Background/Purpose: Systemic sclerosis (SSc) is an autoimmune, fibroinflammatory disease of skin and visceral organs. Current SSc therapies have limited efficacy for progressive fibrosis. Our prior work showed that LIF receptor (LIFR, a member of the IL-6 receptor superfamily) and its ligand LIF were expressed by synovial fibroblasts in rheumatoid arthritis and amplified pathogenic inflammation. We hypothesized that the fibroblast LIF/LIFR axis also drives fibrotic pathobiology in SSc.

Methods: We applied three 10x Genomics platforms (single-cell, Visium CytAssist spatial, and Xenium spatial transcriptomics (curated genes)) and immunofluorescence staining (IF) to explanted lung and skin biopsies from patients with SSc interstitial lung disease(ILD). We examined a published, plasma proteomic dataset of SSc-ILD patients with longitudinal follow-up. Primary lung fibroblast cell lines from control and SSc-ILD lung tissue were used for in vitro studies. Our experimental model of murine SSc (lung, skin, esophageal fibrosis) used intraperitoneal bleomycin (2x/week for 4 weeks). For testing LIFR in vivo, we compared fibroblast-specific Lifr-deficient mice (Pdgfra-CreERT2+/- Lifr flox/flox and Col1a2-CreERT+/- Lifr flox/flox mice) to Lifr+/+ sibling controls. To therapeutically silence Lifr, we administered lipid nanoparticles (LNP) with siLifr payload i.v. from day 7-28 after bleomycin initiation and assessed tissue at day 33.

Results: Xenium spatial analysis of SSc-ILD lungs (N&#3f4) found LIFR+ and LIF+ fibroblasts enriched in inflammatory, interstitial spatial niches in regions of lung injury and fibrosis. The LIF+LIFR+ spatial niches were colocalized with myofibroblast-enriched spatial niches. Using IF, we validated the enrichment of LIF+LIFR+ fibroblasts in “leading edge” regions of fibrosis in both SSc-ILD lung (N&#3f12) and SSc skin (N&#3f6) tissue. Plasma LIFR level was higher in SSc-ILD patients with progressive fibrosis compared to stable disease (N&#3f72).We moved to in vitro and in vivo studies to understand the function of LIFR. SSc-ILD lung fibroblasts had increased constitutive expression of LIF in vitro; stimulation with TGFβ further increased LIF expression in SSc, but not in control fibroblasts. Silencing LIFR with siRNA suppressed collagen expression in SSc-ILD lung fibroblasts following in vitro profibrotic stimuli (IL-4, IL-13, or TGFβ). LIFR also drove increased expression of IL-6 and IL-8 in SSc-ILD lung fibroblasts following stimulation with IL-1β and TNFα. In the murine model of SSc, mice with fibroblast-specific Lifr deletion had reduced lung,skin, and esophageal fibrosis compared to Lifr+/+ control. Therapeutic intervention with LNP-siLifr reduced lung and skin fibrosis in a murine model of SSc.

Conclusion: A LIF/LIFR autocrine circuit drives both inflammatory and fibrogenic programs in SSc skin and lung fibroblasts. Targeting LIFR in a murine model of SSc reduced organ fibrosis. LIFR is a candidate therapeutic target for SSc.

Spatial transcriptomic analysis, re-analysis of multi-omics datasets, and validation studies using immunofluorescence staining, in vitro assays, and animal model revealed fibroblast LIFR as an amplifier of organ fibrosis and inflammation in SSc.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/spatial-transcriptomics-show-fibroblast-lif-receptor-drives-fibrosis-in-systemic-sclerosis/