Objective: To analyze the correlation between serum macrophage migration inhibitory factor (MIF) and cognitive impairment after stroke, as well as its relationship with serum inflammatory factors. Methods: Stroke patients in our hospital from September 2022 to June 2023 were included as the research subjects. They were divided into the control group (without cognitive impairment, n = 43) and the observation group (with cognitive impairment, n = 51) based on whether cognitive impairment occurred. The levels of serum factors and cognitive functions of the two groups were compared, the multiple factors influencing cognitive impairment after stroke were analyzed, and the correlation between the level of serum macrophage MIF and cognitive impairment or inflammatory factors was explored. Results: The levels of serum tumor necrosis factor -α (TNF-α), interleukin-6 (IL-6), and MIF were lower, while the scores of the Montreal Cognitive Scale (MoCa) and the Mini-Mental State Examination (MMSE) were higher in the control group than in the observation group (p < 0.05). Combined diabetes, hypertension, hyperlipidemia, TNF-α, IL-6, and MIF were risk factors affecting cognitive impairment after stroke (p < 0.05). MIF was negatively correlated with both MoCA and MMSE scores (p < 0.05), and positively correlated with the levels of TNF-α and IL-6 (p < 0.05). Conclusion: The levels of serum TNF-α, IL-6 and MIF have a certain correlation with cognitive impairment in stroke patients, the abnormal increase of which is a risk factor affecting the occurrence of cognitive impairment in stroke patients. Early detection of serum levels of TNF-α, IL-6 and MIF in patients can effectively prevent the occurrence of cognitive impairment and improve the prognosis of patients.

Aberrant proteostasis in alveolar type 2 epithelial cells (AEC2s) contributes to idiopathic pulmonary fibrosis (IPF), but the role of the ubiquitin-proteasome system (UPS) is unclear. Here, we show that UPS disruption in AEC2s amplifies profibrotic signaling to macrophages through macrophage migration inhibitory factor (MIF) family proteins in several models. Modeling UPS disruption with an AEC2-specific cullin 3 (Cul3) deletion produced spontaneous fibrosis in a physiological aging mouse model and exacerbated fibrosis in the bleomycin-induced lung injury model. This was accompanied by expansion of transitional epithelial states and increased MIF and MIF-2 in lung tissue and bronchoalveolar lavage fluid (BALF) in the model. Global or conditional AEC2-specific deletions of Mif or Mif-2 attenuated fibrosis in the bleomycin-treated mouse model, as did conditional deletions of Cd74, the cognate receptor for MIF and MIF-2, in C-X3-C motif chemokine receptor 1 (Cx3cr1)-expressing and platelet factor 4 (Pf4)-expressing cells. Pharmacological inhibition of MIF attenuated fibrosis in bleomycin-treated and transforming growth factor-β1 (TGFB1) transgenic mouse models and in ex vivo human precision-cut lung slices treated with fibrotic cocktail. In study participants with IPF, BALF MIF was elevated compared with that in study participants without IPF. In participants with IPF, BALF MIF greater than 4000 picograms per milliliter was associated with increased mortality compared with participants with IPF with lower MIF. Together, these findings define a UPS-sensitive epithelial-macrophage signaling connection and identify MIF-CD74 cross-talk as a potential therapeutic target in fibrotic lung disease.

Integration of scRNA-seq and bulk RNA-seq reveals that macrophage ferroptosis inhibits MSC osteogenic differentiation in inflammatory microenvironments.

Targeting Cellular Senescence in Dystrophin-/-/Utrophin-/-Double Knockout Mice Improves Musculoskeletal Health and Increases Lifespan.

Macrophage migration inhibitory factor (MIF) is broadly produced by various cell types, particularly immune cells, and functions as a key modulator of innate and adaptive immunity. Increasing evidence has linked MIF to the pathogenesis of both solid tumors and hematologic malignancies, including chronic lymphocytic leukemia (CLL). We previously showed that the global deletion of Mif in the TCL1 transgenic mouse model for CLL significantly delayed disease development leading to longer overall survival of the knockout mice. In this study, we demonstrated that adaptive transfer of murine CLL cells failed to establish disease in Mif-deficient recipients due to impaired homing of leukemic cells into the spleens, indicating that host-derived Mif is essential for leukemic infiltration and expansion. To identify the most relevant source of Mif in CLL, we generated two CLL mouse strains with B-lymphoid- or myeloid-lineage-specific Mif deletion. In contrast to the global Mif knockout, neither conditional Mif knockout significantly altered CLL progression, illustrating that the cellular source of Mif is less critical than its systemic presence in the tissue environment.

Lung adenocarcinoma (LUAD), a predominant subtype of non-small cell lung cancer (NSCLC), is characterized by a complex tumor microenvironment (TME) that drives immune evasion and contributes to variable clinical outcomes. This study investigates the role of tumor-derived macrophage migration inhibitory factor (MIF) on immune modulation and prognosis in LUAD. Single-cell RNA sequencing (scRNA-seq) data from three LUAD tumors (E-MTAB-6149; 29,936 cells) were analyzed with Seurat to identify cell types and marker genes. Cell-cell communication was assessed using CellChat, and prognostic significance was evaluated in the TCGA-LUAD cohort with GEPIA2. Malignant cells showed the highest expression of MIF, which may interact with CD74 + CXCR4 + and CD74 + CD44 + receptor complexes on B cells, T cells, and myeloid cells, consistent with known MIF-mediated signaling pathways. A predominant B cell subset (59%) expressing CD74 or CXCR4 (termed as MIFR+ B cells) showed elevated expression of MHC class II genes (such as HLA-DRA and HLA-DPB1) and co-stimulatory genes (such as CD40 and CD83), indicating antigen-presenting cell (APC)-like functions. High MIF expression was associated with a poor prognosis in TRU-subtype LUAD [hazard ratio (HR)=2.5, p-value=0.029], while MIFR+ B cell signatures was correlated with improved survival. Tumor-derived MIF is associated with poor prognosis, likely by suppressing the immune system, but it also promotes the induction of APC-like B cells, which are associated with improved outcomes, highlighting its dual role in LUAD. These findings position MIF as a potential therapeutic target and suggest that MIFR+ B cells could serve as important prognostic markers.

Obacunone inhibits RIPK1/RIPK3/MLKL-mediated necroptosis by suppressing mitochondrial ROS and MIF signaling in intestinal ischemia-reperfusion injury.

Background Intracranial aneurysms (IAs) develop and progress through pathological processes, including inflammation and abnormal changes in the vascular structure. The cytokine Macrophage Migration Inhibitory Factor (MIF) is implicated in the pathology of vascular diseases. However, the role of MIF in IAs remains to be elucidated. Methods Transcriptomic data from IA and normal arteries were analyzed to quantify MIF expression and immune infiltration (CIBERSORT). Methylation sequencing assessed MIF promoter methylation. Single-cell RNA sequencing (scRNA-seq) defined secretory vascular smooth muscle cell (sVSMC) and M1-like macrophage proportions and MIF expression. Intercellular communication via the MIF-CD74 axis was evaluated using CellChat. In vitro functional experiments validated sVSMC-induced macrophage M1 polarization mechanisms. Results MIF mRNA was significantly upregulated in IAs (diagnostic AUC = 0.89) and correlated with increased M1-like macrophage infiltration (r = 0.783, p = 0.008). Hypomethylation of MIF was observed in IAs. scRNA-seq revealed expanded secretory VSMCs and M1-like macrophages, with elevated MIF in secretory VSMCs. CellChat confirmed enhanced MIF-CD74 signaling. In vitro , secretory VSMCs induced M1 polarization (iNOS/CD86↑, Arg1↓) via MIF-CD74; this effect was reversed by MIF knockdown or CD74 inhibition. Conclusion We provide a comprehensive single-cell atlas of IAs and identify the sVSMC-derived MIF-CD74 axis as a novel mechanism driving macrophage M1 polarization and IA inflammation. This uncovers previously unrecognized sVSMC-macrophage crosstalk, establishing the MIF-CD74 axis as a promising immunomodulatory target for IA therapy.

The progression of Parkinson's disease (PD) is closely associated with neuroinflammatory responses and microglial activation. Consequently, research targeting microglia-mediated neuroinflammation has garnered increasing attention. Macrophage migration inhibitory factor (MIF), a multifunctional cytokine, is implicated in neurodegenerative pathologies, including PD. However, its precise regulatory mechanisms in PD-associated microglial activation and neuroinflammatory cascades remain incompletely characterized. In this study, we observe that MIF exacerbates the pathogenesis of PD through its pro-inflammatory effect, and downregulation of MIF could ameliorate motor behavior deficits, attenuate neuroinflammation, and protect midbrain dopamine (DA) neurons in PD mice. Mechanistically, MIF downregulation attenuates neuroinflammation and exerts neuroprotection against microglia-induced neuronal injury and degeneration by regulating the TLR4/MyD88/TRAF6 signaling axis. In conclusion, this study elucidates the pivotal role of MIF in regulating neuroinflammation associated with PD, suggesting that MIF may be a potential therapeutic target for intervening in PD progression, and providing new strategies for PD treatment.

Chemokines-induced infiltration of leukocytes into damaged tissues following spinal cord injury (SCI) profoundly influences the neuropathology and neurological functional recovery. Astrocytes are among the primary cell types rapidly activated to produce various chemokines immediately after SCI. However, the molecular mechanisms regulating the expression of astrocytic chemokines, particularly the inflammation-related chemokine C-C motif ligand 7 (CCL7), remain elusive. D-dopachrome tautomerase (D-DT, also known as MIF-2), a member of the macrophage migration inhibitory factor (MIF) family, has been shown to deteriorate the inflammatory milieu and worsen neurological outcomes following SCI. In this study, CCL7 was dramatically induced in astrocytes following SCI and contributed to the accumulation of microglia/macrophages at lesion sites. Invitro experiments demonstrated that astrocyte-derived CCL7 significantly promoted microglia/macrophages migration through coupling with chemokine C-C motif receptor 2 (CCR2). Blocking of CCL7 with a neutralizing antibody or administering a CCR2 inhibitor substantially ameliorated tissue damage and promoted locomotor recovery. Further mechanistic investigation revealed that the D-DT/CD74 axis enhanced astrocytic CCL7 production by activating the MAPKs/NF-κB and IL-6/STAT3 signaling pathways. Treatment with the D-DT pharmacological inhibitor 4-CPPC reduced astrocytic CCL7 production and consequently limited microglia/macrophages accumulation at lesion sites after SCI. These findings uncover a novel regulatory pathway for astrocyte-derived CCL7 production and highlight its detrimental role in neurological recovery, which might provide new clues for clinical treatment of neuroinflammation after SCI.

Abstract BACKGROUND One mechanism of immunosuppression in the glioblastoma (GBM) microenvironment involves systemic and local accumulation of myeloid-derived suppressor cells (MDSCs) that inhibit cytotoxic immune cell populations and contribute to immune suppression. GBM patients have increased circulating MDSCs compared to lower grade glioma patients, and GBM patients with a better prognosis have reduced MDSCs in their tumors as well as in their peripheral circulation. A trial (NCT02669173) performed at the Cleveland Clinic demonstrated that pre-surgical anti-MDSC therapy (capecitabine) was associated with reduced circulating MDSCs and increased cytotoxic immune infiltration in tumor tissue. This proof-of-principle pilot study demonstrated that targeting MDSCs in patients can attenuate tumor-induced immunosuppression. Subsequent work at the Cleveland Clinic demonstrated that MDSCs require dipeptidyl peptidase 4 (DPP-4) for entry into the brain and overall MDSC function. Screening for a DPP-4 inhibitor identified sitagliptin as a good inhibitor with limited toxicity with efficacy in pre-clinical models. HYPOTHESIS treating GBM patients with sitagliptin will deplete circulating MDSCs and reduce their entry into the brain, reversing systemic and intratumoral immunosuppression. To test this hypothesis, we plan a “window of opportunity” clinical trial to evaluate the safety and biological impact of sitagliptin treatment in patients with recurrent grade 4 glioma undergoing clinically indicated surgical resection. For this trial, we will randomize 48 patients: 36 will receive pre- and post-operative treatment with sitagliptin and 12 will receive post-operative sitagliptin alone. All patients will receive post-operative sitagliptin and chemotherapy until disease progression. Primary endpoint: Difference in tumor CD8+ T cell count between the participants randomized to pre-surgical sitagliptin versus the participants randomized to no pre-surgical treatment. Secondary endpoints: PFS6, OS12, safety. Exploratory endpoints: peripheral and intratumoral immune profiling for assessment of TAMs, MDSCs, and CD8+ T cells; tumor radiomic features on MRI brain pre-surgery predictive of intratumoral and peripheral CD8+ T cell count and peripheral MDSC levels; peripheral blood cytokine and immune gene expression profiling for increase in immune activation signatures;

Macrophage migration inhibitory factor (MIF) is one of several pivotal cytokines that contribute to orchestrate immune regulation, inflammation, and cell survival, acting as both a mediator of host defense and a factor that viruses can exploit. This comprehensive review delineates MIF's multifaceted roles across diverse viral families-including Retroviridae, Herpesviridae, Hepadnaviridae, Orthomyxoviridae, Flaviviridae, Paramyxoviridae, and Picornaviridae-highlighting the mechanisms by which viruses manipulate MIF signaling to promote replication, evade immune responses, and induce tissue damage. Viral strategies often involve upregulating MIF expression or leveraging its receptor pathways, such as CD74, CXCR2, and CXCR4, to enhance viral persistence, disrupt barrier integrity, and skew immune polarization toward pro-viral or immunosuppressive states. Conversely, MIF-driven inflammation can worsen pathogenic processes, including cytokine storms, neuroinvasion, and fibrosis, contributing to disease severity. Notably, pharmacologic inhibition of MIF has shown promise in preclinical models, reducing viral replication and mitigating tissue damage, thereby positioning MIF as one of the compelling targets for host-directed antiviral therapies. Understanding the complex, context-dependent functions of MIF in viral infections provides transformative insights for innovative treatment strategies that aim to disrupt virus-host interactions, control inflammation, and improve clinical outcomes in infectious diseases. Future research exploring MIF's molecular interactions, genetic variations, and therapeutic modulation will be crucial for harnessing its potential for personalized, effective antiviral interventions.

Background: Myocardial ischemia-reperfusion (IR) injury exacerbates cardiomyocyte death following acute myocardial infarction. Macrophage migration inhibitory factor (MIF) is a redox-sensitive cytokine and atypical chemokine known to exert context-dependent cardioprotective effects. The mechanisms are incompletely understood. We hypothesized that recombinant MIF (moMIF), when administered at reperfusion, may mitigate myocardial injury by scavenging neutrophil-derived reactive oxygen species (ROS) / hypochlorous acid (HOCl), a major oxidative effector of reperfusion injury, despite MIF’s effect on neutrophil attraction and its promoting effect on neutrophil priming. Methods: Human neutrophil chemotaxis was quantified using a 3D μ-Slide chamber following stimulation with MIF (40 nM), oxidized MIF (noxMIF, 40 nM) or HOCl (100 nM). Migration was quantified by forward migration index (FMI). In parallel, male C57BL/6N mice (n=18) underwent 60 min left anterior descending (LAD) coronary occlusion followed by 48 h of reperfusion. Mice received intravenous phosphate buffer (control), mouse MIF (moMIF), or noxMIF (10 μg) 5 min before reperfusion. Myocardial infarct size (IS) and area at risk (AAR) were determined by Evans blue/TTC staining. Data were analyzed by one-way ANOVA with Bonferroni post-hoc correction. Results: MIF significantly enhanced neutrophil migration (FMI 0.16±0.05 vs. control 0.02±0.02, P =0.0257), while, similar to HOCl control, noxMIF lacked chemotactic activity (FMI 0.03±0.05, P >0.9999; FMI -0.06±0.09, P =0.2090). In vivo , moMIF markedly reduced IS/AAR (39.23% ± 9.5%) compared to control (65.44% ± 14.03%, P =0.041). noxMIF did not confer protection (55.48% ± 7.6%, P =0.620 vs. control; P =0.056 vs. moMIF). Conclusions: These findings identify moMIF as a dual-function cardioprotective agent when administered at reperfusion: it protects cardiomyocytes from IR damage, but also recruits neutrophils and enhances their HOCl production capacity. Our current data comparing the capacities of MIF vs noxMIF on neutrophil migration and cardiac IR damage in vivo , collectively identify noxMIF formation as a ROS/HOCl scavenging mechanism that also serves to limit the inflammatory recruitment response. Targeting MIF-ROS/HOCl interactions may represent a novel translational strategy to attenuate myocardial reperfusion injury.

Colorectal cancer (CRC) remains a significant global health burden, mainly due to late diagnosis and chemotherapy resistance. Macrophage migration inhibitory factor (MIF), a proinflammatory cytokine associated with tumor progression, has emerged as a promising biomarker in CRC. However, its clinical utility is limited by the lack of rapid and accessible detection methods. In this study, we report an electrochemical immunotechnology for the sensitive and selective quantification of MIF protein in CRC tissue samples. By combining magnetic microparticles (MMPs), antibody-based recognition, horseradish peroxidase (HRP) labeling, and amperometric transduction at disposable screen-printed carbon electrodes (SPCEs), the developed methodology displayed a linear dynamic range from 0.24 to 20 ng mL−1, enabling quantification across clinically relevant MIF levels, and achieving a low limit of detection (0.07 ng mL−1). In addition, the developed method is the only one reported for MIF assembled on MMPs and addresses its determination in a relevant oncological scenario (paired non-tumoral (NT) and tumoral (T) tissues from individuals diagnosed with CRC at different stages of the disease). The analysis, requiring only 100 ng of tissue extract, allowed efficient discrimination between NT and T paired tissues, and successfully differentiated between healthy, early (I–II) and advanced (III–IV) CRC stages, achieving these results in just 105 min.

Celmods potently inhibit m-MDSC induction by targeting IL-10 and MIF in multiple myeloma

Single-cell and spatial transcriptomics analyses decipher malignant B cell heterogeneity and immunosuppressive microenvironment in primary central nervous system lymphoma

The macrophage migration inhibitory factor (MIF) family of cytokines comprised of the MIF and D-dopachrome tautomerase (or MIF-2) paralogs share identical tertiary and quaternary structures that contribute to their overlapping enzymatic and signaling activities. Recent investigations of MIF and MIF-2 have shown them to possess N-to-C-terminal allosteric crosstalk, but despite the similarity of this "allosteric pathway," its regulation of MIF and MIF-2 is not identical. Thus, structure alone does not preserve the precise allosteric mechanism, and additional residues that modulate MIF and MIF-2 function must be characterized. Cysteines have been identified as allosteric switches for the same biochemical functions of MIF, and small molecules targeting its N-terminal enzymatic site have affected the structure of three proximal cysteines. Ebselen is a compound that forms covalent selenylsulfide bonds with MIF cysteines and is hypothesized to destabilize and dissociate the MIF trimer into monomers. Ebselen-bound MIF also displays little-to-no catalysis or biological signaling. However, it is unclear whether Ebselen similarly affects the MIF-2 paralog, despite MIF-2 containing two related cysteines (MIF contains three). We used mutagenesis, nuclear magnetic resonance, molecular dynamics simulations, in vitro and in vivo biochemistry to investigate the mechanism of Ebselen as a modulator of MIF-2 via its cysteines. Our findings suggest that Ebselen partially disrupts the MIF-2 homotrimer, though the overall population of such a structure is <35%, even on the timescale of many hours. Ebselen does attenuate the biological functions of MIF-2, and solution structural biology captures the conformational transitions preceding the destabilized MIF-2 trimer.

Abstract Description Cytokines and chemokines orchestrate immune responses to recognize and eliminate pathogens, but pathogens, like human cytomegalovirus (HCMV), exploit these pathways. HCMV, a herpesvirus that establishes lifelong latent infection, encodes cmvIL-10, an ortholog of human interleukin-10 that binds the cellular IL-10 receptor (cIL-10R), exerting immunosuppressive effects such as reduced inflammatory cytokine production and impaired dendritic cell activation. Notably, cmvIL-10 also enhances host CXCR4 signaling. CXCR4, a key chemokine receptor, mediates cell migration toward its primary ligand, CXCL12 (SDF-1). In monocytes and epithelial cells co-expressing cIL-10R and CXCR4, cmvIL-10 significantly increased calcium mobilization and migration to CXCL12. We further evaluated whether cmvIL-10 could amplify responses to other CXCR4 ligands, including macrophage migration inhibitory factor (MIF), trefoil factor family 2 (TFF2), and extracellular ubiquitin (UB). UB, MIF and TFF2 signaling triggered significant cell proliferation, and these responses were much greater in the presence of cmvIL-10. MIF and TFF2 also stimulated migration that was enhanced by cmvIL-10. These findings highlight the complex crosstalk between cytokine and chemokine signaling, underscoring HCMV’s ability to manipulate host immunity. A deeper understanding of these mechanisms is essential for developing effective vaccines and therapeutics. Funding Sources This project was funded by Biology Faculty Development Funds and the Research Enhancement Program at TWU (JVS). We also thank the Jane Nelson Institute for Women’s Leadership for support for KHS. Topic Categories Cytokines and Chemokines and Their Receptors (CCR)

Caffeic acid reduces Toxoplasma gondii proliferation in human extravillous trophoblast cells (HTR8/SVneo) through induction of pro-inflammatory cytokines and a death process suggestive of apoptosis.

Neoadjuvant gemcitabine plus nab-paclitaxel (AG) is increasingly applied in pancreatic ductal adenocarcinoma (PDAC), yet its effects on the tumor microenvironment (TME) remain incompletely defined. By integrating eight single-cell RNA sequencing datasets and nine multicenter transcriptomic cohorts, the dual impact of AG in PDAC is delineated. AG shifts residual malignant cells from basal toward a more indolent classical phenotype and remodels the TME into a more heterogeneous and intricate landscape. Specifically, AG activates tumor-associated mast cells (TAMCs), reprogrammes myofibroblastic cancer-associated fibroblasts (myCAFs) into inflammatory CAFs (iCAFs), and enhances suppressive crosstalk between TAMCs, iCAFs, and T cells via the macrophage migration inhibitory factor (MIF) axis. Concurrently, AG reduces exhausted T cells and regulatory T cells while enriching cytotoxic natural killer T cells, reshaping the immune milieu in a manner potentially favorable for immunotherapy. In orthotopic and subcutaneous PDAC models, genetic ablation of TAMCs using KitW-sh mice or pharmacologic stabilization using sodium cromoglycate and the MIF antagonist ISO-1 synergistically improves AG efficacy, with further benefit observed upon addition of anti-PD-1 therapy. These findings reveal a previously unrecognized mechanism of AG therapy-induced immunosuppression and nominate TAMCs-MIF signaling as a tractable target to optimize neoadjuvant strategies in PDAC.