Fibroblasts exhibit phenotypic and functional heterogeneity in chronic inflammatory diseases, but how these changes impact immune outcomes remains poorly understood. We identified that a fibroblast po...

Staphylococcus aureus is a major human pathogen that can elicit immune-inflammatory responses and infections, largely driven by its broad repertoire of antigenic proteins. Understanding these factors is valuable for elucidating mechanisms of infection.MethodFifty-two recombinant S. aureus antigen proteins were individually applied to cultured human dermal fibroblasts (HDFs). Following antigen stimulation of confluent HDFs (52 antigens + 44 controls; in 3 replicate plates), host protein responses were quantified using Olink inflammation, cardiovascular II, and III proteomic platforms. Data were analyzed using unsupervised clustering, differential expression analysis, and correlation network modeling to identify patterns of immune-inflammatory signals.ResultsUnsupervised analysis identified 3 distinct host-response clusters, with concordant separation observed across hierarchical clustering (Ward.D2) and t-distributed stochastic neighbor embedding (t-SNE) projection. These clusters can be broadly defined as a cytotoxic/inflammatory antigen cluster (Cluster_1), enriched for key virulence factors (eg, HlgA, Atl.1, SasG.2) and characterized by marked upregulation of inflammatory mediators (including IL-6, IL-8, CXCL1, and CCL3). An immune modulation/surface protein cluster (Cluster_2), comprising adhesins and immune-evasion proteins (eg, Chp, SSL11, Atl.2), was associated with selective upregulation of AXIN1, IL-33, and DECR1. A small outlier antigen cluster (Cluster_4), consisting of LuKE and SdrD.1, did not exhibit a clearly defined host-response profile. Differential expression analysis identified 12 core host proteins—including COL1A1, CXCL1, CXCL16, DLK-1, GLO1, IGFBP-1, IL33, IL6, IL8, MCP-1, TNF, and TRAIL-R2—with consistent and significant changes across clusters (false discovery rate [FDR]-adjusted P < .01).ConclusionsThis preliminary study suggests that S. aureus antigen proteins trigger a coordinated immune-inflammatory cascade in HDFs.

Read the full paper: Single nucleus transcriptomics reveals ITGA8-driven fibroblast remodeling in rheumatic valvular atrial fibrillation

Systemic sclerosis (SSc) is an autoimmune disease of unknown aetiology characterised by vasculopathy with progressive fibrosis of the skin and internal organs. Tissue fibrosis is driven by activated fibroblasts (myofibroblasts) with exacerbated contractile and secretory properties. We previously reported that the long non-coding RNA HOTAIR is a key driver of SSc fibroblast activation. HOTAIR interacts with the chromatin modifiers, the polycomb repressor complex (PRC2) and coREST complex, promoting expression of pro-fibrotic genes. In this study, we show that acute activation of dermal fibroblasts from healthy subjects or SSc patients with transforming growth factor-β and other fibrotic stimuli requires the activity of the lysine-specific demethylase 1 (LSD1) subunit of the co-REST complex. Unexpectedly, LSD1 catalytic activity plays a minor role in fibrotic gene expression in HOTAIR-overexpressing fibroblasts and in maintenance of the stable myofibroblast phenotype of SSc fibroblasts. However, silencing of LSD1 in SSc fibroblasts has a profound effect on pro-fibrotic gene expression, supporting a non-canonical scaffolding function. Our study shows for the first time an essential non-canonical role for LSD1 in pro-fibrotic gene expression in SSc; however, given that this function is insensitive to LSD1 inhibitors, the therapeutic opportunities will depend on future identification of a targetable mediator.

The presence of tertiary lymphoid structures (TLSs) associates with improved anti-tumor immunity, and as such, understanding why some tumors develop TLSs is of prime interest. In the current issue of Cancer Cell, Kirschstein et al. demonstrate that TGFβ-driven programming of myofibroblastic cancer-associated fibroblasts blocks reticular fibroblast differentiation and TLS formation in pancreatic cancer, a barrier reversible by TGFβR1 inhibition.

Thyroid eye disease (TED) is characterized by fibroblast-driven inflammation and extracellular matrix expansion, which contribute to orbital congestio…

Introduction Pain in patients with rheumatoid arthritis (RA) is an unmet clinical need. Targeting joint inflammation with disease modifying antirheumatic drugs (DMARDs) has not resulted in the anticip...

Prostate cancer (PC) progression and mortality are largely driven by therapeutic resistance, increasingly linked to dynamic tumor&#8211;stroma interactions. However, the molecular basis of cancer&#8211;fibroblast crosstalk remains incompletely understood, particularly the contribution of Interleukin (IL)-30, an emerging regulator of PC aggressiveness. Here, we demonstrate that IL30 produced by PC cells reprograms stromal fibroblasts via IL6R&#945;/gp130 signaling, activating AKT and TGF-&#946;/BMP pathways to drive their proliferation and differentiation into pro-angiogenic cancer-associated fibroblasts (CAFs). Reciprocally, these fibroblasts amplify IL30-mediated tumor aggressiveness by enhancing oncogenic transcriptional programs and by promoting cancer cell migration. Notably, while fibroblast co-culture suppresses epithelial-mesenchymal transition (EMT)-associated genes in PC cells, including NOTCH1, SNAI1/2 and ZEB1, IL30 overexpression overrides this effect, inducing EMT regulato

Introduction Diabetic foot ulcers are open wounds with impaired wound closure at the bottom of the foot. Although diabetic plantar skin is stiffer, which should enhance fibroblast mechanotransduction, fibroblasts still fail to migrate effectively. This suggests impaired wound closure is driven by another factor; hyperglycemia (&#8805;11.1 mM glucose), which alters fibroblast mechanotransduction. Purpose To mimic diabetic foot ulcers by developing a 2D circular in vitro wound closure model system to investigate fibroblast mechanoresponses under diabetic plantar skin stiffness and hyperglycemia. Methods Polydimethylsiloxane was used as a substrate, fabricated at 57 kPa and 90 kPa for normal and diabetic plantar skin stiffnesses, respectively. Cell culture media contained a 5.5 mM glucose concentration simulating normal blood glucose or an altered 11.1 mM glucose concentration simulating hyperglycemia. Results Time-lapse fluorescent imaging of wound assays reveals a restrictive effect of

Read the full paper: Lipid‐Driven OLR1/FOXM1/FGF19 Axis Orchestrates Crosstalk in an Epithelial‐Fibroblast Positive Feedback Promoting Progesterone Resistance in Endometrial Cancer

Idiopathic pulmonary fibrosis (IPF), a chronic interstitial lung disease, is characterized by progressive fibrosis and poor prognosis, with no current therapies capable of reversing the fibrotic changes. The aberrant repair driven by fibroblast activation and an inflammatory microenvironment results in irreversible IPF. In this work, a macrophage-derived apoptotic body delivery system (SA&#8201;+&#8201;NAC@AB) co-loaded with sodium arsenite (SA) and N-acetylcysteine (NAC) was developed to exert synergistic antifibrotic activity against IPF via coordinated regulation of TGF-&#946;1 signaling and inflammation. Apoptotic bodies derived from macrophages inherit inflammation-homing capability, enabling targeted delivery to fibrotic lesions. In vivo evaluation in a bleomycin-induced IPF mouse model demonstrated that SA&#8201;+&#8201;NAC@AB effectively targeted the lungs, significantly improved body weight and survival, and alleviated pulmonary fibrosis. Immunofluorescence and Western blot an

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Single-cell transcriptomics of arteriovenous fistulas reveal that failure is likely driven less by smooth muscle proliferation than by continuous inflammation, endothelial dysfunction, and fibroblast-...