Research Article
Abstract
While weight loss is highly recommended for those with obesity, >60% regain their lost weight. This weight cycling is associated with an elevated risk of cardiovascular disease, relative to never having lost weight. How weight loss and regain directly influence atherosclerotic inflammation is unknown. Thus, we studied short-term caloric restriction (stCR) in obese hypercholesterolemic mice, without confounding effects from changes in diet composition. Weight loss promoted atherosclerosis resolution independent of plasma cholesterol. Single-cell RNA sequencing and subsequent mechanistic studies indicated that this can be partly attributed to a unique subset of macrophages accumulating with stCR in epididymal white adipose tissue (eWAT) and atherosclerotic plaques. These macrophages, distinguished by high expression of Fc γ receptor 4 (Fcgr4), helped to clear necrotic cores in atherosclerotic plaques. Conversely, weight regain (WR) following stCR accelerated atherosclerosis progression with disappearance of Fcgr4+ macrophages from eWAT and plaques. Furthermore, WR caused reprogramming of immune progenitors, sustaining hyperinflammatory responsiveness. In summary, we have developed a model to investigate the inflammatory effects of weight cycling on atherosclerosis and the interplay between adipose tissue, bone marrow, and plaques. The findings suggest potential approaches to promote atherosclerosis resolution in obesity and weight cycling through induction of Fcgr4+ macrophages and inhibition of immune progenitor reprogramming.
Authors
Bianca Scolaro, Franziska Krautter, Emily J. Brown, Aleepta Guha Ray, Rotem Kalev-Altman, Marie Petitjean, Sofie Delbare, Casey Donahoe, Stephanie Pena, Michela L. Garabedian, Cyrus A. Nikain, Maria Laskou, Ozlem Tufanli, Carmen Hannemann, Myriam Aouadi, Ada Weinstock, Edward A. Fisher
Abstract
The cyclic GMP-AMP synthase (cGAS)/stimulator of IFN genes (STING) pathway is intimately associated with antitumoral immunity; however, the direct involvement of this pathway in tumor cell demise remains elusive. Here, we identified a compound, dodecyl 6-hydroxy-2-naphthoate (DHN), that induces pyroptosis in melanoma cells by activating noncanonical cGAS/STING signaling. DHN targets mitochondrial protein cyclophilin D (CypD) to induce the release of mitochondrial DNA, leading to cGAS activation and cyclic GMP-AMP (cGAMP) generation. Meanwhile, DHN-caused intracellular acidification induces protein kinase R-like endoplasmic reticulum kinase (PERK) activation, which promotes STING phosphorylation and polymerization in the presence of cGAMP, thereby facilitating the aggregation of STING in the ER, which serves as a platform to recruit Fas-associated via death domain (FADD) and caspase-8, leading to caspase-8 activation and subsequent gasdermin E cleavage, which ultimately results in pyroptosis of tumor cells and tumor regression in mouse models. The occurrence of this noncanonical cGAS/STING pathway–associated pyroptosis is also observed when both cGAS is activated and intracellular pH declines. Collectively, our findings reveal a pathway that links noncanonical cGAS/STING signaling to gasdermin E–mediated pyroptosis, thereby offering valuable insights for tumor therapy.
Authors
Li Xiao, Yuan-li Ai, Xiang-yu Mi, Han Liang, Xiang Zhi, Liu-zheng Wu, Qi-tao Chen, Tong Gou, Chao Chen, Bo Zhou, Wen-bin Hong, Lu-ming Yao, Jun-jie Chen, Xianming Deng, Fu-nan Li, Qiao Wu, Hang-zi Chen
Abstract
Erythropoietic protoporphyria (EPP) is a genetic disorder typically resulting from decreased ferrochelatase (FECH) activity, the last enzyme in heme biosynthesis. Patients with X-linked protoporphyria (XLPP) have an overlapping phenotype caused by increased activity of 5-aminolevulinic acid synthase 2 (ALAS2), the first enzyme in erythroid heme synthesis. In both cases, protoporphyrin IX (PPIX) accumulates in erythrocytes and secondarily in plasma and tissues. Patients develop acute phototoxicity reactions upon brief exposure to sunlight. Some also experience chronic liver disease, and a small fraction develop acute cholestatic liver failure. Therapeutic options are limited, and none, save hematopoietic stem cell transplantation, directly targets erythroid PPIX accumulation. Bitopertin is an investigational orally available small-molecule inhibitor of the erythroid cell-surface glycine transporter GLYT1. We established the bitopertin PPIX inhibitory half-maximal effective concentration in a human erythroblast EPP model and confirmed a marked reduction of PPIX in erythroblasts derived from patients with EPP. We demonstrate that bitopertin also reduced erythrocyte and plasma PPIX accumulation in vivo in both EPP and XLPP mouse models. Finally, the reduction in erythroid PPIX ameliorated liver disease in the EPP mouse model. Altogether, these data support the development of bitopertin to treat patients with EPP or XLPP.
Authors
Sarah Ducamp, Min Wu, Juan Putra, Dean R. Campagna, Yi Xiang, Vu Hong, Matthew M. Heeney, Amy K. Dickey, Rebecca K. Leaf, Mark D. Fleming, Brian MacDonald, Paul J. Schmidt
Abstract
We recently described the evolution of a community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) USA300 variant responsible for an outbreak of skin and soft tissue infections. Acquisition of a mosaic version of the Φ11 prophage (mΦ11) that increases skin abscess size was an early step in CA-MRSA adaptation that primed the successful spread of the clone. The present study shows how prophage mΦ11 exerts its effect on virulence for skin infection without encoding known toxin or fitness genes. Abscess size and skin inflammation were associated with DNA methylase activity of an mΦ11-encoded adenine methyltransferase (designated pamA). pamA increased expression of fibronectin-binding protein A (fnbA; FnBPA), and inactivation of fnbA eliminated the effect of pamA on abscess virulence without affecting strains lacking pamA. Thus, fnbA is a pamA-specific virulence factor. Mechanistically, pamA was shown to promote biofilm formation in vivo in skin abscesses, a phenotype linked to FnBPA’s role in biofilm formation. Collectively, these data reveal a critical mechanism — epigenetic regulation of staphylococcal gene expression — by which phage can regulate virulence to drive adaptive leaps by S. aureus.
Authors
Robert J. Ulrich, Magdalena Podkowik, Rebecca Tierce, Irnov Irnov, Gregory Putzel, Nora M. Samhadaneh, Keenan A. Lacey, Daiane Boff, Sabrina M. Morales, Sohei Makita, Theodora K. Karagounis, Erin E. Zwack, Chunyi Zhou, Randie H. Kim, Karl Drlica, Alejandro Pironti, Harm van Bakel, Victor J. Torres, Bo Shopsin
Abstract
The role of conventional type 1 DCs (cDC1s) in tolerance induction to solid organ allografts is unknown and important for strategies that seek to prolong allograft viability. Using a murine model deficient in cDC1s, we report cDC1s are required for donor antigen and costimulation blockade (DST + CoB) tolerance induction and survival of cardiac allografts. cDC1 deficiency led to decreases in CD4+CD25+FoxP3+ T cells within allograft and spleen tissue of transplant recipients, and this was found to be antigen specific. Donor antigen stimulation induced TGF-β1 expression in both in vivo cDC1s and in vitro Flt3L-derived cDC1s. Genetic deletion of TGF-β1 in cDC1s prevented induction of antigen-specific CD4+CD25+FoxP3+ T cells and was associated with cardiac allograft rejection. In parallel, single-cell RNA sequencing and metabolic analysis revealed upregulation of cDC1 mitochondrial metabolic signatures after in vivo exposure to DST + CoB. Genetic inactivation of cDC1 mitochondrial metabolism reduced expression of cDC1 TGF-β1, decreased antigen-specific Treg populations, and impaired allograft tolerance. Taken together, our findings implicate cDC1s in strategies to preserve solid organ allografts and also implicate mitochondrial metabolism of cDC1s as a molecular mechanism to enhance the generation of antigen-specific CD4+CD25+FoxP3+ T cells through TGF-β1.
Authors
Samantha L. Schroth, Lei Zhang, Rebecca T.L. Jones, Kristofor Glinton, Nikita L. Mani, Hiroyasu Inui, Jesse T. Davidson, Samuel E. Weinberg, Navdeep S. Chandel, Maria-Luisa Alegre, Edward B. Thorp
Abstract
Chronic inflammatory diseases like rheumatoid arthritis (RA) have been described to cause CNS activation. Less is known about environmental factors that enable the CNS to suppress peripheral inflammation in RA. Here, we identified gut microbiota–derived histamine as such a factor. We showed that low levels of histamine activate the enteric nervous system, increase inhibitory neurotransmitter concentrations in the spinal cord, and restore homeostatic microglia, thereby reducing inflammation in the joints. We found that elective histamine 3 receptor (H3R) signaling in the intestine was critical for this effect, as systemic and intrathecal application did not show effects. Microglia depletion or pharmacological silencing of local nerve fibers impaired oral H3R agonist–induced pro-resolving effects on arthritis. Moreover, therapeutic supplementation of the short-chain fatty acid propionate revealed one way to expand local intestinal histamine concentrations in mice and humans. Thus, we define a gut/CNS/joint axis pathway where microbiota-derived histamine initiates the resolution of arthritis via the CNS.
Authors
Kerstin Dürholz, Leona Ehnes, Mathias Linnerbauer, Eva Schmid, Heike Danzer, Michael Hinzpeter-Schmidt, Lena Lößlein, Lena Amend, Michael Frech, Vugar Azizov, Fabian Schälter, Arne Gessner, Sébastien Lucas, Till-Robin Lesker, R. Verena Taudte, Jörg Hofmann, Felix Beyer, Hadar Bootz-Maoz, Yasmin Reich, Hadar Romano, Daniele Mauro, Ruth Beckervordersandforth, Maja Skov Kragsnaes, Torkell Ellingsen, Wei Xiang, Aiden Haghikia, Cezmi A. Akdis, Francesco Ciccia, Tobias Bäuerle, Kerstin Sarter, Till Strowig, Nissan Yissachar, Georg Schett, Veit Rothhammer, Mario M. Zaiss
Abstract
Inactivation of cyclin-dependent kinase 12 (CDK12) defines an immunogenic molecular subtype of prostate cancer characterized by genomic instability and increased intratumoral T cell infiltration. This study revealed that genetic or pharmacologic inactivation of CDK12 and its paralog CDK13 robustly activates stimulator of interferon genes (STING) signaling across multiple cancer types. Clinical cohort analysis showed that reduced CDK12/13 expression correlates with improved survival and response to immune checkpoint blockade (ICB). Mechanistically, CDK12/13 depletion or targeted degradation induced cytosolic nucleic acid release, triggering STING pathway activation. CDK12/13 degradation delayed tumor growth and synergized with anti–PD-1 therapy in syngeneic tumor models, enhancing STING activity and promoting CD8+ T cell infiltration and activation within tumors. Notably, the antitumor effects of this combination required STING signaling and functional CD8+ T cells. These findings establish STING activation as the key driver of T cell infiltration and the immune-hot tumor microenvironment in CDK12-mutant cancers, suggesting that dual CDK12/13 inhibitors and degraders activate antitumor immunity and potentiate responses to immunotherapies.
Authors
Yi Bao, Yu Chang, Jean Ching-Yi Tien, Gabriel Cruz, Fan Yang, Rahul Mannan, Somnath Mahapatra, Radha Paturu, Xuhong Cao, Fengyun Su, Rui Wang, Yuping Zhang, Mahnoor Gondal, Jae Eun Choi, Jonathan K. Gurkan, Stephanie J. Miner, Dan R. Robinson, Yi-Mi Wu, Licheng Zhou, Zhen Wang, Ilona Kryczek, Xiaoju Wang, Marcin Cieslik, Yuanyuan Qiao, Alexander Tsodikov, Weiping Zou, Ke Ding, Arul M. Chinnaiyan
Abstract
Group 2 innate lymphoid cells (ILC2s) play a crucial role in inducing type 2 inflammation in the lungs in response to allergens. Our study investigated the regulatory mechanism of IL-10 production by ILC2s and its impact on airway hyperreactivity (AHR), focusing on the role of ICOS. We found that inhibiting ICOS in pulmonary ILC2s significantly enhanced IL-10 production. The absence of ICOS reprogrammed ILC2 steroid metabolism, leading to increased cholesterol and cortisol biosynthesis and subsequent glucocorticoid receptor (GR) activation. This reprogramming regulated MAF and NFIL3 activation, promoting IL-10 production. Notably, in vivo GR inhibition or ILC2-specific GR deficiency exacerbated AHR development in multiple mouse models. We extended these findings to human ILC2s, demonstrating concordant results between murine models and human cells. Our results indicate that ICOS negatively regulates IL-10 production in ILC2s by controlling cholesterol and cortisol biosynthesis. This mechanism provides new insights into the complex interplay between ILC2s, ICOS, and glucocorticoid signaling in the context of allergic airway inflammation.
Authors
Yoshihiro Sakano, Kei Sakano, Benjamin P. Hurrell, Mohammad H. Kazemi, Xin Li, Stephen Shen, Omid Akbari
Abstract
Somatic mutations that increase clone fitness or resist disease are positively selected, but the impact of these mutations on organismal health remains unclear. We previously showed that Tbx3 deletion increases hepatocyte fitness within fatty livers. Here, we detected TBX3 somatic mutations in patients with metabolic dysfunction–associated steatotic liver disease (MASLD). In mice, Tbx3 deletion protected against, whereas Tbx3 overexpression exacerbated, MASLD. Tbx3 deletion reduced lipid overload by accelerating VLDL secretion. Choline-deficient diets, which block VLDL secretion, abrogated this protective effect. TBX3 transcriptionally suppressed the conventional secretory pathway and cholesterol biosynthesis. Hdlbp is a direct target of TBX3 that is responsible for the altered VLDL secretion. In contrast to wild-type TBX3, the TBX3 I155S and A280S mutations found in patients failed to suppress VLDL secretion. In conclusion, TBX3 mutant clones expand during MASLD through increased lipid disposal, demonstrating that clonal fitness can benefit the liver at the cost of hyperlipidemia.
Authors
Gregory Mannino, Gabriella Quinn, Min Zhu, Zixi Wang, Xun Wang, Boyuan Li, Meng-Hsiung Hsieh, Thomas Mathews, Lauren Zacharias, Wen Gu, Purva Gopal, Natalia Brzozowska, Peter Campbell, Matt Hoare, Glen Liszczak, Hao Zhu
Abstract
Hypertonic and hyperosmolar stimuli frequently pose challenges to the intestinal tract. Therefore, a resilient epithelial barrier is essential for maintaining gut homeostasis in the presence of osmotic perturbations. Nuclear factor of activated T cells 5 (NFAT5), an osmosensitive transcription factor, primarily maintains cellular homeostasis under hypertonic conditions. However, the osmoprotective role of NFAT5 in enterocyte homeostasis is poorly understood. Here, we demonstrate that NFAT5 was critical for the survival and proliferation of intestinal epithelial cells (IECs) and that its deficiency accelerated chemically induced or spontaneous colitis in mice. Mechanistically, NFAT5 promoted the survival of IECs and the renewal of intestinal stem cells, thereby regulating the production of mucus and antimicrobial compounds, including RegIII and lysozyme, which consequently shape the gut microbial composition to prevent colitis. Transcriptome analysis identified HSP70 as a key downstream target of NFAT5 in epithelial regeneration. Loss- and gain-of-function experiments involving HSP70 revealed that NFAT5 mitigated experimental colitis through IEC Hsp70, which protected stem cells from inflammation-induced injury and maintained barrier function. In conclusion, our study demonstrates what we believe to be a previously unknown role for NFAT5 in dictating the crosstalk between intestinal stem cells and the microbiota, underscoring the importance of the NFAT5/HSP70 axis in maintaining epithelial regeneration related to gut barrier function, balancing microbial composition, and subsequently preventing colitis progression.
Authors
Se-Hyeon Park, Dae Hee Cheon, Yu-Mi Kim, Yeji Choi, Yong-Joon Cho, Bong-Ki Hong, Sang-Hyun Cho, Mi-Na Kweon, Hyug Moo Kwon, Eugene B. Chang, Donghyun Kim, Wan-Uk Kim
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ISSN: 0021-9738 (print), 1558-8238 (online)