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The pathogenesis of systemic lupus erythematosus (SLE) is linked to the differential roles of toll-like receptors (TLRs), particularly TLR7, TLR8, and TLR9. TLR7 overexpression or gene duplication, as seen with the Y-linked autoimmune accelerator (Yaa) locus or TLR7 agonist imiquimod, correlates with increased SLE severity, and specific TLR7 polymorphisms and gain-of-function variants are associated with enhanced SLE susceptibility and severity. In addition, the X-chromosome location of TLR7 and its escape from X-chromosome inactivation provide a genetic basis for female predominance in SLE. The absence of TLR8 and TLR9 have been shown to exacerbate the detrimental effects of TLR7, leading to upregulated TLR7 activity and increased disease severity in mouse models of SLE. The regulatory functions of TLR8 and TLR9 have been proposed to involve competition for the endosomal trafficking chaperone UNC93B1. However, recent evidence implies more direct, regulatory functions of TLR9 on TLR7 activity. The association between age-associated B cells (ABCs) and autoantibody production positions these cells as potential targets for treatment in SLE, but the lack of specific markers necessitates further research for precise therapeutic intervention. Therapeutically, targeting TLRs is a promising strategy for SLE treatment, with drugs like hydroxychloroquine already in clinical use.

There are several autoimmune and rheumatic diseases affecting different organs of the human body. Multiple sclerosis (MS) mainly affects brain, rheumatoid arthritis (RA) mainly affects joints, Type 1 diabetes (T1D) mainly affects pancreas, Sjogren’s syndrome (SS) mainly affects salivary glands, while systemic lupus erythematosus (SLE) affects almost every organ of the body. Autoimmune diseases are characterized by production of autoantibodies, activation of immune cells, increased expression of pro-inflammatory cytokines, and activation of type I interferons. Despite improvements in treatments and diagnostic tools, the time it takes for the patients to be diagnosed is too long, and the main treatment for these diseases is still non-specific anti-inflammatory drugs. Thus, there is an urgent need for better biomarkers, as well as tailored, personalized treatment. This review focus on SLE and the organs affected in this disease. We have used the results from various rheumatic and autoimmune diseases and the organs involved with an aim to identify advanced methods and possible biomarkers to be utilized in the diagnosis of SLE, disease monitoring, and response to treatment.

Tertiary lymphoid structures (TLSs) are formed in tissues targeted by chronic inflammation processes, such as infection and autoimmunity. In Sjögren’s disease, the organization of immune cells into TLS is an important part of disease progression. Here, we investigated the dynamics of tissue resident macrophages in the induction and expansion of salivary gland TLS. We induced Sjögren’s disease by cannulation of the submandibular glands of C57BL/6J mice with LucAdV5. In salivary gland tissues from these mice, we analyzed the different macrophage populations prior to cannulation on day 0 and on day 2, 5, 8, 16 and 23 post-infection using multicolored flow cytometry, mRNA gene analysis, and histological evaluation of tissue specific macrophages. The histological localization of macrophages in the LucAdV5 induced inflamed salivary glands was compared to salivary glands of NZBW/F1 lupus prone mice, a spontaneous mouse model of Sjögren’s disease. The evaluation of the dynamics and changes in macrophage phenotype revealed that the podoplanin (PDPN) expressing CX3CR1 + macrophage population was increased in the salivary gland tissue during LucAdV5 induced inflammation. This PDPN + CX3CR1 + macrophage population was, together with PDPN + CD206 + macrophages, observed to be localized in the parenchyma during the acute inflammation phase as well as surrounding the TLS structure in the later stages of inflammation. This suggests a dual role of tissue resident macrophages, contributing to both proinflammatory and anti-inflammatory processes, as well as their possible interactions with other immune cells within the inflamed tissue. These macrophages may be involved with lymphoid neogenesis, which is associated with disease severity and progression. In conclusion, our study substantiates the involvement of proinflammatory and regulatory macrophages in autoimmune pathology and underlines the possible multifaceted functions of macrophages in lymphoid cell organization.

Periodontitis is a multifactorial inflammatory disease initiated by pathogenic bacteria, such as . Resolvin D1 (RvD1) plays a pivotal role in inflammation resolution. This study aimed to identify the mechanism of the regulatory effects of RvD1 on the inflammatory response of human periodontal ligament cells (hPDLCs). To investigate the mechanism of RvD1's impact on the hPDLCs, RNA-sequencing (RNA-seq) was used and differentially expressed genes (DEGs) were identified. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to assess the signaling pathways in which NF-κB and MAPK were determined to play a significant role. Alterations in NF-κB and MAPK pathways were verified by immunofluorescence (IF), quantitative real-time PCR (qRT-PCR), and Western blotting (WB). The expression of RvD1 and lipoxin A4/formyl peptide receptor 2 (ALX/FPR2) was assessed by IF and WB. Inflammatory cytokine interleukin (IL) 6 and IL-1β release was measured by ELISA. GO and KEGG analyses indicated that RvD1 regulates the inflammatory process in PDLCs primarily via TLR4-MyD88-mediated NF-κB and MAPK signaling. RvD1 suppressed lipopolysaccharide (LPS)-induced TLR4 and MyD88 expression, inhibited phosphorylation of NF-κB p65 and its inhibitor IKBKB, and attenuated phosphorylation of p38 MAPK, ERK, and JNK. ALX/FPR2 was expressed on hPDLCs and was further upregulated upon treatment with RvD1. RvD1 significantly down-regulated the IL-6 and IL-1β levels in LPS-stimulated hPDLCs. RvD1 regulates the inflammatory response of LPS-stimulated hPDLCs by the TLR4-MyD88-MAPK and TLR4-MyD88-NF-κB signaling pathways, suggesting the potential role of RvD1 in restoring periodontal tissue homeostasis by regulating PDLC response to inflammatory and infectious stimuli.

Histology involves the observation of structural features in tissues using a microscope. While diffraction-limited optical microscopes are commonly used in histological investigations, their resolving capabilities are insufficient to visualize details at subcellular level. Although a novel set of super-resolution optical microscopy techniques can fulfill the resolution demands in such cases, the system complexity, high operating cost, lack of multi-modality, and low-throughput imaging of these methods limit their wide adoption for histological analysis. In this study, we introduce the photonic chip as a feasible high-throughput microscopy platform for super-resolution imaging of histological samples. Using cryopreserved ultrathin tissue sections of human placenta, mouse kidney, pig heart, and zebrafish eye retina prepared by the Tokuyasu method, we demonstrate diverse imaging capabilities of the photonic chip including total internal reflection fluorescence microscopy, intensity fluctuation-based optical nanoscopy, single-molecule localization microscopy, and correlative light-electron microscopy. Our results validate the photonic chip as a feasible imaging platform for tissue sections and pave the way for the adoption of super-resolution high-throughput multimodal analysis of cryopreserved tissue samples both in research and clinical settings.

We have previously demonstrated that continuous infusion of low molecular weight (LMW) heparin delays autoantibody production and development of lupus nephritis in (NZBxNZW)F1 (B/W) mice. In this study we investigated the effect of LMW heparin on renal cytokine and chemokine expression and on nucleosome-mediated activation of nucleosome-specific splenocytes. Total mRNA extracted from kidneys of heparin-treated or -untreated B/W mice was analysed by qPCR for the expression of several cytokines, chemokines, and Toll-like receptors. Splenocytes taken from B/W mice were stimulated with nucleosomes with or without the presence of heparin. Splenocyte cell proliferation as thymidine incorporation and the expression of costimulatory molecules and cell activation markers were measured. Heparin treatment of B/W mice reduced the in vivo expression of CCR2, IL1β, and TLR7 compared to untreated B/W mice. Nucleosome-induced cell proliferation of splenocytes was not influenced by heparin. The expression of CD80, CD86, CD69, CD25, CTLA-4, and TLR 2, 7, 8, and 9 was upregulated upon stimulation by nucleosomes, irrespective of whether heparin was added to the cell culture or not. In conclusion, treatment with heparin lowers the kidney expression of proinflammatory mediators in B/W mice but does not affect nucleosomal activation of splenocytes.

The mesangium is a crucial microenvironment in the kidney. It consists of mesangial cells and extracellular matrix that lends structural integrity to the glomerulus and aids renal filtration. The mesangial cells function in a delicate balance of matrix mechanics and chemical cues to engage in matrix formation, cell interactions, and cytokine production. Irregularities such as diabetes disturb this delicate balance leading to declining kidney function and kidney failure. While chemical and molecular studies on mesangium during diabetic kidney disease (DKD) are abundant, little is known about how the changing matrix mechanics affect the mesangial function. Here we demonstrate the co-stimulatory effects of chemical cues and matrix properties within the mesangial niche afflicted with DKD. To avail control of both mechanical and chemical parameters typical of DKD, we used photo-cured gelatin methacryloyl hydrogels to emulate mesangium in different disease stages. We simulated soft and stiff matrices to mechanically match mesangium in healthy and long-term DKD with fibrosis conditions. The mechanical properties play a dominant role over chemical factors in α-smooth muscle actin formation. This coincided with a reduction in mesangial cell processes and motility, crucial for cell interactions. The fibrotic matrix also profoundly influences Collagen IV expression, potentially resulting in a thickened renal basement membrane around capillaries, reducing renal filtration efficiency. The study implies that the mechano-chemical dual input in late-stage DKD causes an accelerated decline in glomerular function. The finding consolidates viable reasoning for therapeutic challenges in late-stage kidney disease and directs future studies to find the missing pieces in understanding kidney disease through such in-vitro pathotypic models.Competing Interest StatementThe authors have declared no competing interest.

Diabetic kidney disease (DKD) is often diagnosed only after irreversible damage, limiting early treatment. The kidney mesangium, a structure highly sensitive to mechanical forces, plays a key role in early fibrosis development, yet its response to early disease cues like stiffness and biochemical changes is poorly understood. This is due to limitations in current in vitro models, poor in vivo accessibility, and static biopsy samples. To address this, we developed a 3D in vitro model of the mesangial microenvironment using stiffness-tunable gelatin methacrylate (GelMA) hydrogels that mimic healthy and fibrotic kidney tissue. Exposing mesangial cells to glucose and TGF-β1 led to altered cell shape, increased dry mass, and elevated expression of fibrotic markers (α-SMA and collagen IV), especially under stiffer conditions, indicating a synergistic effect of biochemical and mechanical stress. These responses were integrated using Gaussian process regression to create a 3D “severity cube” that maps DKD progression across mechanical and chemical inputs. This system quantifies early mesangial transitions and reveals key fibrosis-related mechanisms. By combining organotypic modeling with interpretable inference, our platform offers a predictive tool for early disease stratification and a basis for studying subclinical fibrosis progression in DKD.

Histopathological assessment involves the identification of anatomical variations in tissues that are associated with diseases. While diffraction-limited optical microscopes assist in the diagnosis of a wide variety of pathologies, their resolving capabilities are insufficient to visualize some anomalies at subcellular level. Although a novel set of super-resolution optical microscopy techniques can fulfill the resolution demands in such cases, the system complexity, high operating cost, lack of multimodality, and low-throughput imaging of these methods limit their wide adoption in clinical settings. In this study, we interrogate the photonic chip as an attractive high-throughput super-resolution microscopy platform for histopathology. Using cryopreserved ultrathin tissue sections of human placenta, mouse kidney, and zebrafish eye retina prepared by the Tokuyasu method, we validate the photonic chip as a multi-modal imaging tool for histo-anatomical analysis. We demonstrate that photonic-chip platform can deliver multi-modal imaging capabilities such as total internal reflection fluorescence microscopy, intensity fluctuation-based optical nanoscopy, single-molecule localization microscopy, and correlative light-electron microscopy. Our results demonstrate that the photonic chip-based super-resolution microscopy platform has the potential to deliver high-throughput multimodal histopathological analysis of cryopreserved tissue samples.