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Pansclerotic morphea is characterized by IFN-γ responses priming dendritic cell fibroblast crosstalk to promote fibrosis.

ABSTRACT: Pansclerotic morphea (PSM) is a rare, devastating disease characterized by extensive soft tissue fibrosis, secondary contractions, and significant morbidity. PSM pathogenesis is unknown, and aggressive immunosuppressive treatments rarely slow disease progression. We aimed to characterize molecular mechanisms driving PSM and to identify therapeutically targetable pathways by performing single-cell and spatial RNA-Seq on 7 healthy controls and on lesional and nonlesional skin biopsies of a patient with PSM 12 months apart. We then validated our findings using immunostaining and in vitro approaches. Fibrotic skin was characterized by prominent type II IFN response, accompanied by infiltrating myeloid cells, B cells, and T cells, which were the main IFN-γ source. We identified unique CXCL9+ fibroblasts enriched in PSM, characterized by increased chemokine expression, including CXCL9, CXCL10, and CCL2. CXCL9+ fibroblasts were related to profibrotic COL8A1+ myofibroblasts, which had enriched TGF-β response. In vitro, TGF-β and IFN-γ synergistically increased CXCL9 and CXCL10 expression, contributing to the perpetuation of IFN-γ responses. Furthermore, cell-to-cell interaction analyses revealed cDC2B DCs as a key communication hub between CXCL9+ fibroblasts and COL8A1+ myofibroblasts. These results define PSM as an inflammation-driven condition centered on type II IFN responses. This work identified key pathogenic circuits between T cells, cDC2Bs, and myofibroblasts, and it suggests that JAK1/2 inhibition is a potential therapeutic option in PSM.

SUBMITTER: Xing E

PROVIDER: S-EPMC10543736 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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Pansclerotic morphea is characterized by IFN-γ responses priming dendritic cell fibroblast crosstalk to promote fibrosis.

Xing Enze E Ma Feiyang F Wasikowski Rachael R Billi Allison C AC Gharaee-Kermani Mehrnaz M Fox Jennifer J Dobry Craig C Victory Amanda A Sarkar Mrinal K MK Xing Xianying X Plazyo Olesya O Chen Henry W HW Barber Grant G Jacobe Heidi H Tsou Pei-Suen PS Modlin Robert L RL Varga John J Kahlenberg J Michelle JM Tsoi Lam C LC Gudjonsson Johann E JE Khanna Dinesh D

JCI insight 20230822 16

Pansclerotic morphea (PSM) is a rare, devastating disease characterized by extensive soft tissue fibrosis, secondary contractions, and significant morbidity. PSM pathogenesis is unknown, and aggressive immunosuppressive treatments rarely slow disease progression. We aimed to characterize molecular mechanisms driving PSM and to identify therapeutically targetable pathways by performing single-cell and spatial RNA-Seq on 7 healthy controls and on lesional and nonlesional skin biopsies of a patient ...[more]

PMID: 37471168

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Project description:BackgroundInflammatory and immune responses in the brain that contribute to various neuropsychiatric disorders may begin as microglial "priming". Interferon (IFN)-γ is known to cause microglial priming, but the mechanism is unclear.MethodsWe examined the effects of IFN-γ on gene expression, microglial activation, inflammatory and immune responses and activity of the NLRP3 inflammasome in primary microglia and in the brains of mice.ResultsOur results showed that treating microglial cultures with IFN-γ induced a hedgehog-like morphology and upregulated markers of microglial activation (CD86, CD11b) and pro-inflammatory molecules (IL-1β, IL-6, TNF-α, iNOS), while downregulating markers of microglial homeostasis (CX3CR1, CD200R1), anti-inflammatory molecules (MCR1, Arg-1) and neurotrophic factors (IGF-1, BDNF). IFN-γ also upregulated markers of NLRP3 inflammasome activation (NLRP3, caspase-1, gasdermin D, IL-18). This particular transcriptional profiling makes IFN-γ-primed microglia with exaggerated responses upon lipopolysaccharide (LPS) stimulation. The level of NLRP3, caspase-1, gasdermin D, IL-1β, IL-18, TNF-α and iNOS in microglia cultures treated with both IFN-γ and LPS were highest than with either one alone. Injecting IFN-γ into the lateral ventricle of mice induced similar morphological and functional changes in hippocampal microglia as in primary microglial cultures. The effects of IFN-γ on NLRP3 inflammasome and microglia from cultures or hippocampus were abolished when STAT1 was inhibited using fludarabin. Injecting mice with IFN-γ alone or together with LPS induced anxiety- and depression-like behaviors and impaired hippocampus-dependent spatial memory; these effects were mitigated by fludarabin.ConclusionsIFN-γ primes microglia by activating STAT1, which upregulates genes that activate the NLRP3 inflammasome. Inhibiting the IFN-γ/STAT1 axis may be a way to treat neurodegenerative diseases and psychiatric disorders that involve microglial priming.

Project description:BackgroundInterferon-gamma (IFN-gamma) and interleukin-6 (IL-6) are multifunctional cytokines that regulate immune responses, cell proliferation, and tumour development and progression, which frequently have functionally opposing roles. The cellular responses to both cytokines are activated via the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway. During the past 10 years, the crosstalk mechanism between the IFN-gamma and IL-6 pathways has been studied widely and several biological hypotheses have been proposed, but the kinetics and detailed crosstalk mechanism remain unclear.ResultsUsing established mathematical models and new experimental observations of the crosstalk between the IFN-gamma and IL-6 pathways, we constructed a new crosstalk model that considers three possible crosstalk levels: (1) the competition between STAT1 and STAT3 for common receptor docking sites; (2) the mutual negative regulation between SOCS1 and SOCS3; and (3) the negative regulatory effects of the formation of STAT1/3 heterodimers. A number of simulations were tested to explore the consequences of cross-regulation between the two pathways. The simulation results agreed well with the experimental data, thereby demonstrating the effectiveness and correctness of the model.ConclusionIn this study, we developed a crosstalk model of the IFN-gamma and IL-6 pathways to theoretically investigate their cross-regulation mechanism. The simulation experiments showed the importance of the three crosstalk levels between the two pathways. In particular, the unbalanced competition between STAT1 and STAT3 for IFNR and gp130 led to preferential activation of IFN-gamma and IL-6, while at the same time the formation of STAT1/3 heterodimers enhanced preferential signal transduction by sequestering a fraction of the activated STATs. The model provided a good explanation of the experimental observations and provided insights that may inform further research to facilitate a better understanding of the cross-regulation mechanism between the two pathways.

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Pansclerotic morphea is characterized by IFN-γ responses priming dendritic cell fibroblast crosstalk to promote fibrosis.

Publications

Pansclerotic morphea is characterized by IFN-γ responses priming dendritic cell fibroblast crosstalk to promote fibrosis.

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