Inflammation
Abstract
The pathogenesis of thoracic aortic aneurysm (TAA) in Marfan syndrome (MFS) is generally attributed to vascular smooth muscle cell (VSMC) pathologies. However, the role of immune cell–mediated inflammation remains elusive. Single-cell RNA sequencing identified a subset of CX3CR1+ macrophages mainly located in the intima in the aortic roots and ascending aortas of Fbn1C1041G/+ mice, further validated in MFS patients. Specific elimination of CX3CR1+ cells by diphtheria toxin in Cx3cr1-CreERT2iDTRF/+Fbn1C1041G/+ mice efficiently ameliorated TAA progression. Administering the monoclonal antibodies to respectively neutralize TNF-α and IGF1 produced by CX3CR1+ cells from MFS patients greatly suppressed the cocultured MFS patient–specific induced pluripotent stem cell–derived VSMC inflammation. BM transplantation and parabiosis revealed that CX3CR1+ macrophages are mainly originated from BM-derived monocytes. Targeting TNF-α and IGF1 in CX3CR1+ macrophages via shRNA lentivirus transduction in BM cells efficiently suppressed TAA development in BM-transplanted Fbn1C1041G/+ mice. Application of the CCR2 antagonist RS504393 to inhibit monocyte infiltration markedly reduced the accumulation of CX3CR1+ macrophages and subsequently alleviated TAA progression in Fbn1C1041G/+ mice. In summary, CX3CR1+ macrophages mainly located in aortic intima mediate TAA formation by paracrinally causing VSMC inflammation, and targeting them offers a potential antiinflammatory therapeutic strategy for MFS-related TAA.
Authors
Jiaqi Huang, Hao Liu, Zhujiang Liu, Zhenting Wang, Hanshi Xu, Zhuofan Li, Shan Huang, Xueyuan Yang, Yicong Shen, Fang Yu, Yulin Li, Junming Zhu, Wei Li, Li Wang, Wei Kong, Yi Fu
Abstract
Type-2 innate lymphoid cells (ILC2s) play a pivotal role in the development of airway hyperreactivity (AHR). However, the regulatory mechanisms governing ILC2 function remain inadequately explored. This study uncovers V-domain Ig suppressor of T cell activation (VISTA) as an inhibitory immune checkpoint crucial for modulating ILC2-driven lung inflammation. VISTA is upregulated in activated pulmonary ILC2s and plays a key role in regulating lung inflammation, as VISTA-deficient ILC2s demonstrate increased proliferation and function, resulting in elevated type-2 cytokine production and exacerbation of AHR. Mechanistically, VISTA stimulation activates Forkhead box O1 (FOXO1), leading to modulation of ILC2 proliferation and function. The suppressive effects of FOXO1 on ILC2 effector function were confirmed using FOXO1 inhibitors and activators. Moreover, VISTA-deficient ILC2s exhibit enhanced fatty acid oxidation and oxidative phosphorylation to meet their high energy demands. Therapeutically, VISTA agonist treatment reduces ILC2 function both ex vivo and in vivo, significantly alleviating ILC2-driven AHR. Our murine findings were validated in human ILC2s, where a VISTA agonist reduces their function ex vivo and in a humanized mouse model of ILC2-driven AHR. Our studies unravel VISTA as an immune checkpoint for ILC2 regulation via the FOXO1 pathway, presenting potential therapeutic strategies for allergic asthma by modulating ILC2 responses.
Authors
Mohammad Hossein Kazemi, Zahra Momeni-Varposhti, Xin Li, Benjamin P. Hurrell, Yoshihiro Sakano, Stephen Shen, Pedram Shafiei-Jahani, Kei Sakano, Omid Akbari
Abstract
Various factors play key roles in maintaining intestine homeostasis. Disruption of the balance may lead to intestinal inflammatory diseases (IBDs) and even colorectal cancer (CRC). Loss or gain of function of many key proteins can result in dysregulated intestinal homeostasis. Our research demonstrated that neural precursor cells expressed developmentally down-regulated 4-like protein, NEDD4L (NEDD4-2), a type of HECT family E3 ubiquitin ligase, played an important role in maintaining intestinal homeostasis. NEDD4L expression was significantly inhibited in intestinal epithelial cells (IECs) of patients with Crohn's disease (CD), ulcerative colitis (UC), and CRC. Global knockout of NEDD4L or its deficiency in IECs exacerbated dextran sulfate sodium (DSS)-/2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis and azoxymethane (AOM)/DSS-induced colorectal cancer. Mechanistically, NEDD4L deficiency in IECs inhibited the key ferroptosis regulator glutathione peroxidase 4 (GPX4) expression by reducing the protein expression of solute carrier family 3 member 2 (SLC3A2) without affecting its gene expression, ultimately promoting DSS-induced IEC ferroptosis. Importantly, ferroptosis inhibitors reduced the susceptibility of NEDD4L-deficient mice to colitis and colitis-associated colorectal cancer (CAC). Thus, NEDD4L was an important regulator in IEC ferroptosis, maintaining intestinal homeostasis, making it a potential clinical target for diagnosing and treating IBDs.
Authors
Jingjing Liang, Ning Wang, Yihan Yao, Yingmei Wang, Xiang An, Haofei Wang, Huan Liu, Yu Jiang, Hui Li, Xiaoqing Cheng, Jiaqi Xu, Xiaojing Liang, Jun Lou, Zengfeng Xin, Ting Zhang, Xiaojian Wang, Wenlong Lin
Abstract
Red blood cells (RBCs), traditionally recognized for their role in transporting oxygen, play a pivotal role in the body's immune response by expressing TLR9 and scavenging excess host cell-free DNA. DNA capture by RBCs leads to accelerated RBC clearance and triggers inflammation. Whether RBCs can also acquire microbial DNA during infections is unknown. Murine RBCs acquire microbial DNA in vitro and bacterial-DNA-induced macrophage activation was augmented by WT but not Tlr9-deleted RBCs. In a mouse model of polymicrobial sepsis, RBC-bound bacterial DNA was elevated in WT but not in erythroid Tlr9-deleted mice. Plasma cytokine analysis in these mice revealed distinct sepsis clusters characterized by persistent hypothermia and hyperinflammation in the most severely affected subjects. RBC-Tlr9 deletion attenuated plasma and tissue IL-6 production in the most severe group. Parallel findings in human subjects confirmed that RBCs from septic patients harbored more bacterial DNA compared to healthy individuals. Further analysis through 16S sequencing of RBC-bound DNA illustrated distinct microbial communities, with RBC-bound DNA composition correlating with plasma IL-6 in patients with sepsis. Collectively, these findings unveil RBCs as overlooked reservoirs and couriers of microbial DNA, capable of influencing host inflammatory responses in sepsis.
Authors
LK Metthew Lam, Nathan J. Klingensmith, Layal Sayegh, Emily Oatman, Joshua S. Jose, Christopher V. Cosgriff, Kaitlyn A. Eckart, John McGinnis, Piyush Ranjan, Matthew Lanza, Nadir Yehya, Nuala J. Meyer, Robert P. Dickson, Nilam S. Mangalmurti
Abstract
Dysregulations of epithelial-immune interactions frequently culminate in chronic inflammatory diseases of the skin, lungs, kidneys, and gastrointestinal tract. Yet, the intraepithelial processes which initiate and perpetuate inflammation in these organs are poorly understood. Here, by utilizing redox lipidomics we identified ferroptosis-associated peroxidation of polyunsaturated phosphatidylethanolamines in the epithelia of patients with asthma, cystic fibrosis, psoriasis and renal failure. Focusing on psoriasis as a disease model, we used high-resolution mass spectrometry imaging and identified keratin 14 (K14)-expressing keratinocytes executing a ferroptotic death program in human psoriatic skin. Psoriatic phenotype with characteristic Th1/Th17 skin and extracutaneous immune responses was initiated and maintained in a murine model designed to actuate ferroptosis in a fraction of K14+ glutathione peroxidase 4 (Gpx4)-deficient epidermal keratinocytes. Importantly, an anti-ferroptotic agent, Liproxstatin-1, was as effective as clinically relevant biologic IL-12/IL-23/TNFα-targeting therapies or the depletion of T cells in completely abrogating molecular, biochemical and morphologic features of psoriasis. As ferroptosis in select epidermal keratinocytes triggers and sustains a pathologic psoriatic multi-organ inflammatory circuit, we suggest that strategies targeting ferroptosis, or its causes, may be effective in preventing or ameliorating a variety of chronic inflammatory diseases.
Authors
Kavita Vats, Hua Tian, Kunal Singh, Yulia Y. Tyurina, Louis J. Sparvero, Vladimir A. Tyurin, Oleg Kruglov, Alexander Chang, Jiefei Wang, Felicia Green, Svetlana N. Samovich, Jiying Zhang, Ansuman Chattopadhyay, Natalie Murray, Vrusha K. Shah, Alicia R. Mathers, Uma R. Chandran, Joseph M. Pilewski, John A. Kellum, Sally E. Wenzel, Hülya Bayir, Valerian E. Kagan, Yuri L. Bunimovich
Abstract
Tissue regeneration is orchestrated by macrophages that clear damaged cells and promote regenerative inflammation. How macrophages spatially adapt and diversify their functions to support the architectural requirements of actively regenerating tissue remains unknown. In this study, we reconstructed the dynamic trajectories of myeloid cells isolated from acutely injured and early-stage dystrophic muscles. We identified divergent subsets of monocytes/macrophages and dendritic cells (DCs) and validated markers (e.g., GPNMB) and transcriptional regulators associated with defined functional states. In dystrophic muscle, specialized repair-associated subsets exhibited distinct macrophage diversity and reduced DC heterogeneity. Integrating spatial transcriptomics analyses with immunofluorescence uncovered the ordered distribution of subpopulations and multilayered regenerative inflammation zones (RIZs) where distinct macrophage subsets are organized in functional zones around damaged myofibers supporting all phases of regeneration. Importantly, intermittent glucocorticoid treatment disrupted the RIZs. Our findings suggest that macrophage subtypes mediated the development of the highly ordered architecture of regenerative tissues, unveiling the principles of the structured yet dynamic nature of regenerative inflammation supporting effective tissue repair.
Authors
Andreas Patsalos, Laszlo Halasz, Darby Oleksak, Xiaoyan Wei, Gergely Nagy, Petros Tzerpos, Thomas Conrad, David W. Hammers, H. Lee Sweeney, Laszlo Nagy
The NR4A2/VGF pathway fuels inflammation-induced neurodegeneration via promoting neuronal glycolysis
Abstract
A disturbed balance between excitation and inhibition (E/I balance) is increasingly recognized as a key driver of neurodegeneration in multiple sclerosis (MS), a chronic inflammatory disease of the central nervous system. To understand how chronic hyperexcitability contributes to neuronal loss in MS, we transcriptionally profiled neurons from mice lacking inhibitory metabotropic glutamate signaling with shifted E/I balance and increased vulnerability to inflammation-induced neurodegeneration. This revealed a prominent induction of the nuclear receptor NR4A2 in neurons. Mechanistically, NR4A2 increased susceptibility to excitotoxicity by stimulating continuous VGF secretion leading to glycolysis-dependent neuronal cell death. Extending these findings to people with MS (pwMS), we observed increased VGF levels in serum and brain biopsies. Notably, neuron-specific deletion of Vgf in a mouse model of MS ameliorated neurodegeneration. These findings underscore the detrimental effect of a persistent metabolic shift driven by excitatory activity as a fundamental mechanism in inflammation-induced neurodegeneration.
Authors
Marcel S. Woo, Lukas C. Bal, Ingo Winschel, Elias Manca, Mark Walkenhorst, Bachar Sevgili, Jana K. Sonner, Giovanni Di Liberto, Christina Mayer, Lars Binkle-Ladisch, Nicola Rothammer, Lisa Unger, Lukas Raich, Alexandros Hadjilaou, Barbara Noli, Antonio L. Manai, Vanessa Vieira, Nina Meurs, Ingrid Wagner, Ole Pless, Cristina Cocco, Samuel B. Stephens, Markus Glatzel, Doron Merkler, Manuel A. Friese
Abstract
Endometriosis is a debilitating, chronic inflammatory disease affecting ~10% of reproductive age women worldwide with no cure. While macrophages have been intrinsically linked to the pathophysiology of endometriosis, targeting them therapeutically has been extremely challenging due to their high heterogeneity and because these disease-associated macrophages (DAMs) can be either pathogenic or protective. Here, we reported identification of pathogenic macrophages characterized by TET3 overexpression in human endometriosis lesions. We showed that factors from the disease microenvironment upregulated TET3 expression transforming macrophages into pathogenic DAMs. TET3 overexpression stimulated pro-inflammatory cytokine production via a feedback mechanism involving inhibition of let-7 miRNA expression. Remarkably, these cells relied on TET3 overexpression for survival, hence vulnerable to TET3 knockdown. We demonstrated that Bobcat339, a synthetic cytosine derivative, triggered TET3 degradation both in human and mouse macrophages. This degradation was dependent on a VHL E3 ubiquitin ligase whose expression was also upregulated in TET3-overexpressing macrophages. Furthermore, depleting TET3-overexpressing macrophages either through myeloid-specific Tet3 ablation or using Bobcat339 strongly inhibited endometriosis progression in mice. Our results defined TET3-overexpressing macrophages as key pathogenic contributors to and attractive therapeutic targets for endometriosis. Our findings may also be applicable to other chronic inflammatory diseases where DAMs have important roles.
Authors
Haining Lv, Beibei Liu, Yangyang Dai, Feng Li, Stefania Bellone, Yuping Zhou, Ramanaiah Mamillapalli, Dejian Zhao, Muthukumaran Venkatachalapathy, Yali Hu, Gordon G. Carmichael, Da Li, Hugh S. Taylor, Yingqun Huang
Abstract
Crohn's disease (CD) is marked by recurring intestinal inflammation and tissue injury, often resulting in fibro-stenosis and bowel obstruction, necessitating surgical intervention with high recurrence rates. To elucidate to the mechanisms underlying fibro-stenosis in CD, we analysed the transcriptome of cells isolated from the transmural ileum of CD patients, including a trio of lesions from each patient: non-affected, inflamed, and stenotic ileum samples, and compared them with samples from non-CD patients. Our computational analysis revealed that pro-fibrotic signals from a subset of monocyte-derived cells expressing CD150 induced a disease-specific fibroblast population, resulting in chronic inflammation and tissue fibrosis. The transcription factor TWIST1 was identified as a key modulator of fibroblast activation and extracellular matrix (ECM) deposition. Genetic and pharmacological inhibition of TWIST1 prevents fibroblast activation, reducing ECM production and collagen deposition. Our findings suggest that the myeloid-stromal axis may offer a promising therapeutic target to prevent fibro-stenosis in CD.
Authors
Bo-Jun Ke, Saeed Abdurahiman, Francesca Biscu, Gaia Zanella, Gabriele Dragoni, Sneha Santhosh, Veronica De Simone, Anissa Zouzaf, Lies van Baarle, Michelle Stakenborg, Veronika Bosáková, Yentl Van Rymenant, Emile Verhulst, Sare Verstockt, Elliott Klein, Gabriele Bislenghi, Albert M. Wolthuis, Jan Frič, Christine Breynaert, Andre D'Hoore, Pieter Van der Veken, Ingrid De Meester, Sara Lovisa, Lukas J.A.C. Hawinkels, Bram Verstockt, Gert De Hertogh, Séverine Vermeire, Gianluca Matteoli
Abstract
Emerging evidence has linked the dysregulation of N6-methyladenosine (m6A) modification to inflammation and inflammatory diseases, but the underlying mechanism still needs investigation. Here, we found that high levels of m6A modification in a variety of hyperinflammatory states are p65-dependent because Wilms tumor 1–associated protein (WTAP), a key component of the “writer” complex, is transcriptionally regulated by p65, and its overexpression can lead to increased levels of m6A modification. Mechanistically, upregulated WTAP is more prone to phase separation to facilitate the aggregation of the writer complex to nuclear speckles and the deposition of m6A marks on transcriptionally active inflammatory transcripts, thereby accelerating the proinflammatory response. Further, a myeloid deficiency in WTAP attenuates the severity of LPS-induced sepsis and DSS-induced IBD. Thus, the proinflammatory effect of WTAP is a general risk-increasing mechanism, and interrupting the assembly of the m6A writer complex to reduce the global m6A levels by targeting the phase separation of WTAP may be a potential and promising therapeutic strategy for alleviating hyperinflammation.
Authors
Yong Ge, Rong Chen, Tao Ling, Biaodi Liu, Jingrong Huang, Youxiang Cheng, Yi Lin, Hongxuan Chen, Xiongmei Xie, Guomeng Xia, Guanzheng Luo, Shaochun Yuan, Anlong Xu
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Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)