Zhu et al. report that reduced expression of cold-inducible RNA-binding protein (CIRBP) in aged donor hearts promotes ferroptosis and blunts cardioprotective effects of hypothermia during heart transplantation in a rat model. Image credit: Shanghai Bangtu Culture Media Co.
Alyssa Duffy, Maryam I. Azeem, Smriti Kanangat, Melinda Yushak, David Lawson, Madhav V. Dhodapkar, Kavita M. Dhodapkar
We describe a previously-unappreciated role for Bruton's tyrosine kinase (BTK) in fungal immune surveillance against aspergillosis, an unforeseen complication of BTK inhibitors (BTKi) used for treating B-cell lymphoid malignancies. We studied BTK-dependent fungal responses in neutrophils from diverse populations, including healthy donors, BTKi-treated patients, and X-linked agammaglobulinemia patients. Upon fungal exposure, BTK was activated in human neutrophils in a TLR2-, Dectin-1-, and FcγR-dependent manner, triggering the oxidative burst. BTK inhibition selectively impeded neutrophil-mediated damage to Aspergillus hyphae, primary granule release, and the fungus-induced oxidative burst by abrogating NADPH oxidase subunit p40phox and GTPase RAC2 activation. Moreover, neutrophil-specific Btk deletion in mice enhanced aspergillosis susceptibility by impairing neutrophil function, not recruitment or lifespan. Conversely, GM-CSF partially mitigated these deficits by enhancing p47phox activation. Our findings underline the crucial role of BTK signaling in neutrophils for antifungal immunity and provide a rationale for GM-CSF use to offset these deficits in susceptible patients.
Jigar V. Desai, Marissa A. Zarakas, Andrew L. Wishart, Mark Roschewski, Mariano A. Aufiero, Ágnes Donkó, Gustaf Wigerblad, Neta Shlezinger, Markus Plate, Matthew R. James, Jean K. Lim, Gulbu Uzel, Jenna R.E. Bergerson, Ivan Fuss, Robert A. Cramer, Luis M. Franco, Emily S. Clark, Wasif N. Khan, Daisuke Yamanaka, Georgios Chamilos, Jamel El-Benna, Mariana J. Kaplan, Louis M. Staudt, Thomas L. Leto, Steven M. Holland, Wyndham H. Wilson, Tobias M. Hohl, Michail S. Lionakis
Dicarboxylic fatty acids are generated in the liver and kidney in a minor pathway called fatty acid ω-oxidation. The effects of consuming dicarboxylic fatty acids as an alternative source of dietary fat have not been explored. Here, we fed dodecanedioic acid, a 12-carbon dicarboxylic (DC12), to mice at 20% of daily caloric intake for nine weeks. DC12 increased metabolic rate, reduced body fat, reduced liver fat, and improved glucose tolerance. We observed DC12-specific breakdown products in liver, kidney, muscle, heart, and brain, indicating that oral DC12 escaped first-pass liver metabolism and was utilized by many tissues. In tissues expressing the “a” isoform of acyl-CoA oxidase-1 (ACOX1), a key peroxisomal fatty acid oxidation enzyme, DC12 was chain shortened to the TCA cycle intermediate succinyl-CoA. In tissues with low peroxisomal fatty acid oxidation capacity, DC12 was oxidized by mitochondria. In vitro, DC12 was catabolized even by adipose tissue and was not stored intracellularly. We conclude that DC12 and other dicarboxylic acids may be useful for combatting obesity and for treating metabolic disorders.
Eric S. Goetzman, Bob B. Zhang, Yuxun Zhang, Sivakama S. Bharathi, Joanna Bons, Jacob Rose, Samah Shah, Keaton J. Solo, Alexandra V. Schmidt, Adam C. Richert, Steven J. Mullett, Stacy L. Gelhaus, Krithika S. Rao, Sruti S. Shiva, Katherine E. Pfister, Anne Silva Barbosa, Sunder Sims-Lucas, Steven F. Dobrowolski, Birgit Schilling
One critical mechanism through which prostate cancer (PCa) adapts to treatments targeting androgen receptor (AR) signaling is the emergence of ligand-binding domain-truncated and constitutively active AR splice variants, particularly AR-V7. While AR-V7 has been intensively studied, its ability to activate distinct biological functions compared to the full-length AR (AR-FL), and its role in regulating the metastatic progression of castration-resistant PCa (CRPC), remains unclear. Our study found that, under castrated conditions, AR-V7 strongly induced osteoblastic bone lesions, a response not observed with AR-FL overexpression. Through combined ChIP-seq, ATAC-seq, and RNA-seq analyses, we demonstrated that AR-V7 uniquely accesses the androgen-responsive elements in compact chromatin regions, activating a distinct transcription program. This program was highly enriched for genes involved in epithelial-mesenchymal transition and metastasis. Notably, we discovered that SOX9, a critical metastasis driver gene, was a direct target and downstream effector of AR-V7. Its protein expression was dramatically upregulated in AR-V7-induced bone lesions. Moreover, we found that Ser81 phosphorylation enhanced AR-V7’s pro-metastasis function by selectively altering its specific transcription program. Blocking this phosphorylation with CDK9 inhibitors impaired the AR-V7-mediated metastasis program. Overall, our study has provided molecular insights into the role of AR splice variants in driving the metastatic progression of CRPC.
Dong Han, Maryam Labaf, Yawei Zhao, Jude Owiredu, Songqi Zhang, Krishna Patel, Kavita Venkataramani, Jocelyn S. Steinfeld, Wanting Han, Muqing Li, Mingyu Liu, Zifeng Wang, Anna Besschetnova, Susan Patalano, Michaela J. Mulhearn, Jill A. Macoska, Xin Yuan, Steven P. Balk, Peter S. Nelson, Stephen R. Plymate, Shuai Gao, Kellee R. Siegfried, Ruihua Liu, Mary M. Stangis, Gabrielle Foxa, Piotr J. Czernik, Bart O. Williams, Kourosh Zarringhalam, Xiaohong Li, Changmeng Cai
Neuroinflammation is a recognized complication of immunotherapeutic approaches such as immune checkpoint inhibitor treatment, chimeric antigen receptor therapy, and graft versus host disease (GVHD) occurring after allogeneic hematopoietic stem cell transplantation. While T cells and inflammatory cytokines play a role in this process, the precise interplay between the adaptive and innate arms of the immune system that propagates inflammation in the central nervous system remains incompletely understood. Using a murine model of GVHD, we demonstrate that type 2 cannabinoid receptor (CB2R) signaling plays a critical role in the pathophysiology of neuroinflammation. In these studies, we identify that CB2R expression on microglial cells induces an activated inflammatory phenotype which potentiates the accumulation of donor-derived proinflammatory T cells, regulates chemokine gene regulatory networks, and promotes neuronal cell death. Pharmacological targeting of this receptor with a brain penetrant CB2R inverse agonist/antagonist selectively reduces neuroinflammation without deleteriously affecting systemic GVHD severity. Thus, these findings delineate a therapeutically targetable neuroinflammatory pathway and has implications for the attenuation of neurotoxicity after GVHD and potentially other T cell-based immunotherapeutic approaches.
Alison Moe, Aditya Rayasam, Garrett Sauber, Ravi K. Shah, Ashley Doherty, Cheng-Yin Yuan, Aniko Szabo, Bob M. Moore II, Marco Colonna, Weiguo Cui, Julian Romero, Anthony E. Zamora, Cecilia J. Hillard, William R. Drobyski
JCI celebrates a century of publishing scientific discoveries with a special collection highlighting major innovations in medicine and key contributing mechanistic studies.
Vascular malformations in arteries, veins, and lymphatic vessels occur in a broad range of conditions that vary widely in severity and presentation. Leveraging the mechanisms specific to each type of malformation will be essential for optimizing disease management. This review series, developed with series editor Miikka Vikkula, will span hemangioma, hereditary hemorrhagic telangiectasia, lymphatic abnormalities, cerebral small vessel disease, capillary malformations, and more, with reviews contributed by leading experts in each condition.
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