Infection and inflammation stimulate expansion of a CD74+ Paneth cell subset to regulate disease progression.

Paneth cells (PCs), a specialized secretory cell type in the small intestine, are increasingly recognized as having an essential role in host responses to microbiome and environmental stresses. Whether and how commensal and pathogenic microbes modify PC composition to modulate inflammation remain unclear. Using newly developed PC-reporter mice under conventional and gnotobiotic conditions, we determined PC transcriptomic heterogeneity in response to commensal and invasive microbes at single cell level. Infection expands the pool of CD74+ PCs, whose number correlates with auto or allogeneic inflammatory disease progressions in mice. Similar correlation was found in human inflammatory disease tissues. Infection-stimulated cytokines increase production of reactive oxygen species (ROS) and expression of a PC-specific mucosal pentraxin (Mptx2) in activated PCs. A PC-specific ablation of MyD88 reduced CD74+ PC population, thus ameliorating pathogen-induced systemic disease. A similar phenotype was also observed in mice lacking Mptx2. Thus, infection stimulates expansion of a PC subset that influences disease progression.

Single-cell transcriptomic analysis reveals that the APP-CD74 axis promotes immunosuppression and progression of testicular tumors.

Testicular tumors represent the most common malignancy among young men. Nevertheless, the pathogenesis and molecular underpinning of testicular tumors remain largely elusive. We aimed to delineate the intricate intra-tumoral heterogeneity and the network of intercellular communication within the tumor microenvironment. A total of 40,760 single-cell transcriptomes were analyzed, encompassing samples from six individuals with seminomas, two patients with mixed germ cell tumors, one patient with a Leydig cell tumor, and three healthy donors. Five distinct malignant subclusters were identified in the constructed landscape. Among them, malignant 1 and 3 subclusters were associated with a more immunosuppressive state and displayed worse disease-free survival. Further analysis identified that APP-CD74 interactions were significantly strengthened between malignant 1 and 3 subclusters and 14 types of immune subpopulations. In addition, we established an aberrant spermatogenesis trajectory and delineated the global gene alterations of somatic cells in seminoma testes. Sertoli cells were identified as the somatic cell type that differed the most from healthy donors to seminoma testes. Cellular communication between spermatogonial stem cells and Sertoli cells is disturbed in seminoma testes. Our study delineates the intra-tumoral heterogeneity and the tumor immune microenvironment in testicular tumors, offering novel insights for targeted therapy. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

CD74 is a functional MIF receptor on activated CD4+ T cells.

Next to its classical role in MHC II-mediated antigen presentation, CD74 was identified as a high-affinity receptor for macrophage migration inhibitory factor (MIF), a pleiotropic cytokine and major determinant of various acute and chronic inflammatory conditions, cardiovascular diseases and cancer. Recent evidence suggests that CD74 is expressed in T cells, but the functional relevance of this observation is poorly understood. Here, we characterized the regulation of CD74 expression and that of the MIF chemokine receptors during activation of human CD4+ T cells and studied links to MIF-induced T-cell migration, function, and COVID-19 disease stage. MIF receptor profiling of resting primary human CD4+ T cells via flow cytometry revealed high surface expression of CXCR4, while CD74, CXCR2 and ACKR3/CXCR7 were not measurably expressed. However, CD4+ T cells constitutively expressed CD74 intracellularly, which upon T-cell activation was significantly upregulated, post-translationally modified by chondroitin sulfate and could be detected on the cell surface, as determined by flow cytometry, Western blot, immunohistochemistry, and re-analysis of available RNA-sequencing and proteomic data sets. Applying 3D-matrix-based live cell-imaging and receptor pathway-specific inhibitors, we determined a causal involvement of CD74 and CXCR4 in MIF-induced CD4+ T-cell migration. Mechanistically, proximity ligation assay visualized CD74/CXCR4 heterocomplexes on activated CD4+ T cells, which were significantly diminished after MIF treatment, pointing towards a MIF-mediated internalization process. Lastly, in a cohort of 30 COVID-19 patients, CD74 surface expression was found to be significantly upregulated on CD4+ and CD8+ T cells in patients with severe compared to patients with only mild disease course. Together, our study characterizes the MIF receptor network in the course of T-cell activation and reveals CD74 as a novel functional MIF receptor and MHC II-independent activation marker of primary human CD4+ T cells.

Macrophage migration inhibitory factor mediates skin aging via CD74: Insights from single-cell and bulk RNA sequencing data.

Cell-cell communication is crucial for regulating signaling and cellular function. However, the precise cellular and molecular changes remain poorly understood in skin aging. Based on single-cell and bulk RNA data, we explored the role of cell-cell ligand-receptor interaction in skin aging. We found that the macrophage migration inhibitory factor (MIF)/CD74 ligand-receptor complex was significantly upregulatedin aged skin, showing the predominant paracrine effect of keratinocytes on fibroblasts. Enrichment analysis and in vitro experiment revealed a close association of the activation of the MIF/CD74 with inflammatory pathways and immune response. Mechanistically, MIF/CD74 could significantly inhibit PPARγ protein, which thus significantly increased the degree of fibroblast senescence, and significantly up-regulated the expression of senescence-associated secretory phenotype (SASP) factors and FOS gene. Therefore, our study reveals that MIF/CD74 inhibits the activation of the PPAR signaling pathway, subsequently inducing the production of SASP factors and the upregulation of FOS expression, ultimately accelerating fibroblast senescence.

CD74 facilitates immunotherapy response by shaping the tumor microenvironment of hepatocellular carcinoma.

BACKGROUND: CD74 is ectopically expressed in many tumors and can regulate tumor immunity. However, there are many gaps in the study of the prognostic value of CD74 expression and immune infiltration in hepatocellular carcinoma (HCC). METHODS: An online tumor database was searched to obtain data on gene/protein expression. Immune infiltration analysis was performed using the Tumor Immune Estimation Resource and Comprehensive Analysis on Multi-Omics of Immunotherapy in Pan-cancer databases. Single-cell data were obtained from the Tissue-specific Gene Expression and Regulation, Single-cell Transcriptomes of Tumor Immune Microenvironment and Tumor Immune Single-cell Hub 2 databases. RESULTS: CD74 was highly expressed in HCC patients. HCC patients with high CD74 expression who consumed alcohol or were negative for hepatitis virus had a better prognosis than patients with low CD74 expression. CD74 was mainly enriched in immune response regulation pathways. Both copy number variations in CD74 and CD74 expression patterns affected the infiltration levels of immune cells. Interestingly, CD74 regulated the differentiation of myeloid cells. CD74 in macrophages and dendritic cells (DCs) forms complex networks with malignant cells and hepatic progenitor cell (HPC)-like cells, respectively. High CD74 expression in HPC-like cells and malignant cells significantly decreased the fraction of C-type lectin domain family 9 A (CLEC9A)-cDC1+ DCs and IL-1B+ macrophages, respectively. Their crosstalk subsequently shaped the tumor microenvironment of HCC, possibly through the CD74-MIF axis. Importantly, patients with high CD74 expression presented higher immune scores and achieved good outcomes after receiving immunotherapy. CONCLUSION: High CD74 expression is associated with the abundance of a variety of immune cell types, mediating interactions among tumor and immune cells and shaping the malignant behavior of HCC. In summary, CD74 may be a hallmark for determining the prognosis and immune cell infiltration levels of HCC patients.

CD74 is associated with inflamed tumor immune microenvironment and predicts responsiveness to PD-1/CTLA-4 bispecific antibody in patients with solid tumors.

INTRODUCTION: Cadonilimab (AK104) is a first-in-class tetravalent bispecific antibody that targets both PD-1 and CTLA-4, showing a manageable safety profile and favorable clinical benefits. This study aimed to identify the biomarkers of clinical response and explore the immune response within the tumor microenvironment upon the AK104 therapy in advanced solid tumors. MATERIAL AND METHODS: Gene expression profiles of paired pre- and post-treatment tumor tissues from twenty-one patients were analyzed. The association of gene expression levels with either clinical efficacy or prognosis was evaluated and subsequently validated with published datasets using log-rank for Kaplan-Meier estimates. Comparative immune profile analyses of tumor microenvironment before and after AK104 treatment were conducted. The visualization of tumor-infiltrating lymphocytes was performed using multiplex immunohistochemistry. The predictive value of CD74 was further validated with protein expression by immunohistochemistry. RESULTS: Baseline CD74 gene expression was associated with favorable patient outcomes (overall survival [OS], HR = 0.33, 95% CI 0.11-1.03, p = 0.0463), which was further confirmed with the published datasets. Tumors with high CD74 gene expression at baseline were more likely to exhibit an immune-inflamed microenvironment. AK104 efficiently enhanced the infiltration of immune cells in the tumor microenvironment. Additionally, high CD74 protein expression (≥ 10% of the tumor area occupied by CD74 stained immune cells) at baseline was associated with better progressive-free survival (HR = 0.21, 95% CI 0.06-0.68, p = 0.0065) and OS (HR = 0.35, 95% CI 0.12-1.08, p = 0.0615). CONCLUSIONS: Our findings demonstrate that CD74 is a promising predictive biomarker for AK104 therapeutic response in advanced solid tumors. Trial registration number NCT03261011.

Traumatic brain injury alters the effects of class II invariant peptide (CLIP) antagonism on chronic meningeal CLIP + B cells, neuropathology, and neurobehavioral impairment in 5xFAD mice.

BACKGROUND: Traumatic brain injury (TBI) is a significant risk factor for Alzheimer's disease (AD), and accumulating evidence supports a role for adaptive immune B and T cells in both TBI and AD pathogenesis. We previously identified B cell and major histocompatibility complex class II (MHCII)-associated invariant chain peptide (CLIP)-positive B cell expansion after TBI. We also showed that antagonizing CLIP binding to the antigen presenting groove of MHCII after TBI acutely reduced CLIP + splenic B cells and was neuroprotective. The current study investigated the chronic effects of antagonizing CLIP in the 5xFAD Alzheimer's mouse model, with and without TBI. METHODS: 12-week-old male wild type (WT) and 5xFAD mice were administered either CLIP antagonist peptide (CAP) or vehicle, once at 30 min after either sham or a lateral fluid percussion injury (FPI). Analyses included flow cytometric analysis of immune cells in dural meninges and spleen, histopathological analysis of the brain, magnetic resonance diffusion tensor imaging, cerebrovascular analysis, and assessment of motor and neurobehavioral function over the ensuing 6 months. RESULTS: 9-month-old 5xFAD mice had significantly more CLIP + B cells in the meninges compared to age-matched WT mice. A one-time treatment with CAP significantly reduced this population in 5xFAD mice. Importantly, CAP also improved some of the immune, histopathological, and neurobehavioral impairments in 5xFAD mice over the ensuing six months. Although FPI did not further elevate meningeal CLIP + B cells, it did negate the ability of CAP to reduce meningeal CLIP + B cells in the 5xFAD mice. FPI at 3 months of age exacerbated some aspects of AD pathology in 5xFAD mice, including further reducing hippocampal neurogenesis, increasing plaque deposition in CA3, altering microgliosis, and disrupting the cerebrovascular structure. CAP treatment after injury ameliorated some but not all of these FPI effects.

Reconstituted CD74+ NK cells trigger chronic graft versus host disease after allogeneic bone marrow transplantation.

Chronic graft-versus-host disease (cGVHD) is the most common long-term complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). The patients with pulmonary cGVHD in particular have a very poor prognosis. NK cells are the first reconstituted lymphocyte subset after allo-HSCT; however, the impact of reconstituted NK cells on cGVHD is unclear. Here, we found allogeneic recipients showed obvious pulmonary cGVHD. Surprisingly, deletion of reconstituted NK cells resulted in maximal relief of pulmonary cGVHD. Mechanistically, reconstituted NK cells with donor profiles modulated the pulmonary inflammatory microenvironment to trigger cGVHD. Reconstituted NK cells secreted IFN-γ and TNF-α to induce CXCL10 production by epithelial cells, which recruited macrophages and CD4+ T cells to the lungs. Then macrophages and CD4+ T cells were activated by the inflammatory microenvironment, thereby mediating lung injury. Through assessment of differences in cellular energy, we found that CD74+ NK cells with high mitochondrial potential and pro-inflammatory activity triggered pulmonary cGVHD. Furthermore, targeted elimination of CD74+ NK cells using the anti-CD74 antibody significantly alleviated pulmonary cGVHD but preserved the CD74- NK cells to exert graft-versus-leukemia (GVL) effects. Data from human samples corroborated our findings in mouse models. Collectively, our results reveal that reconstituted CD74+ NK cells trigger pulmonary cGVHD and suggest that administration of CD74 antibody was a potential therapeutic for patients with cGVHD.

CD74 is a potential biomarker predicting the response to immune checkpoint blockade.

BACKGROUND: Immune checkpoint blockade (ICB) has been improving the patient outcome in multiple cancer types. However, not all patients respond to ICB. Biomarkers are needed for selecting appropriate patients to receive ICB. CD74 is an important chaperone that regulates antigen presentation for immune response. However, the relationship between CD74 expression and ICB response remains elusive. METHODS: The unified normalized pan-cancer dataset was downloaded from the UCSC database. Wilcoxon Rank Sum Rank Tests were used to analyze the expression differences between normal and tumor samples in each tumor type. Then, the prognostic value of CD74 was determined using univariable Cox proportional hazards regression analysis. The STRING database was utilized to construct the protein-protein interaction (PPI) network of CD74 and the signal pathways were analyzed as well. The correlation of CD74 expression with immune cells and immune regulating genes was investigated in the TIMER database. The TIDE framework was utilized to evaluate the relationship between CD74 expression and the response to immunotherapy. Moreover, the localization of CD74 in the tumor immune microenvironment was verified using multiplex immunohistochemistry. Clinically annotated samples from 38 patients with esophageal cancer treated with neoadjuvant chemotherapy combined with ICB were analyzed for CD74 expression using immunohistochemistry. RESULTS: In this study, we investigated the prognostic and predictive value of CD74 in different types of cancer. Compared with normal tissue, the expression of CD74 was higher in tumor tissue in various cancers. High expression of CD74 was associated with improved patient prognosis in the majority of cancers. CD74 and its interacting proteins were mainly enriched in the immune-related pathways. The expression of CD74 was significantly positively correlated with B cells, CD4 T-cells, CD8 T-cells, neutrophils, macrophages and dendritic cells. TIDE analysis showed that tumors with high CD74 expression may have better responses to immunotherapy and improved patient survival. In patients with esophageal cancer who had received ICB, higher intratumoral CD74 expression was associated with improved response to ICB. CONCLUSIONS: The findings of this study suggest that the high expression of CD74 may be a potential predictive biomarker of response to ICB.

The role of macrophage migration inhibitory factor family and CD74 in the pathogenesis of melanoma.

Melanoma is an aggressive tumour with poor prognosis that arises from the malignant transformation of melanocytes. Over the past few decades, intense research into the pathogenesis of melanoma has led to the development of BRAF and immune checkpoint inhibitors, including antibodies against programmed cell death protein 1 (PD-1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4), which have shown clinically significant efficacy. However, some tumours do not respond to these therapies initially or become treatment resistant. Most melanoma tissues appear to possess biological characteristics that allow them to evade these treatments, and identifying these characteristics is one of the major challenges facing cancer researchers. One such characteristic that has recently gained attention is the role of macrophage migration inhibitory factor (MIF) and its receptor CD74. This review outlines the cellular and molecular functions of CD74, MIF and their family of proteins. We then review their roles in tumours based on previous reports, highlight their pathological significance in melanoma and discuss their potential as therapeutic targets.

Single-cell RNA Sequencing Identifies a Novel Subtype of Microglia with High Cd74 Expression that Facilitates White Matter Inflammation During Chronic Cerebral Hypoperfusion.

Vascular dementia (VaD) causes progressive cognitive decline in the elderly population, but there is short of available therapeutic measures. Microglia-mediated neuroinflammation is vigorously involved in the pathogenesis of VaD, but the traditional classification of microglial M1/M2 phenotypes remains restrictive and controversial. This study aims to investigate whether microglia transform into novel subtypes in VaD. Chronic cerebral hypoperfusion (CCH) rat model was constructed to mimic VaD. Microglia were isolated via magnetic-activated cell sorting and analyzed by single-cell RNA sequencing (scRNA-seq) and bioinformatics. The findings inferred from scRNA-seq and bioinformatics were further validated through in vivo experiments. In this study, microglia were divided into eight clusters. The proportion of MG5 cluster was significantly increased in the white matter of the CCH group compared with the Sham group and was named chronic ischemia-associated microglia (CIAM). Immunity- and inflammation-related genes, including RT1-Db1, RT1-Da, RT1-Ba, Cd74, Spp1, C3, and Cd68, were markedly upregulated in CIAM. Enrichment analysis illustrated that CIAM possessed the function of evoking neuroinflammation. Further studies unveiled that Cd74 is associated with the most abundant GO terms involved in inflammation as well as cell proliferation and differentiation. In addition, microglia-specific Cd74 knockdown mediated by adeno-associated virus decreased the abundance of CIAM in the white matter, thereby mitigating inflammatory cytokine levels, alleviating white matter lesions, and improving cognitive impairment for CCH rats. These findings indicate that Cd74 is the core molecule of CIAM to trigger neuroinflammation and induce microglial differentiation to CIAM, suggesting that Cd74 may be a potential therapeutic target for VaD.

Infliximab modifies CD74-mediated lymphatic abnormalities and adipose tissue alterations in creeping fat of Crohn's disease.

BACKGROUND: Lymphatic abnormalities are essential for pathophysiologic changes of creeping fat (CrF) in Crohn's disease (CD). Anti-tumor necrosis factor (TNF) therapy has been proved to alleviate CrF lesions, however, whether it achieves these by remodeling lymphatics is unknown. METHODS: CD74 expression was detected in CrF and uninvolved mesentery of CD patients. Lymphatic functions in vitro were evaluated and lymphatic endothelium barrier were checked by transendothelial electrical resistance (TEER) and FITC-Dextran permeability. Protein level of tight junction and signaling pathways were detected by western blotting. RESULTS: CD74 was upregulated in LECs of CrF and positively correlated with TNF-α synthesis. This was suppressed by IFX administration. In vitro, TNF-α stimulated LECs to express CD74 through NF-κB signaling pathway, and this was rescued by IFX. CD74 downregulation suppressed the abilities of LECs in proliferation, migration and tube formation. Interaction of CD74-MIF impaired LECs' barrier via reducing tight junction proteins in an ERK1/2-dependent manner, which was reversed by CD74 downregulation. Consistently, the CD patients receiving IFX therapy displayed decreased lymphangiogenesis and improved mesenteric lymphatic endothelium barrier, companied with reduced adipocyte size and adipokine levels in CrF. CONCLUSIONS: Anti-TNF therapy could modify pathological changes in CrF by alleviating CD74-mediated lymphatic abnormalities.

Curcumin/pEGCG-encapsulated nanoparticles enhance spinal cord injury recovery by regulating CD74 to alleviate oxidative stress and inflammation.

Spinal cord injury (SCI) often accompanies impairment of motor function, yet there is currently no highly effective treatment method specifically for this condition. Oxidative stress and inflammation are pivotal factors contributing to severe neurological deficits after SCI. In this study, a type of curcumin (Cur) nanoparticle (HA-CurNPs) was developed to address this challenge by alleviating oxidative stress and inflammation. Through non-covalent interactions, curcumin (Cur) and poly (-)-epigallocatechin-3-gallate (pEGCG) are co-encapsulated within hyaluronic acid (HA), resulting in nanoparticles termed HA-CurNPs. These nanoparticles gradually release curcumin and pEGCG at the SCI site. The released pEGCG and curcumin not only scavenge reactive oxygen species (ROS) and prevents apoptosis, thereby improving the neuronal microenvironment, but also regulate CD74 to promote microglial polarization toward an M2 phenotype, and inhibits M1 polarization, thereby suppressing the inflammatory response and fostering neuronal regeneration. Moreover, in vivo experiments on SCI mice demonstrate that HA-CurNPs effectively protect neuronal cells and myelin, reduce glial scar formation, thereby facilitating the repair of damaged spinal cord tissues, restoring electrical signaling at the injury site, and improving motor functions. Overall, this study demonstrates that HA-CurNPs significantly reduce oxidative stress and inflammation following SCI, markedly improving motor function in SCI mice. This provides a promising therapeutic approach for the treatment of SCI.

Increased Expression of CD74 in Atherosclerosis Associated with Inflammatory Responses of Endothelial Cells and Macrophages.

To clarify the relationship between CD74 and atherosclerosis (AS) and the mechanisms in oxidized LDL (ox-LDL)-induced endothelial cell and macrophage injury. Datasets obtained from the Gene Expression Omnibus database are integrated. Differentially expressed genes (DEGs) were obtained using R software. Weighted gene co-expression network analysis (WGCNA) was performed to screen the target genes. The endothelial cell injury model and macrophage foaming model were established using ox-LDL, and CD74 expression was detected by Quantitative reverse transcription PCR (RT-qPCR) and Western blot (WB). Then, after silencing CD74, cell viability and ROS production were measured, and WB detected the expression of p-p38 MAPK and NF-κB. There were 268 DEGs associated with AS, of which CD74 was up-regulated. The turquoise module containing CD74 in WGCNA was positively associated with AS. Cell viability was significantly decreased in the endothelial cell injury and macrophage foaming models, while CD74, ROS production, NF-κB, and p-p38MAPK expression increased (P < 0.05). After silencing CD74, ROS production, NF-κB, and p-p38MAPK expression were decreased and cell viability was higher than the model group (P < 0.05). CD74 is up-regulated in endothelial cell injury and macrophage foaming models and is involved in AS progression via the NF-κB and MAPK signaling pathways.

MIF-Modulated Spinal Proteins Associated with Persistent Bladder Pain: A Proteomics Study.

Bladder pain is a prominent symptom in Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS). We studied spinal mechanisms of bladder pain in mice using a model where repeated activation of intravesical Protease Activated Receptor-4 (PAR4) results in persistent bladder hyperalgesia (BHA) with little or no bladder inflammation. Persistent BHA is mediated by spinal macrophage migration inhibitory factor (MIF), and is associated with changes in lumbosacral proteomics. We investigated the contribution of individual spinal MIF receptors to persistent bladder pain as well as the spinal proteomics changes associated with relief of persistent BHA by spinal MIF antagonism. Female mice with persistent BHA received either intrathecal (i.t.) MIF monoclonal antibodies (mAb) or mouse IgG1 (isotype control antibody). MIF antagonism temporarily reversed persistent BHA (peak effect: 2 h), while control IgG1 had no effect. Moreover, i.t. antagonism of the MIF receptors CD74 and C-X-C chemokine receptor type 4 (CXCR4) partially reversed persistent BHA. For proteomics experiments, four separate groups of mice received either repeated intravesical scrambled peptide and sham i.t. injection (control, no pain group) or repeated intravesical PAR4 and: sham i.t.; isotype IgG1 i.t. (15 µg); or MIF mAb (15 µg). L6-S1 spinal segments were excised 2 h post-injection and examined for proteomics changes using LC-MS/MS. Unbiased proteomics analysis identified and relatively quantified 6739 proteins. We selected proteins that showed significant changes compared to control (no pain group) after intravesical PAR4 (sham or IgG i.t. treatment) and showed no significant change after i.t. MIF antagonism. Six proteins decreased during persistent BHA (V-set transmembrane domain-containing protein 2-like confirmed by immunohistochemistry), while two proteins increased. Spinal MIF antagonism reversed protein changes. Therefore, spinal MIF and MIF receptors mediate persistent BHA and changes in specific spinal proteins. These novel MIF-modulated spinal proteins represent possible new targets to disrupt spinal mechanisms that mediate persistent bladder pain.

Immunohistochemical study of CD74 biomarker in normal and malignant breast tissues.

OBJECTIVE: Aim: To detect the role of CD74 expression in breast carcinoma as a predictive marker for identifying the biological behavior of malignancy in Iraqi women.. PATIENTS AND METHODS: Materials and Methods: The study used technique of immunohistochemistry for detection CD74 protein role in breast cancer, and its expression in breast cancer tissue samples. Samples were collected in Al-Najaf city in Iraq, from Al-Forat Al-Awsat Oncology Center. The study was achieved at the Laboratories of the Faculty of Science in the University of Kufa. Fifty samples of breast cancer tissue, and twenty controls benign tissue were included in the study. The study has investigated relationship between expression of biomarker with grade, age of patient and tumor size. RESULTS: Results: The study showed that the cytoplasmic expression of CD74 with more clear and intensive staining in the cytoplasm, and reported that CD74 positivity rate was 52%. A significant association between CD74 expression and grade and size of tumor, so CD74 can be considered as a biomarker for prediction of breast cancer in women. No association was found between CD74 expression and each of patients' age and node metastasis. CONCLUSION: Conclusions: The study represents an important step in our region because there are a few studies about this topic; more efforts are required to approve the function of this biomarker.

Tumor Necrosis Factor α-Dependent Lung Inflammation Promotes the Progression of Lung Adenocarcinoma Originating From Alveolar Type II Cells by Upregulating MIF-CD74.

Lung adenocarcinoma is the most common type of lung cancer. We recently reported that inflammation-driven lung adenocarcinoma (IDLA) originates from alveolar type (AT)-II cells, which depend on major histocompatibility complex (MHC) class II to promote the expansion of regulatory T cells. The MHC class II-associated invariant chain (CD74) binds to the macrophage migration inhibitory factor (MIF), which is associated with promoting tumor growth and invasion. However, the role of MIF-CD74 in the progression of lung adenocarcinoma and the underlying mechanisms remain unclear. We aimed to explore the role of MIF-CD74 in the progression of lung adenocarcinoma and elucidate the mechanisms by which tumor necrosis (TNF)-α-mediated inflammation regulates CD74 and MIF expression in IDLA. In human lung adenocarcinoma, CD74 was upregulated on the surface of tumor cells originating from AT-II cells, which correlated positively with lymph node metastasis, tumor origin/nodal involvement/metastasis stage, and TNF-α expression. MIF interaction with CD74 promoted the proliferation and migration of A549 and H1299 cells in vitro. Using a urethane-induced IDLA mouse model, we observed that CD74 was upregulated in tumor cells and macrophages. MIF expression was upregulated in macrophages in IDLA. Blocking TNF-α-dependent inflammation downregulated CD74 expression in tumor cells and CD74 and MIF expression in macrophages in IDLA. Conditioned medium from A549 cells or activated mouse AT-II cells upregulated MIF in macrophages by secreting TNF-α. TNF-α-dependent lung inflammation contributes to the progression of lung adenocarcinoma by upregulating CD74 and MIF expression, and AT-II cells upregulate MIF expression in macrophages by secreting TNF-α. This study provides novel insights into the function of CD74 in the progression of IDLA.

Extracellular MIF, but not its homologue D-DT, promotes fibroblast motility independently of its receptor complex CD74/CD44.

Macrophage migration inhibitory factor (MIF) and its homologue D-dopachrome tautomerase (D-DT) are widely expressed pro-inflammatory cytokines with chemokine-like functions that coordinate a wide spectrum of biological activities, such as migration. Here, we biotin-tagged intracellular MIF/D-DT in vivo to identify important cytosolic interactors and found a plethora of actin cytoskeleton-associated proteins. Although the receptor complex between CD74 and CD44 (CD74/CD44) is essential for signalling transduction in fibroblasts via extracellular MIF/D-DT, our interactome data suggested direct effects. We, thus, investigated whether MIF/D-DT can modulate cell migration independently of CD74/CD44. To distinguish between receptor- and non-receptor-mediated motility, we used fibroblasts that are either deficient or that express CD74/CD44 proteins, and treated them with recombinant MIF/D-DT. Interestingly, only MIF could stimulate chemokinesis in the presence or absence of CD74/CD44. The pro-migratory effects of MIF depended on lipid raft/caveolae-mediated but not clathrin-mediated endocytosis, on its tautomerase activity and, probably, on its thiol protein oxidoreductase activity. As MIF treatment restrained actin polymerisation in vitro, our findings establish a new intracellular role for MIF/D-DT in driving cell motility through modulation of the actin cytoskeleton.

Decoding meningioma heterogeneity and neoplastic cell-macrophage interaction through single-cell transcriptome profiling across pathological grades.

BACKGROUND: Analyzing meningioma of distinct pathological types at the single-cell level can provide new and valuable insights into the specific biological mechanisms of each cellular subpopulation, as well as their vital interplay within the tumor microenvironment. METHODS: We recruited patients diagnosed with four distinct types of meningioma and performed single-cell RNA sequencing on their tumor samples, concurrently analyzing a publicly available dataset for comparison. Next, we separated the cells into discrete clusters and identified their unique identities. Using pseudotime analysis, we demonstrated cellular differentiation and dynamics. To investigate biological function, we employed weighted gene co-expression network analysis, gene regulatory network, and gene set enrichment analysis. Additionally, we conducted cell-cell communication analyses to characterize interactions among different clusters and validated a crucial interaction using multiple immunofluorescence staining. RESULTS: The single-cell transcriptomic profiles for five meningioma of different pathological types demonstrated that neoplastic cells exhibited high inter-sample heterogeneity and diverse biological functions featured by metabolic regulation. A small cluster of neoplastic cells (N5 cluster, < 3%) was most proliferative, indicated by high expression of MKI67 and TOP2A. They were primarily observed in our atypical and transitional meningioma samples and located at the beginning of the pseudotime differentiation branch for neoplastic cells. Macrophages, the most abundant immune cells present, showed two distinct developmental trajectories, one promoting and the other suppressing meningioma growth, with the MIF-CD74 interaction serving as the primary signaling pathway for MIF signals in the tumor environment. Unexpectedly, despite its small cluster size, the N5 cluster demonstrated a significant contribution in this interaction. By staining pathological sections of more samples, we found that this interaction was widely present in different types of meningiomas. CONCLUSIONS: Meningioma neoplastic cells' diverse types cause inter-sample heterogeneity and a wide range of functions. Some proliferative neoplastic cell may educate macrophages, which promotes tumorigenesis possibly through the MIF-CD74 interaction. It provides novel clues for future potential therapeutic avenues.

Anti-CD74 IgA antibodies show diagnostic potential for axial spondyloarthritis but are not associated with microscopic gut inflammation.

OBJECTIVES: Gut inflammation commonly occurs in axial SpA (axSpA), and is linked to disease activity and outcome. Given the role of IgA in mucosal immunity, we explored the association between anti-CD74 IgA antibodies, gut inflammation and axSpA. METHODS: Anti-CD74 IgA was measured by ELISA in serum samples of axSpA patients, fulfilling the 2009 Assessment of SpondyloArthritis international Society classification criteria. A group of fibromyalgia (FM) and RA patients served as non-inflammatory and inflammatory controls. Newly diagnosed axSpA patients underwent ileocolonoscopy; mucosal biopsies were histopathologically assessed as normal, acute or chronically inflamed. Optimal anti-CD74 IgA cut-off values were determined with a receiver operating characteristics curve. RESULTS: axSpA patients (n = 281) showed higher anti-CD74 IgA levels [mean (s.d.) 18.8 (12.4) U/ml] compared with 100 FM patients [10.9 (5.0) U/ml, P < 0.001] and 34 RA patients [13.7 (9.6) U/ml, P = 0.02]. The area under the receiver operating characteristics curve for diagnosis (axSpA vs FM) was 0.70, providing a sensitivity of 60% and specificity of 87% (cut-off 15 U/ml). Antibody concentrations were not significantly different between axSpA patients with (n = 40) and without (n = 69) gut inflammation (P = 0.83), yielding an area under the receiver operating characteristics curve of 0.51. Anti-CD74 IgA levels were not associated with degree of bone marrow oedema on MRI of the sacroiliac joints, CRP or any other disease-specific feature such as the use of NSAIDs or biological treatment. CONCLUSION: Serum anti-CD74 IgA is a potentially useful diagnostic biomarker for axSpA. However, antibody levels do not correlate with any phenotypical feature, including microscopic gut inflammation, suggesting this to be a disease-specific rather than an inflammatory marker.