affect almost every tissue or organ, including skin, heart, and lungs, and are associated with high morbidity and premature mortality, while lacking efficient therapeutic strategies. Single-cell multiomics studies have uncovered specific subsets of SSc-associated skin fibroblasts that exhibit morphological and molecular perturbations and underlie diseas development. Recent work found both commonality and divergence in fibroblast subsets across tissues and disease with pan-tissue populations displaying a progenitor or inflammatory phenotype across tissues and other populations displaying tissue specificity.

With recent advances in single-cell sequencing technologies and complementary highly multiplexed spatial assays, the granularity at which cellular constituents of tissues during health and disease can be investigated has greatly increased. Additionally, new methods of analysis allow greater interpretation and comparison between datasets. These developments have resulted in the discovery of diverse subsets of fibroblasts within each tissue providing a prime opportunity to understand the diversity, commonality, and development of fibroblasts in IMIDs and fibrotic diseases. Understanding which fibroblast populations are shared across tissues and IMIDs/fibrotic diseases, which are discrete, and the function of each population offers the potential of discovering new therapeutic targets or repurposing from other indications, for both tissue-agnostic and precision therapies.

This research topic will provide an understanding of fibroblast biology across IMIDs and fibrotic diseases focusing on commonalities and differences between diseases. Themes that will be addressed include:
- In depth characterization of fibroblast subsets in specific IMIDs and fibrotic diseases
- Integration of datasets to allow the comparison of fibroblast subsets across tissue and disease
- Discovery of drivers/signaling pathways/transcription factors key to distinct fibroblast populations
- Investigation of fibroblast communication with leukocytes and contribution to pathogenesis
- Innovative bioinformatic methods furthering understanding of fibroblast populations in IMIDs.

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