Ulcerative colitis (UC) is a chronic inflammatory disorder targeting the colon with an increasing global prevalence. The development of the disease involves multiple factors, including genetic susceptibility, impaired epithelial barrier function, abnormal immune reactions, and environmental influences [[1], [2], [3]]. In affected individuals, mucosal inflammation typically begins in the rectum and may progressively spread to other parts of the colon. Common symptoms include bloody diarrhea, and diagnosis relies on colonoscopy and tissue examination. Presently, T helper 17 cells (Th17) are recognized as a major pathogenic factor in UC. Indeed, studies have documented massive infiltration of Th17 in the inflamed intestinal mucosa of UC patients, accompanied by upregulated expression of STAT3 and IL-17 in inflamed colonic tissues relative to normal controls. Concurrently, Treg cells have been implicated in UC pathogenesis, with their anti-colitis function underscored by findings that Treg lacking the IL-10 receptor exhibit heightened susceptibility to colitis. Moreover, ablation of Treg or impairment of TGF-β1 signaling within these cells exacerbates colitis progression [1]. The primary treatment goal for UC is to achieve and sustain remission, characterized by symptom relief and mucosal healing. Therapeutic options consist of 5-aminosalicylic acid medications and immune-modulating drugs [4]. In cases where medication fails or to address cancerous changes, surgical removal of the colon may be necessary. The range of available treatments for UC is growing, and the coming years will likely see a surge in novel targeted therapies [5,6].

Fibroblasts are part of a group of related cells known as “mesenchymal”, and in certain instances, “stromal”. They are closely associated with the body's immunoregulatory processes. Recent single-cell RNA sequencing (scRNA-seq) investigations have systematically documented stromal, epithelial, immune, and various cell populations in both healthy and inflamed intestines. These studies not only provided transcriptome-wide expression patterns for well-established cell types but also identified less-recognized cell populations and functions. For example, repair-related epithelium, different subsets of goblet cells, and the immunoregulatory roles of non-immune cells were discovered. Among these findings, the impact on fibroblasts is particularly significant. The molecular, functional, and phenotypic diversity of fibroblasts has only been recognized recently [[7], [8], [9], [10]]. Moreover, it has been newly understood that during the inflammatory process, fibroblasts can undergo polarization to generate inflammation-associated fibroblasts (IAFs) [11,12]. IAFs have been identified in Crohn's disease and UC biopsies and in mouse models of inflammatory bowel diseases (IBD) and have proposed roles in extracellular matrix (ECM) remodeling, immune recruitment, oxidative tissue damage, and inflammatory cytokine production [13]. Fibroblasts communicate their spatial position to immune cells in circulation by generating surface molecules and factors for recruiting leukocytes [14]. They utilize diverse signaling pathways, and the signals they send can distinctly reveal the nature of the recruited cell population. Beyond their essential function in regulating immune activities in primary and secondary lymphoid organs, tissue-resident fibroblasts display multiple pathophysiological activities during acute inflammation and infection. Upon encountering inflammatory stimuli, these cells generate chemokines, which facilitate the migration of immune cells. In stromal areas, fibroblasts secrete numerous cytokines and can function as antigen-presenting cells. By doing so, they initiate innate and adaptive immune responses, thereby contributing to the proliferation, sustenance, and metabolic adjustment of infiltrating memory T cells [[15], [16], [17]].

The Wnt signaling pathways comprise multiple critical regulatory cascades, categorized into β-catenin-dependent (canonical) and β-catenin-independent (noncanonical) subtypes, both of which exert vital functions in intestinal epithelium homeostasis [[18], [19], [20]]. Comparative studies have revealed dysregulated expression of multiple Wnt ligands and receptors in ulcerative colitis (UC) biopsies relative to healthy controls [21]. Beyond epithelial regulation, Wnt pathway plays a multifaceted part in immune modulation. Canonical Wnt proteins, for instance, modulate T-cell differentiation and effector functions across diverse pathological contexts, including inflammatory bowel disease (IBD), cancer, autoimmune disorders, and viral infections [22]. Furthermore, Wnt signaling contributes considerably to the pathogenesis of inflammatory and fibrotic diseases through crosstalk with other inflammatory cascades, collectively regulating the secretion of inflammatory mediators during colitis development [23]. Reducing the activity of the Wnt signaling pathway may offer a novel therapeutic approach to alleviate the progression of fibrosis in chronic kidney disease [24]. The Sfrp2 gene encodes secreted frizzled-related protein 2 (SFRP2), which is a key regulator and an antagonist of the classical Wnt signaling pathway by inhibiting the binding of Wnt ligands to Frizzled receptors on cell membrane [25]. SFRP2 is closely associated with fibroblasts and immune regulatory functions. SFRP2 in fibroblast-derived exosomes attenuates inflammatory responses by improving macrophage M1/M2 polarization [26,27]. In addition, SFRP2 is also closely related to the infiltration of immune cells such as T cells, macrophages, neutrophils and dendritic cells [28]. A recent study based on single-cell analysis have also found that SFRP2hi odontogenic fibroblasts play an important role in root regeneration and the maintenance of cell stemness [17]. SFRP2hi fibroblasts, which are prominently expressed in dental pulp progenitor cells, play a role in maintaining a fine equilibrium between dormancy and activation. This balance enables efficient tissue repair and regeneration while safeguarding the stem cell reserve.

According to the currently known evidence, in this study, we intended to investigate the role of fibroblastic SFRP2 in exerting immunomodulation in inflammatory diseases. To this end, we generated a novel conditional transgenic mouse with a fibroblast-specific SFRP2 knockout (Sfrp2Col1a2 CKO). Using this conditional fibroblastic SFRP2 knockout mouse, we found that fibroblast-specific Sfrp2 deficiency caused severer damage in mice with DSS-induced colitis, leading to an increased Th17 cell ratio and a decreased Treg cell proportion. Moreover, knockdown of Sfrp2 in murine fibroblasts promoted a pro-inflammatory phenotype. This study will provide a deeper understanding of the functional role of fibroblastic SFRP2 and may hold new promise for the treatment of immune-mediated inflammatory diseases.