Inflammation
Abstract
Increased consumption of ultra-processed foods (UPFs) is a risk factor for metabolic disorders-associated heart failure (HF). Here, we demonstrate that UPF-induced calpain-1 aggravated oxidative stress, thereby increasing high mobility group box 1 (HMGB1)-mediated myocardial inflammation, which contributes to cardiac dysfunction. After illustrating the dysregulated inflammatory pathways in human and murine hearts upon metabolic stress, we revealed an increase in calpain-1 alongside profound oxidative stress and inflammation in the failing myocardium. Mechanistically, in neonatal rat cardiomyocytes (NRCMs) and human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), HMGB1 was upregulated by calpain-1 and reactive oxygen species (ROS) upon stress of saturated and trans fatty acids (FA). Consequently, HMGB1 promoted a pro-inflammatory response in macrophages. On the contrary, inhibition of calpain or ROS efficiently repressed HMGB1 in cardiomyocytes. Therapeutically, either recombinant adeno-associated virus 9 (AAV9) delivered inhibitor of calpain-1 or its pharmacological inhibitor attenuated ROS and HMGB1-induced inflammation in the myocardium and mitigated HF in both male and female mice fed with an ultra-processed diet (UPD). Collectively, we have demonstrated the effects of suppressing calpain-1 and oxidative stress on alleviating myocardial inflammation via blockage of HMGB1 and cardiac dysfunction. The results provide a promising therapeutic strategy for preventing or treating HF in metabolic disorders.
Authors
Claire Ross, Sanskruti Ravindra Gare, Nasser H. Alatawi, Oveena Fonseka, Xinyi Chen, Jiayan Zhang, Yihua Han, Andrea Ruiz-Velasco, Riham R.E. Abouleisa, Yingjuan Liu, Xiangjun Zhao, Han Xiao, Bernard Keavney, Gareth J. Howell, Tao Wang, Tamer M.A. Mohamed, Elizabeth J. Cartwright, Wei Liu
Abstract
Although inflammatory complications are common in preterm infants, the effects of these conditions on neonatal immune development remain poorly defined. We therefore investigated whether severe bronchopulmonary dysplasia (BPD) and systemic infection, two major complications of prematurity, produce distinct immune signatures and change immune composition over time. We performed longitudinal high-dimensional immune profiling of residual whole blood from 38 preterm infants sampled every two weeks, along with 10 term infants at birth. Preterm infants with severe BPD showed a progressive increase in Th17-polarized CD4+ T cells, neutrophils, and Th17-related cytokines compared to age-matched infants with moderate BPD. In contrast, some preterm infants with systemic bacterial or viral infections mounted exceptionally robust CD8+, CD4+, and γδ T cell responses, with oligoclonal expansion, terminal differentiation, and coordinated plasma cytokine shifts that persisted well beyond resolution of infection. These findings demonstrate that different preterm comorbidities imprint the neonatal immune system in divergent ways. Thus, comprehensive and longitudinal immune profiling may not only identify connections between clinical inflammatory complications and underlying immune pathways but also reveal potential targets for intervention.
Authors
Benjamin A. Fensterheim, Michelle L. McKeague, Divij Mathew, Shwetank, Ajinkya Pattekar, Matthew Lee, Zahabia Rangwala, Sean Nasta, Macy C. Kee, Cynthia Clendenin, Zachary Martinez, Caroline Diorio, Allison R. Greenplate, Krithika Lingappan, E. John Wherry
Abstract
Natural killer (NK) cells are pivotal in the early immune response to Plasmodium falciparum infection, yet their functional dynamics and regulation remain incompletely understood. In a longitudinal study of malaria patients in a non-endemic setting, we observed a transient but potent activation of NK cell cytotoxicity during acute malaria, characterized by rapid granzyme B-mediated killing and elevated expression of genes associated with cytotoxicity (PRF1, GZMB, and GZMA). This heightened activity was supported by increased plasma levels of granzymes and proinflammatory cytokines, which enhanced NK cell function in vitro. However, plasma samples from clinical malaria also contained inhibitory mediators, including soluble cytokine receptors, which dampened NK cell responses. These findings reveal that the host microenvironment orchestrates a tightly regulated NK cell response that potentiates cytotoxicity during acute infection and rapidly downmodulate it after treatment. Understanding this balance between activation and suppression may inform strategies to harness NK cells for malaria control while minimizing immunopathology.
Authors
Pengjun Xi, Patrick A. Sandoz, Maximilian Julius Lautenbach, Eleni Bilev, Björn Önfelt, Anna Färnert, Quirin Hammer, Christopher Sundling
Abstract
Sepsis is a leading cause of death for which host-directed therapies are urgently needed. We performed high-dimensional flow cytometry, measurement of soluble biomarkers, and lipopolysaccharide (LPS) stimulation of neutrophils to characterize neutrophil heterogeneity and function in patients with sepsis. We observed that in sepsis patients, low-density neutrophils (LDNs) are elevated and phenotypically diverse populations of innate immune cells with varying degrees of maturity and myeloperoxidase expression. Spleen tyrosine kinase (SYK) expression was found to be higher in whole blood neutrophils and LDNs of sepsis patients compared to healthy donors. Importantly, SYK+LDNs associated with increased levels of intracellular myeloperoxidase (MPO) and soluble biomarkers. Furthermore, SYK+LDNs correlated with clinical outcomes of sepsis disease severity including sequential organ failure assessment (SOFA) score, mechanical ventilation, and vasopressors. Functionally, the SYK inhibitor R406 suppressed changes in neutrophil features of activation from normal-density neutrophils and LDNs including the SYK+ and SYK- neutrophil subsets and MPO release from LDNs following LPS stimulation of sepsis neutrophils. Combined, these results establish LDNs as a heterogenous population of neutrophils that express high levels of SYK and support SYK inhibition as a novel therapeutic target aimed at suppressing overactive neutrophils in sepsis.
Authors
Heather L. Teague, Lauren Knabe, Raquel S. Da Cruz, Xianglan Yao, Kiana C. Allen, Trenton Williams, Cumhur Y. Demirkale, Merte Woldehanna, Ernest Evans, Amir Hobson, Jared D. Wilkinson, Steven D. Nathan, Christopher S. King, Jeffrey R. Strich
Abstract
Systemic inflammation is now recognized as a key contributor to epilepsy pathophysiology, yet the role of innate immune cells, particularly neutrophils, remains poorly defined in epilepsy. While preclinical studies in rodent models have implicated neutrophils in seizure activity, their phenotype in human epilepsy has not been thoroughly investigated. In this study, we aimed to characterize systemic inflammatory profiles and neutrophil-associated immune signatures in the blood of patients with drug-resistant epilepsy, compared to healthy controls. We identified a systemic low-grade inflammatory profile in patients, characterized by elevated neutrophil-to-lymphocyte ratio, C-reactive protein, pro-inflammatory cytokines (IL-6, CXCL8/IL-8, TNF-α), and activated neutrophils (CXCR4+CD62Llow). Neutrophil phenotyping revealed two distinct immune profiles. Patients with longer disease duration exhibited a more immature systemic signature, characterized by immature neutrophils (CD15⁺CD10⁻), resting neutrophils (CXCR4⁺CD62L⁺), and elevated IL-6 levels. In contrast, patients with higher seizure frequency displayed a more inflammatory profile, marked by increased IL-12 and activated (CXCR4+CD62Llow) and hyperactivated (CXCR4highCD62Llow) neutrophil subsets. Moreover, elevated pre-surgical levels of inflammatory profile TNF-α, IL-6, and hyperactivated CXCR4high CD62Llow neutrophils were associated with seizure recurrence one year after surgery. This pioneering study highlights the heterogeneity of peripheral immune responses in drug-resistant epilepsy and identifies neutrophil-related signatures as promising prognostic biomarkers in this context.
Authors
Coraly Simoës Da Gama, Aurelie Hanin, Gwen Goudard, Veronique Masson, Aurore Besnard, Karim Dorgham, Guy Gorochov, Guillaume Dorothee, Valerio Frazzini, Vincent Navarro, Mélanie Morin-Brureau
Abstract
Giant cell aortitis (GCA) is an inflammatory disease of the aortic wall with a characteristic giant cell pattern on pathology and can lead to life-threatening aortic aneurysm and dissection. Pathogenic GCA mechanisms underlying aortic inflammation and persistence remain elusive. Here, we demonstrate the complexity of medial layer destruction and immune cell infiltration in clinical granulomatous GCA and lymphoplasmacytic IgG4-related aortitis samples using imaging-based gene expression profiling. Single-cell spatial profiling revealed aortic wall remodeling in the GCA aortas, highlighting substantial phenotypic modulation in stromal cells, including vascular smooth muscle cells (SMCs) and fibroblasts. Specifically, we observed the expansion of stromal cells expressing Tenascin-C (TNC) mRNA and spatially refined TNC accumulation in lesion areas. We confirmed these findings histologically using diseased aortas resected from individuals with giant cell arteritis and clinically isolated aortitis. Mechanistically, our data suggest that TNC promotes a proinflammatory phenotype in primary human SMCs, elevating IL-6 levels partially through the TLR4/NF-κB pathway. IL-6 signaling propagates the proinflammatory loop by activating STAT3. Pharmacological blockade of the IL-6 receptor using tocilizumab alleviated the TNC-driven proinflammatory phenotype. We propose that TNC acts as a local catalyst of inflammatory disease persistence mainly via IL-6 signaling activation and offers a potential avenue for sustained disease remission.
Authors
Hui Shi, Ying Tang, Jing Li, Ora Gewurz-Singer, Bo Yang, Dogukan Mizrak
Abstract
Temporomandibular joint osteoarthritis (TMJOA), a prevalent subtype of temporomandibular disorders, is characterized by progressive cartilage degradation and subchondral bone destruction. Despite advancements in understanding TMJOA pathogenesis, the molecular mechanisms underlying its progression remain unclear. In this study, elevated Slit guidance ligand 2 (SLIT2) expression was observed in TMJ tissues of unilateral anterior crossbite–induced TMJOA mice and synovial fluid from patients with TMJOA, correlating with disease severity. Furthermore, SLIT2 overexpression in transgenic mice intensified TMJOA progression, whereas heterozygous deletion of roundabout guidance receptor 1/2 (ROBO1/2) alleviated cartilage and bone damage. Mechanistically, SLIT2 promoted ROBO1-LRP6 complex formation, facilitating LRP6 phosphorylation and β-catenin nuclear translocation. This cascade upregulated matrix-degrading enzymes while downregulating cartilage structural proteins, exacerbating cartilage destruction and subchondral bone loss. These findings suggest that the SLIT2/ROBO1/LRP6 axis may represent a potential therapeutic target for TMJOA and provide mechanistic insights into disease progression.
Authors
Guan Luo, Baoyi Chen, Wenjun Chen, Huiyi Lin, Weiqi Guo, Qingbin Zhang, Jiang Li, Lijing Wang, Janak Lal Pathak, Yuhui Yang, Weijun Zhang, Xiaoyu Zhang, Beining Zheng, Ziyi Wang, Shiting Wei, Jiaxin He, Wei-Jie Zhou, Chang Liu
Abstract
Pancreatic ductal adenocarcinoma (PDAC) shows profound resistance to immunotherapy due to its immunosuppressive tumor microenvironment. Here, we studied the relationship between T cell infiltration and innate immune signaling in PDAC, identifying Toll-like receptor 2 (TLR2) as a key regulator of T cell exclusion. TLR2 expression correlated with T cell infiltration in both human and mouse PDAC tumors. Using genetic knockout models and adoptive T cell transfer experiments, we found that TLR2 expression in both T cells and non-T cells contributes to T cell exclusion in PDAC. Notably, successful infiltration of adoptively transferred tumor-specific T cells required TLR2 deletion in both the transferred cells and the recipient host. The therapeutic implications of these findings are demonstrated through both genetic deletion and pharmacological inhibition of TLR2 using AAV-mediated and antibody-based approaches in murine models, resulting in decreased tumor growth and extended survival. Collectively, these findings identify TLR2 as a key modulator of T cell trafficking and immune suppression within the PDAC microenvironment, suggesting its potential as a therapeutic target for improving treatment outcomes.
Authors
Jacqueline Plesset, Meredith L. Stone, John C. McVey, Heather Coho, Kelly Markowitz, Kayjana Coho, Jesse Lee, Anna S. Thickens, Devora Delman, Gregory L. Beatty
Abstract
HIV infection rapidly impairs the gastrointestinal (GI) barrier, contributing to persistent mucosal immune dysfunction, microbial translocation, and systemic inflammation despite antiretroviral therapy (ART). Using SIV-infected rhesus macaques on long-term ART, we investigated mechanisms underlying impairment in gut barrier-protective IL-17/IL-22 responses and the potential modulation of this pathway by dietary indoles. Longitudinal profiling of colonic epithelial and lamina propria cells revealed a selective loss of IL-17/IL-22–producing γδT cells and type 3 innate lymphoid cells (ILC3s). This loss correlated with reduced expression of the transcription factors AHR and RORγt and was associated with elevated plasma markers of intestinal epithelial barrier disruption (IEBD), including intestinal fatty acid–binding protein (iFABP), zonulin, and LPS-binding protein (LBP). Targeting this transcriptional deficiency, dietary indole supplementation for one month restored colonic AHR⁺IL-22-producing γδ T cells, RORγt⁺ ILC3s, and Vδ1 T cells, and was associated with reduced iFABP and zonulin levels. Immunohistochemical analyses further demonstrated enrichment of AHR/RORγt-co-expressing cells in the colon of indole-supplemented animals during chronic SIV infection on ART. Collectively, these findings indicate that disruption of the AHR-RORγt axis is a key pathogenic mechanism underlying persistent IEBD in chronic SIV/HIV infection. Modulation of AHR and RORγt signaling pathways in the gut may therefore represent a promising therapeutic strategy to reinforce mucosal barrier function and mitigate chronic inflammation in people living with HIV.
Authors
Siva Thirugnanam, Alison R. Van Zandt, Alexandra B. McNally, Victoria A. Hart, Isabelle Berthelot, Cecily C. Midkiff, Lara A. Doyle-Meyers, David A. Welsh, Robert V. Blair, Andrew G. MacLean, Namita Rout
Abstract
Common variable immunodeficiency (CVID) is the most prevalent symptomatic primary antibody deficiency. For unclear reasons, inflammatory complications, like gastrointestinal (GI) disease, occur in ~50% of CVID cases, worsening morbidity and mortality. NFKB1 variants are among the most frequent genetic variants in CVID. While effect of NFKB1 variants is not well understood, we previously found frameshift heterozygous NFKB1 variants to increase cytokines, monocytes, and inflammatory complications in CVID. In this report, we used induced pluripotent stem cell–derived (iPSC-derived) monocytes (iMONOs) with CRISPR/Cas9-mediated gene editing to study a heterozygous NFKB1 frameshift found in a patient with CVID with severe GI disease. The heterozygous NFKB1 variant similarly reduced NFKB1 protein in CVID patient– and healthy donor–derived iMONOs, but elevated LPS-induced IL-1β release and expression of inflammatory genes, including IL1B, IL6, TNF, and neutrophil chemoattractants, only in CVID patient iMONOs. CVID patient iMONOs also had elevations of IL-12, CCL4, and CCL12 unaffected by presence or absence of the NFKB1 variant. TNF antagonism improved the patient’s GI disease, diminishing neutrophilic gastritis, circulating neutrophils, and the neutrophil chemoattractant CXCL1 in the blood. While the biology remains complex, our approach found heterozygous NFKB1 variant–induced inflammatory changes intensified in CVID iMONOs, corresponding with clinical response to TNF antagonism.
Authors
Kevin M. Hayes, Kai Boldt, Peter J. Schnorr, Pushpinder Bawa, Miranda L. Abyazi, Matthew S. Ware, Gavin Gyimesi, Marianne James, Huaibin M. Ko, Charlotte Cunningham-Rundles, Joseph P. Mizgerd, Gustavo Mostoslavsky, Darrell N. Kotton, Paul J. Maglione
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