Immunology
Abstract
Infectious diseases remain a global health challenge, driven by increasing antimicrobial-resistance and the threat of emerging epidemics. Mycobacterium tuberculosis and Staphylococcus aureus are leading causes of mortality worldwide. Trained immunity—a form of innate immune memory—offers a promising approach to enhance pathogen clearance. Here, we demonstrate that IFN-γ induces trained immunity in human monocytes through a mechanism involving mTORC1 activation, glutaminolysis, and epigenetic remodeling. Macrophages derived from IFN-γ–trained monocytes exhibited increased glycolytic activity with enhanced cytokine and chemokine responses upon stimulation or infection. Crucially, trained macrophages had increased production of reactive oxygen species which mediated enhanced bactericidal activity against methicillin-resistant S. aureus. Furthermore, ATAC-sequencing analysis of IFN-γ trained macrophages revealed increased chromatin accessibility in regions associated with host defence. Lastly, IFN-γ training restored impaired innate responses in macrophages from individuals homozygous for the TIRAP 180L polymorphism, a genetic variant associated with increased susceptibility to infection. These findings establish IFN-γ as a potent inducer of trained immunity in human monocytes and support its potential as a host-directed strategy to strengthen antimicrobial defenses, particularly in genetically susceptible individuals and high-risk clinical contexts.
Authors
Dearbhla M. Murphy, Isabella Batten, Aoife O'Farrell, Simon R. Carlile, Sinead A. O'Rourke, Chloe Court, Brenda Morris, Gina Leisching, Gráinne Jameson, Sarah A. Connolly, Adam H. Dyer, John P. McGrath, Emma McNally, Olivia Sandby-Thomas, Anjali Yennemadi, Conor M. Finlay, Clíona Ni Cheallaigh, Jean Dunne, Cilian Ó Maoldomhnaigh, Laura E. Gleeson, Aisling Dunne, Nollaig Bourke, Reinout van Crevel, Donal J. Cox, Niall Conlon, Arjun Raj, Rachel M. McLoughlin, Joseph Keane, Sharee A. Basdeo
Abstract
Immunosuppression and metastasis are critical hallmarks of breast cancer, often linked to poor patient outcomes. The secreted cytokine chitinase-3 like 1 (CHI3L11) is frequently overexpressed in breast cancer samples and promotes an immunosuppressed tumor microenvironment. Notably, CHI3L1 expression is elevated in metastatic patient samples when compared to the matched primary breast tumor. To investigate its role in breast cancer metastasis, we generated an inducible Genetically Engineered Mouse Model (GEMM) that overexpresses CHI3L1 in the mammary epithelium. Ectopic expression of CHI3L1 in the Polyomavirus Middle T (PyMT) mouse model of breast cancer suppressed anti-tumor immune responses, accelerated mammary tumor onset and enhanced lung metastasis. Mechanistically, elevated CHI3L1 expression in the mammary epithelium enhanced neutrophil recruitment, which subsequently degraded the extracellular matrix and increased the number of circulating tumor cells. These findings reveal a key mechanism driving metastatic dissemination and argue that therapeutically targeting Chi3l1 could enhance anti-tumor immunity and suppress metastasis.
Authors
Tarek Taifour, Adéline Massé, Yu Gu, Virginie Sanguin-Gendreau, Dongmei Zuo, Bin Xiao, Emilie Solymoss, Yunyun Shen, Hailey Proud, Sherif Samer Attalla, Vasilios Papavasiliou, Nancy U. Lin, Melissa E. Hughes, Kalie Smith, Chun Geun Lee, Suchitra Kamle, Josie Ursini-Siegel, Jack A. Elias, Peter M. Siegel, Rinath Jeselsohn, William J. Muller
Abstract
We hypothesized that performing bone marrow transplant (BMT) using marrow extracted from the vertebral bodies (VB) of an unrelated deceased lung transplant (LTX) donor would be able to establish persistent hematopoiesis, generate immunity, and tolerance. A teenager with severe combined immunodeficiency with lung failure due to recurrent pneumonias underwent LTX in 2016 from a 1/8 HLA allele-matched unrelated donor, followed by BMT 4 months later using T-cell/B-cell-depleted, cryopreserved VB marrow. Rapid engraftment was followed by accelerating immune competence at 6 months, with independence from immunosuppression by 16 months. Donor T-cell (>95%) and myeloid chimerism (7-10%) have persisted for over nine years. At two years post-BMT, circulating T cells were hyporesponsive to host dendritic cells in vitro. T-cell receptor clonotyping revealed the disappearance of host-reactive clones, and T-cell RNA-sequencing exhibited downmodulated signaling pathways for cytotoxicity/rejection, paired with upregulated immunomodulatory pathways, suggesting active suppression. In parallel, host monocytes upregulated certain signaling pathways, indicating active interactions between post-thymic donor T cells and host monocytes. In summary, durable hematopoietic engraftment, immunity, and tolerance were demonstrable for the first time in a recipient of BMT obtained from VB graft.
Authors
Paul Szabolcs, Xiaohua Chen, Marian G. Michaels, Memphis Hill, Evelyn Garchar, Zarreen Amin, Heather M. Stanczak, Shawna McIntyre, Aleksandra Petrovic, Dhivyaa Rajasundaram, Ansuman Chattopadhyay, Jonathan E. Spahr, Peter D. Wearden, Geoffrey Kurland
Abstract
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by immune dysregulation and widespread inflammation. Natural killer (NK) cells display marked functional impairment in SLE, including defective cytotoxicity and cytokine production, but the underlying mechanisms remain poorly defined. Here, we show that mitochondrial dysfunction and impaired mitophagy are key contributors to NK cell abnormalities in SLE. Using complementary structural, metabolic, and proteomic analyses, we found that SLE NK cells accumulate enlarged and dysfunctional mitochondria, exhibit impaired lysosomal acidification, and release mitochondrial DNA into the cytosol—features consistent with defective mitochondrial quality control. Transcriptional and proteomic profiling revealed downregulation of key mitophagy-related genes and pathways. These abnormalities correlated with reduced NK cell degranulation and cytokine production. We then tested whether enhancing mitochondrial quality control could restore NK cell function. The mitophagy activator Urolithin A improved mitochondrial and lysosomal parameters and rescued NK cell effector responses in vitro. Hydroxychloroquine partially restored mitochondrial recycling and reduced cytosolic mtDNA. These findings suggest that defective mitophagy and mitochondrial dysfunction are major contributors to NK cell impairment in SLE and that targeting mitochondrial quality control may represent a promising strategy for restoring immune balance in this disease.
Authors
Natalia W. Fluder, Morgane Humbel, Emeline Recazens, Alexis A. Jourdain, Camillo Ribi, George C. Tsokos, Denis Comte
Abstract
Chronic hyperglycemia changes the expression of various transcription factors and mRNA transcripts, which impair the cellular functionality and delayed wound healing. ZEB2 (zinc finger E-box binding homeobox 2), a key transcription factor maintains the tissue specific macrophage identities, however, its role in regulating macrophage polarization during wound healing under hyperglycemic conditions remains unclear. Here, we have found that persistent hyperglycemia increases ZEB2 expression in wound macrophages via histone acetylation, contributing to chronic inflammation, and delayed wound healing. Exposure to high glucose levels activates P300/CBP, a transcriptional coactivator involved in histone acetylation, enhances ZEB2 expression in wound macrophages. The forced expression of ZEB2 shifts macrophage polarity toward a pro-inflammatory state by upregulating myeloid lineage directed transcription factors (MLDTFs). Conversely, silencing Zeb2 at the wound site reduced hyperglycemia induced macrophage inflammation. Topical application of C646, an inhibitor of P300, at the wound edges of streptozotocin induced high-fat diet fed diabetic mice significantly decreased ZEB2 expression, reduced inflammation and accelerated wound healing. Therefore, targeted inhibition of P300 represents a promising therapeutic strategy for improving diabetic wound healing by modulating ZEB2 driven inflammation in wound macrophages.
Authors
Soumyajit Roy, Debarun Patra, Palla Ramprasad, Shivam Sharma, Parul Katiyar, Ashvind Bawa, Kanhaiya Singh, Kulbhushan Tikoo, Suman Dasgupta, Chandan K. Sen, Durba Pal
Abstract
CD4 T cells are essential for immunity to M. tuberculosis (Mtb), and emerging evidence indicates that IL-17-producing Th17 cells contribute to immunity to Mtb. While identifying protective T cell effector functions is important for TB vaccine design, T cell antigen specificity is also likely to be important. To identify antigens that induce protective immunity, we reasoned that, as in other pathogens, effective immune recognition drives sequence diversity in individual Mtb antigens. We previously identified Mtb genes under evolutionary diversifying selection pressure whose products we term Rare Variable Mtb Antigens (RVMA). Here, in two distinct human cohorts with recent exposure to TB, we found that RVMA preferentially induce CD4 T cells that express RoRγt and produce IL-17, in contrast to ‘classical’ Mtb antigens that induce T cells that produce IFNγ. Together with emerging evidence showing human Th17 responses are associated with prevention of progression to TB disease, our results suggest that RVMA can be valuable antigens in vaccines for those already infected with Mtb to amplify existing antigen-specific Th17 responses to prevent TB disease.
Authors
Paul Ogongo, Liya Wassie, Anthony Tran, Devin Columbus, Julia Huffaker, Lisa Sharling, Gregory Ouma, Samuel Gurrion Ouma, Kidist Bobosha, Cecilia S. Lindestam Arlehamn, Neel R. Gandhi, Sara C. Auld, Jyothi Rengarajan, Cheryl L. Day, Artur Queiroz, Mariana Araújo-Pereira, Eduardo Fukutani, Bruno B. Andrade, John D. Altman, Henry M. Blumberg, Joel D. Ernst
Abstract
Alveolar hemorrhage (AH) is a life-threatening condition with high mortality, yet the immunologic mechanisms governing disease severity remain poorly defined. Here, we demonstrate a protective role for T cell–intrinsic β-catenin stabilization in AH using a transgenic mouse model (CAT-Tg) in which β-catenin is stabilized under the Lck promoter. β-Catenin stabilization induced a distinct T cell phenotype marked by expansion of central effector memory cells (CD44+CD122+Eomes+T-bet+) and suppression of proinflammatory signaling, including reduced phosphorylation of STAT1, STAT3, and JAK1. Pristane-induced AH was attenuated in CAT-Tg mice, which exhibited reduced lung injury, decreased proteinuria, and diminished pulmonary proinflammatory cytokine production compared with wild-type controls. Protection was associated with a marked expansion of FOXP3+ regulatory T cells (Tregs). Mechanistically, β-catenin stabilization enhanced lung expression of Amphiregulin and BATF, mediators of Treg stability and tissue repair. Adoptive transfer of CAT-Tg–derived Tregs into wild-type mice conferred superior protection against AH, reducing lung inflammation and proteinuria. Transcriptomic analyses revealed enrichment of tissue repair and immune homeostasis pathways, including PI3K–Akt, angiogenesis, and STAT5 signaling. Collectively, these findings identify β-catenin as a regulator of a protective Amphiregulin–BATF–Treg axis, highlighting a immunomodulatory pathway with therapeutic potential for AH and inflammatory lung disease.
Authors
Fiona Mason, Hui Xiong, Ali Mobeen, Md Saddam Hossain, Sara Mahmudlu, Rosanne Trevail, Mikyal Mobeen, Li Chen, Sunny Lee, Tuncay Delibasi, Jyoti Misra Sen, Mobin Karimi
Abstract
Rheumatoid arthritis (RA) is characterized by joint inflammation and bone erosion. Understanding cytokine pathways, particularly those targeting TNF, is crucial for understanding pathology and advancing treatment development. Arid5a is a noncanonical RNA binding protein (RBP) that augments inflammation through stabilizing proinflammatory mRNAs and enhancing protein translation. We examined published datasets for ARID5A in human RA blood, T cells, and synovial tissues. A stromal cell line, epithelial cells, and primary synovial fibroblasts were used to assess the effect of TNF on Arid5a expression, localization, and function. To determine how TNF induces Arid5a, WT or Traf2–/– stromal cells were treated with NIK or IKK inhibitors. To evaluate the necessity of Arid5a in arthritis progression, Arid5a–/– mice were subjected to collagen-induced arthritis. ARID5A was elevated in patients with RA and reduced by anti-TNF therapy. TNF upregulated Arid5a through the NF-κB1/TRAF2 pathway, causing cytoplasmic relocalization. Arid5a stabilized proinflammatory transcripts and enhanced expression of chemokines that drive RA. Arid5a–/– mice were resistant to collagen-induced arthritis correlating with reduced Th17 cells in synovial tissue. Thus, Arid5a serves as a newly recognized signaling intermediate downstream of TNF that is elevated in human RA and drives pathology in murine CIA, potentially positioning this RBP as a possible therapeutic target.
Authors
Yang Li, Ipsita Dey, Shachi P. Vyas, Alzbeta Synackova, Decheng Li, Erik Lubberts, Dana P. Ascherman, Peter Draber, Sarah L. Gaffen
Abstract
Treatment with anti-CD3 monoclonal antibody (mAb) can delay or prevent type 1 diabetes in mice and humans by modulating the immune-mediated destruction of β cells. A single course of treatment may have lasting efficacy, but the mechanisms that account for these prolonged effects, i.e., “operational tolerance,” are not clear. Here, we used paired single-cell RNA and T cell receptor sequencing to characterize islet-infiltrating T cells and their counterpart in paired pancreatic lymph nodes from anti-CD3 mAb–treated nonobese diabetic (NOD) mice in remission. We found that after anti-CD3 mAb treatment, T cells that infiltrate the islets are more heterogeneous and have hybrid features including characteristics of T stem cell–like memory and reduced effector function compared with those from untreated prediabetic NOD mice. Autoantigen-reactive CD8+ T cells persist after treatment, but they also show features of stemness and reduced pathogenicity. Our findings describe the reshaping of islet-infiltrating and autoreactive T cells and β cells that lead to operational, but tenuous, tolerance to autoimmune diabetes following anti-CD3 mAb treatment.
Authors
Ying Wu, Maxwell Spurrell, Ana Lledó-Delgado, Songyan Deng, Dejiang Wang, Yang Liu, Mahsa Nouri Barkestani, Ana Luisa Perdigoto, Kevan C. Herold
Abstract
Acute severe joint pain is a major symptom in gouty arthritis (GA), and its adequate treatment represents an unmet medical need. Mrgprb2, a specific mast cell receptor, has been implicated in the generation of chronic pain by mobilizing mast cell degranulation, yet its significance in GA pain and joint inflammation is still not well defined. Here, we found that Mrgprb2 was expressed in mouse synovial mast cells. In a murine model of GA, acute blockade or genetic deletion of Mrgprb2 significantly attenuated arthritis pain and hyperexcitability of joint nociceptors with significant reductions in innate immune cell recruitment in the synovium. Under naive conditions, activation of synovial Mrgprb2 was sufficient to excite peripheral terminals of joint nociceptors to induce acute joint hypernociception via the mobilization of mast cell degranulation. Additionally, the level of the neuropeptide substance P (SP) was elevated in the synovium of GA model mice. Using humanized MRGPRX2-knockin mice, we revealed that SP contributed to joint pain and inflammation by activating mast cells through Mrgprb2/MRGPRX2. These findings suggest that synovial mast cell–expressed Mrgprb2/MRGPRX2 merits consideration as a key neuroimmune player and a potential therapeutic target for treating GA pain and joint inflammation.
Authors
Lin Yang, Chengxi Liu, Jin Xiao, Yu Song, Huan Chen, Dan Li, Cong Zou, Tao Hong, Yinglan Liu, Dake Qi, Nathachit Limjunyawong, Wenjie Liu, Lintao Qu
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