Biology subjects

Rashighi, M.

Publications and source records attributed to Rashighi, M..

6 recordsLinked to original sources

bioRxiv2026

IFN-κ directs antiviral immunity in human skin

Inducible expression of type I IFNs is a well-established host innate defense mechanism to limit virus infection. Yet, many viruses have evolved strategies to suppress the induction of these cytokines to enhance replication, spread, and transmission between hosts. Whether additional antiviral mechanisms protect against infection when inducible responses are compromised is not well understood. Here, we demonstrate that human keratinocytes preemptively protect the skin against virus infection through constitutive production of IFN-kappa (IFN-{kappa}), a poorly studied type I IFN family member. We find that constitutive IFNK expression protects keratinocytes against skin tropic RNA and DNA viruses, including vesicular stomatitis virus (VSV) and herpes simplex virus-1 (HSV-1). Using a human skin organoid model, we further demonstrate that keratinocyte-derived IFN-{kappa} establishes an antiviral state in dermal fibroblasts. Genetic and chemical analysis of the type I IFN receptor (IFNAR) signaling pathway in monocultured keratinocytes and skin organoids revealed that distinct pathways control VSV and HSV-1 replication. While canonical JAK-STAT signaling provided protection against VSV, HSV-1 infection was controlled through a JAK-STAT-independent mechanism. Using transcriptomic analysis, we further identified an IFN-{kappa}-dependent gene signature in keratinocytes that is not similarly driven by other type I IFNs. Together, this work establishes constitutive IFN-{kappa} production by keratinocytes as a broadly antiviral tissue autonomous defense mechanism.

immunology↗

bioRxiv2025

A Spatially Coordinated Keratinocyte-Fibroblast Circuit Recruits MMP9+ Myeloid Cells to Drive IFN-I-Driven Inflammation in Photosensitive Autoimmunity

Photosensitivity is a hallmark of cutaneous lupus erythematosus (CLE) and dermatomyositis (DM), yet the mechanisms linking ultraviolet B (UVB) exposure to tissue-specific autoimmunity remain incompletely defined. Here, we use an integrative human-based approach, including single-cell RNA sequencing, spatial transcriptomics (seqFISH+), in vivo UVB provocation, and in vitro modeling, to uncover a spatially coordinated inflammatory circuit that underlies interferon-I (IFN-I)-amplified skin pathology. We identify MMP9+ CD14+ myeloid cells as central effectors of photosensitivity in both CLE and DM. These cells are markedly expanded in lesional skin, serve as the dominant source of IFN-{beta}, and colocalize with cytotoxic CD4+ T cells at the dermal-epidermal junction. Spatial transcriptomics further reveals a keratinocyte-fibroblast-myeloid axis, wherein keratinocytes activate discrete subsets of pro-inflammatory fibroblasts in the superficial dermis to produce monocyte-attracting chemokines, including CCL2, CCL19, CCL7, CCL8, and CXCL12, directing MMP9+ CD14+ cell recruitment toward the interface. In our in-vitro model, IFN-I-primed basal keratinocytes undergo heightened UVB-induced cell death and release membrane-associated cytokines such as TNF-, IL-1, which activate monocyte-derived dendritic cells (moDCs) and induce transcriptional programs mirroring those of MMP9+ CD14+ cells in vivo. In vivo, UVB irradiation of non-lesional DM skin, but not healthy controls, elicits rapid infiltration of these myeloid cells, confirming their disease-specific responsiveness to UVB. Finally, in a proof-of-concept clinical study, treatment with anifrolumab (anti-IFN-I receptor) blocked UVB-induced MMP9+ CD14+ infiltration and attenuated photosensitivity in CLE. Together, these findings define a multicellular inflammatory cascade linking keratinocyte injury, fibroblast chemotactic programming, and myeloid effector function in IFN-I-driven skin autoimmunity and nominate MMP9+ CD14+ cells as actionable targets in photosensitive dermatoses. Photosensitivity is central to cutaneous lupus erythematosus (CLE) and dermatomyositis (DM), but the mechanisms linking UVB exposure to tissue-specific autoimmunity are poorly defined. Using single-cell RNA sequencing, spatial transcriptomics, UVB provocation, and in vitro modeling, we identify MMP9+ CD14+ myeloid cells as critical mediators of photosensitivity. These cells expand significantly in lesional skin, produce IFN-{beta}, and colocalize with cytotoxic CD4+ T cells at the dermal-epidermal junction. Keratinocytes activate fibroblasts in the superficial dermis, prompting them to release chemokines (CCL2, CCL19, CCL7, CCL8, CXCL12) that recruit MMP9+ CD14+ cells. IFN-I-primed keratinocytes exposed to UVB release cytokines activating dendritic cells, mirroring in vivo responses. UVB irradiation of non-lesional DM skin rapidly recruits these myeloid cells. In a clinical proof-of-concept study, anti-IFN-I treatment with anifrolumab prevented UVB-induced myeloid infiltration and reduced photosensitivity. Thus, targeting MMP9+ CD14+ cells may offer therapeutic potential for managing photosensitive autoimmune skin conditions.

immunology↗

bioRxiv2025

Endothelial Cell Expression of STINGV154M Gain-of-Function Mutation Delays the Resolution of UVB-induced Skin Injury

Gain-of-function mutations in STimulator of INterferon Genes (STING) cause STING-Associated Vasculopathy with Onset in Infancy (SAVI), a rare autoinflammatory disease characterized by debilitating inflammatory lung disease and hallmark skin manifestations, such as chilblains and progressive, non-healing ulcers. Mice expressing the most common SAVI-associated variant STINGV154M (VM) recapitulate many clinical features of SAVI, including inflammatory lung disease, but do not develop spontaneous skin lesions. In this study, we show that a single low dose of ultraviolet B (UVB) irradiation, which induces only transient skin inflammation in wild-type (WT) mice, causes severe and progressive skin injury in VM mice. Notably, this phenotype persisted in VM mice depleted of hematopoietic cells and reconstituted with WT bone marrow, demonstrating that STINGV154M expression in non-hematopoietic cells is sufficient to drive persistent skin inflammation. Further analysis identified endothelial cells expressing STINGV154M as the primary driver of the cutaneous phenotype. Flow cytometry and bulk RNA sequencing showed that VM mice exhibited reduced early skin infiltration of macrophages and dendritic cells after UVB exposure. These findings establish a critical link between endothelial STING activation, impaired recruitment of skin myeloid cells, and defective resolution of acute inflammation, offering new insights into the pathogenesis of SAVI-associated skin disease.

immunology↗

bioRxiv2025

Spatial Transcriptomics Identifies Immune-Stromal Niches Associated with Cancer in Adult Dermatomyositis

Adult-onset dermatomyositis (DM) is an autoimmune inflammatory myopathy with distinct cutaneous manifestations and a strong malignancy association. Through comparative analysis with cutaneous lupus erythematosus (CLE), our integrated spatial and single-cell transcriptomics analysis revealed unique immune and stromal niches associated with DM subtypes. Unexpectedly, we found an association between cancer-associated DM skin lesions and the presence of dispersed immune infiltrates enriched with macrophages, CD8+ T cells, plasma cells, and B cells with preserved vascular architecture. In contrast, non-cancer associated DM skin exhibited dense myeloid cell infiltrates, including neutrophils, monocytes, and macrophages, with elevated expression of IL1B and CXCL10 localized near injured vascular endothelia. Cytokines produced by these myeloid infiltrates together with local tissue hypoxia triggered dramatic stromal remodeling, leading to loss of vascular-associated fibroblasts. In addition to the CXCL10+ myeloid signature, non-cancer-associated DM skin with pDC presence showed the emergence of specific cellular pairs: PD-L1-expressing mregDCs and activated Tregs expressing NFKB2 and TNF receptors. While both DM and CLE showed strong interferon signatures, DM uniquely displayed IFN-{beta} expression. Together, our study provides the first comprehensive spatial mapping of immune and stromal cells in adult-onset DM.

immunology↗

bioRxiv2024

Spatial characterization of interface dermatitis in cutaneous lupus reveals novel chemokine ligand-receptor pairs that drive disease

BackgroundChemokines play critical roles in the recruitment and activation of immune cells in both homeostatic and pathologic conditions. Here, we examined chemokine ligand-receptor pairs to better understand the immunopathogenesis of cutaneous lupus erythematosus (CLE), a complex autoimmune connective tissue disorder. ObjectivesOur objectives were to (1) characterize the cellular and proteomic constitution of interface dermatitis in CLE using blister biopsies, (2) map chemokine:ligand receptor pairs that govern recruitment of immune cells to form interface dermatitis in CLE, and (3) perform unbiased analyses in tandem on different clinical subtypes to identify novel genes and proteins underlying discoid versus subacute CLE. MethodsWe used suction blister biopsies to measure cellular infiltrates with spectral flow cytometry in the interface dermatitis reaction, as well as 184 protein analytes in interstitial skin fluid using 96-plex immunoassay targeted proteomics. Flow and 96-plex immunoassay data concordantly demonstrated significant increases in T cells and antigen presenting cells (APCs). We also performed spatial transcriptomics and spatial proteomics of punch biopsies using digital spatial profiling (DSP) technology on CLE skin and healthy margin controls to examine discreet locations within the tissue. ResultsSpatial and 96-plex immunoassay data confirmed elevation of interferon (IFN) and IFN-inducible CXCR3 chemokine ligands. Comparing involved versus uninvolved keratinocytes in CLE samples revealed upregulation of essential inflammatory response genes in areas near interface dermatitis, including AIM2. 96-plex immunoassay data confirmed upregulation of Caspase 8, IL-18 which is the final product of AIM2 activation, and induced chemokines including CCL8 and CXCL6 in CLE lesional samples. Chemotaxis assays using PBMCs from healthy and CLE donors revealed that T cells are equally poised to respond to CXCR3 ligands, whereas CD14+CD16+ APC populations are more sensitive to CXCL6 via CXCR1 and CD14+ are more sensitive to CCL8 via CCR2. ConclusionsTaken together, our data map a pathway from keratinocyte injury to lymphocyte recruitment in CLE via AIM2-Casp8-IL-18-CXCL6/CXCR1 and CCL8/CCR2, and IFNG/IFNL1-CXCL9/CXCL11-CXCR3, and identify potential novel biomarkers of disease. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=168 SRC="FIGDIR/small/574422v2_ufig1.gif" ALT="Figure 1"> View larger version (46K): org.highwire.dtl.DTLVardef@1e86dbeorg.highwire.dtl.DTLVardef@7d0208org.highwire.dtl.DTLVardef@1108aa8org.highwire.dtl.DTLVardef@ff255f_HPS_FORMAT_FIGEXP M_FIG C_FIG Model of chemokine systems governing recruitment of immune cell subsets to form interface dermatitis in cutaneous lupus. A. Summary of fresh tissue blister biopsy studies demonstrating increases in HLADR+ cells in nonlesional lupus biopsies as assessed by flow cytometry, and increased CXCL6 and CCL8 as assessed by 96 plex immunoassay. Lesional lupus biopsies also demonstrated significant increases in T cells and CXCL9/10/11 production. B. Model of chemokine-directed formation of interface dermatitis in cutaneous lupus. 1. Whole transcriptome atlas (WTA) digital spatial profiling (DSP) revealed increased AIM2 in keratinocytes proximal to inflammation, which is reported to be induced by environmental triggers including UV light and toxins. We also noted increased Caspase 8 (Casp8) and IL18 at the protein level, which can be induced downstream of AIM2. Chemokines including CXCL6 and CCL8 can be induced downstream of IL18, explaining how CCL8 and CXCL6 might be induced. 2. Recruitment of myeloid cell first responders by CCL8 and CXCL6. CD14+CD16+ myeloid cells, which were recently described in nonlesional lupus skin, express CXCR1 and migrate towards CXCL6, whereas CD14+CD16-myeloid cells express more CCR2 and migrate towards CCL8. 3. The CXCR3 ligands CXCL9/10/11 are expressed by keratinocytes, but more strongly in CD45+ immune cell and T cell regions of interest (ROIs). 4. T cells express CXCR3 and migrate towards CXCL9 and to a greater extent CXCL11. 5. The recruited HLADR+ myeloid populations and T cells contribute to formation of interface dermatitis. Thus, we propose a model in which keratinocyte/myeloid crosstalk can reinforce chemokine systems to optimally recruit lymphocytes and other immune cells to form interface dermatitis. Created with Biorender.com. Plain language summaryLupus skin rashes arise during flares, after exposure to medications or sunlight, or in response to other triggers of inflammation. To understand how white blood cells enter the skin to cause these rashes, we used new technologies to look at proteins that attract them into the skin. We found proteins that are expressed by skin cells in lesions that can recruit specific types of white blood cells that are thought to be the initiators of skin rashes. Once in the skin, these and other white blood cells can make additional proteins that bring in more and more cells. We hope that our findings will be used to test new topical treatments for lupus and other autoimmune skin rashes.

immunology↗

bioRxiv2021

Type I interferon modulates Langerhans cell ADAM17 to promote photosensitivity in lupus

BackgroundThe autoimmune disease lupus erythematosus (lupus) is characterized by photosensitivity, where even ambient ultraviolet radiation (UVR) exposure inflames skin. Beneficial effects of anifrolumab (anti-interferon /breceptor (anti-IFNAR)) on lupus skin disease support a pathogenic role for IFN-I, but mechanistic understanding is limited. We have shown that Langerhans cell (LC) dysfunction contributes to photosensitivity. Healthy LCs act via a disintegrin and metalloprotease 17 (ADAM17) to release epidermal growth factor receptor (EGFR) ligands that limit UVR-induced keratinocyte apoptosis and photosensitivity. However, LC ADAM17 activity is reduced in non-lesional lupus model skin, and data point to reduced LC-mediated protection in human lupus. Here, we asked about the role of the IFN-rich lupus skin environment in LC dysfunction and the implications of this regulation for photosensitivity. MethodsGene expression patterns in non-lesional skin from human lupus and multiple murine models were examined. We used MRL/lpr, B6.Sle1yaa, and imiquimod models of lupus in in vivo studies to assess the role of IFN-I in LC ADAM17 dysfunction and photosensitivity. ResultsWe show a shared IFN-rich environment in non-lesional skin across human and murine model systems, that IFN-I inhibits LC ADAM17 activity, and that anti-IFNAR in lupus models restores LC ADAM17 function and reduces photosensitivity in EGFR and LC ADAM17-dependent manners. Reactive oxygen species (ROS) can mediate ADAM17 activity, and we show reduced LC ROS expression in lupus models that is restored by anti-IFNAR. ConclusionsOur findings suggest that IFN-I promotes photosensitivity by causing LC ADAM17 dysfunction and that anifrolumab ameliorates lupus skin disease at least in part by restoring LC function. This work provides insight into IFN-I-mediated disease mechanisms, LC regulation, and a mechanism of action for anifrolumab in lupus.

immunology↗