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The role of complement in long COVID pathogenesis
Rafael Bayarri-Olmos, … , William Bain, Akiko Iwasaki
Rafael Bayarri-Olmos, … , William Bain, Akiko Iwasaki
Published August 22, 2025
Citation Information: JCI Insight. 2025;10(16):e194314. https://doi.org/10.1172/jci.insight.194314.
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The role of complement in long COVID pathogenesis

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Abstract

Long COVID is a debilitating condition that can develop after a SARS-CoV-2 infection and is characterized by a wide range of chronic symptoms, including weakness, neurocognitive impairment, malaise, fatigue, and many others, that affect multiple organ systems. At least 10% of individuals with a previous infection may develop long COVID, which affects their ability to perform daily functions and work. Despite its severity and widespread impact, this multisystemic condition remains poorly understood. Recent studies suggest that dysregulation of the complement system, a key component of the innate immune response, may contribute to the pathogenesis of long COVID, particularly in connection with coagulation, inflammation, and vascular injury. In this Review, we examine the evidence linking complement system dysregulation to long COVID and explore its potential role in driving disease pathology.

Authors

Rafael Bayarri-Olmos, William Bain, Akiko Iwasaki

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Enhancing the potency of CAR-T cells against solid tumors through transcription factor engineering
Ruoqi Chen, … , Xingchao Shentu, Jie Sun
Ruoqi Chen, … , Xingchao Shentu, Jie Sun
Published July 22, 2025
Citation Information: JCI Insight. 2025;10(14):e193048. https://doi.org/10.1172/jci.insight.193048.
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Enhancing the potency of CAR-T cells against solid tumors through transcription factor engineering

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Abstract

Transcription factors (TFs) play a pivotal role in the development and differentiation of T cells. Recent studies have highlighted unique transcriptional profiles in chimeric antigen receptor T (CAR-T) cells derived from patients with favorable clinical outcomes, suggesting a potential link between TF modulation and improved therapeutic efficacy. Although CAR-T cell therapies have shown some success in treating hematological malignancies, they are limited by challenges such as poor persistence, functional exhaustion, and tumor resistance. To overcome these limitations, researchers have attempted to enhance the efficacy of CAR-T cells through manipulation of TF expression. This Review provides a comprehensive overview of TF engineering in CAR-T cells and elucidates the complex regulatory network between TFs. Notably, modification of basic leucine zipper ATF-like transcription factor in CAR-T cells results in contradictory functional outcomes in different studies. We summarize the potential factors leading to such results and elucidate the importance of setting up a relevant in vitro model to evaluate the effect of TFs on CAR-T cells. In conclusion, this Review highlights the latest advances in TF modifications and proposes strategies for harnessing these insights to empower CAR-T cells with superior antitumor efficacy.

Authors

Ruoqi Chen, Lianqing Chen, Yu Tang, Xiaolin Shen, Yajie Wang, Peng Tang, Xingchao Shentu, Jie Sun

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Transcriptional signatures of endothelial cells shape immune responses in cardiopulmonary health and disease
Elisabeth Fließer, … , Andrew H. Baker, Grazyna Kwapiszewska
Elisabeth Fließer, … , Andrew H. Baker, Grazyna Kwapiszewska
Published May 22, 2025
Citation Information: JCI Insight. 2025;10(10):e191059. https://doi.org/10.1172/jci.insight.191059.
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Transcriptional signatures of endothelial cells shape immune responses in cardiopulmonary health and disease

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Abstract

The cardiopulmonary vasculature and its associated endothelial cells (ECs) play an essential role in sustaining life by ensuring the delivery of oxygen and nutrients. Beyond these foundational functions, ECs serve as key regulators of immune responses. Recent advances in single-cell RNA sequencing have revealed that the cardiopulmonary vasculature is composed of diverse EC subpopulations, some of which exhibit specialized immunomodulatory properties. Evidence for immunomodulation includes distinct expression profiles associated with antigen presentation, cytokine secretion, immune cell recruitment, translocation, and clearance — functions critical for maintaining homeostasis in the heart and lungs. In cardiopulmonary diseases, ECs undergo substantial transcriptional reprogramming, leading to a shift from homeostasis to an activated state marked by heightened immunomodulatory activity. This transformation has highlighted the critical role for ECs in disease pathogenesis and their potential as future therapy targets. This Review emphasizes the diverse functions of ECs in the heart and lungs, particularly adaptive and maladaptive immunoregulatory roles in cardiopulmonary health and disease.

Authors

Elisabeth Fließer, Katharina Jandl, Shiau-Haln Chen, Mei-Tzu Wang, Jonas C. Schupp, Wolfgang M. Kuebler, Andrew H. Baker, Grazyna Kwapiszewska

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The immune system and metabolic products in epilepsy and glioma-associated epilepsy: emerging therapeutic directions
Shashwat Tripathi, … , Stephen D. Miller, Amy B. Heimberger
Shashwat Tripathi, … , Stephen D. Miller, Amy B. Heimberger
Published January 9, 2024
Citation Information: JCI Insight. 2024;9(1):e174753. https://doi.org/10.1172/jci.insight.174753.
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The immune system and metabolic products in epilepsy and glioma-associated epilepsy: emerging therapeutic directions

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Abstract

Epilepsy has a profound impact on quality of life. Despite the development of new antiseizure medications (ASMs), approximately one-third of affected patients have drug-refractory epilepsy and are nonresponsive to medical treatment. Nearly all currently approved ASMs target neuronal activity through ion channel modulation. Recent human and animal model studies have implicated new immunotherapeutic and metabolomic approaches that may benefit patients with epilepsy. In this Review, we detail the proinflammatory immune landscape of epilepsy and contrast this with the immunosuppressive microenvironment in patients with glioma-related epilepsy. In the tumor setting, excessive neuronal activity facilitates immunosuppression, thereby contributing to subsequent glioma progression. Metabolic modulation of the IDH1-mutant pathway provides a dual pathway for reversing immune suppression and dampening seizure activity. Elucidating the relationship between neurons and immunoreactivity is an area for the prioritization and development of the next era of ASMs.

Authors

Shashwat Tripathi, Cody L. Nathan, Matthew C. Tate, Craig M. Horbinski, Jessica W. Templer, Joshua M. Rosenow, Timothy L. Sita, Charles D. James, Benjamin Deneen, Stephen D. Miller, Amy B. Heimberger

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Muscle: an independent contributor to the neuromuscular spinal muscular atrophy disease phenotype
Narendra N. Jha, … , Yoon-Ra Her, Umrao R. Monani
Narendra N. Jha, … , Yoon-Ra Her, Umrao R. Monani
Published September 22, 2023
Citation Information: JCI Insight. 2023;8(18):e171878. https://doi.org/10.1172/jci.insight.171878.
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Muscle: an independent contributor to the neuromuscular spinal muscular atrophy disease phenotype

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Abstract

Spinal muscular atrophy (SMA) is a pediatric-onset neuromuscular disorder caused by insufficient survival motor neuron (SMN) protein. SMN restorative therapies are now approved for the treatment of SMA; however, they are not curative, likely due to a combination of imperfect treatment timing, inadequate SMN augmentation, and failure to optimally target relevant organs. Here, we consider the implications of imperfect treatment administration, focusing specifically on outcomes for skeletal muscle. We examine the evidence that muscle plays a contributing role in driving neuromuscular dysfunction in SMA. Next, we discuss how SMN might regulate the health of myofibers and their progenitors. Finally, we speculate on therapeutic outcomes of failing to raise muscle SMN to healthful levels and present strategies to restore function to this tissue to ensure better treatment results.

Authors

Narendra N. Jha, Jeong-Ki Kim, Yoon-Ra Her, Umrao R. Monani

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Vascular changes in the cycling and early pregnant uterus
Noura Massri, … , Ripla Arora, Nataki C. Douglas
Noura Massri, … , Ripla Arora, Nataki C. Douglas
Published June 8, 2023
Citation Information: JCI Insight. 2023;8(11):e163422. https://doi.org/10.1172/jci.insight.163422.
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Vascular changes in the cycling and early pregnant uterus

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Abstract

Uterine vascular remodeling is intrinsic to the cycling and early pregnant endometrium. Maternal regulatory factors such as ovarian hormones, VEGF, angiopoietins, Notch, and uterine natural killer cells significantly mediate these vascular changes. In the absence of pregnancy, changes in uterine vessel morphology and function correlate with different stages of the human menstrual cycle. During early pregnancy, vascular remodeling in rodents and humans results in decreased uterine vascular resistance and increased vascular permeability necessary for pregnancy success. Aberrations in these adaptive vascular processes contribute to increased risk of infertility, abnormal fetal growth, and/or preeclampsia. This Review comprehensively summarizes uterine vascular remodeling in the human menstrual cycle, and in the peri- and post-implantation stages in rodent species (mice and rats).

Authors

Noura Massri, Rachel Loia, Jennifer L. Sones, Ripla Arora, Nataki C. Douglas

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Contemporary perspectives on heterotopic ossification
Charles D. Hwang, … , Aaron W. James, Benjamin Levi
Charles D. Hwang, … , Aaron W. James, Benjamin Levi
Published July 22, 2022
Citation Information: JCI Insight. 2022;7(14):e158996. https://doi.org/10.1172/jci.insight.158996.
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Contemporary perspectives on heterotopic ossification

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Abstract

Heterotopic ossification (HO) is the formation of ectopic bone that is primarily genetically driven (fibrodysplasia ossificans progressiva [FOP]) or acquired in the setting of trauma (tHO). HO has undergone intense investigation, especially over the last 50 years, as awareness has increased around improving clinical technologies and incidence, such as with ongoing wartime conflicts. Current treatments for tHO and FOP remain prophylactic and include NSAIDs and glucocorticoids, respectively, whereas other proposed therapeutic modalities exhibit prohibitive risk profiles. Contemporary studies have elucidated mechanisms behind tHO and FOP and have described new distinct niches independent of inflammation that regulate ectopic bone formation. These investigations have propagated a paradigm shift in the approach to treatment and management of a historically difficult surgical problem, with ongoing clinical trials and promising new targets.

Authors

Charles D. Hwang, Chase A. Pagani, Johanna H. Nunez, Masnsen Cherief, Qizhi Qin, Mario Gomez-Salazar, Balram Kadaikal, Heeseog Kang, Ashish R. Chowdary, Nicole Patel, Aaron W. James, Benjamin Levi

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MicroRNAs in kidney development and disease
Débora Malta Cerqueira, … , Maliha Tayeb, Jacqueline Ho
Débora Malta Cerqueira, … , Maliha Tayeb, Jacqueline Ho
Published May 9, 2022
Citation Information: JCI Insight. 2022;7(9):e158277. https://doi.org/10.1172/jci.insight.158277.
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MicroRNAs in kidney development and disease

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Abstract

MicroRNAs (miRNAs) belong to a class of endogenous small noncoding RNAs that regulate gene expression at the posttranscriptional level, through both translational repression and mRNA destabilization. They are key regulators of kidney morphogenesis, modulating diverse biological processes in different renal cell lineages. Dysregulation of miRNA expression disrupts early kidney development and has been implicated in the pathogenesis of developmental kidney diseases. In this Review, we summarize current knowledge of miRNA biogenesis and function and discuss in detail the role of miRNAs in kidney morphogenesis and developmental kidney diseases, including congenital anomalies of the kidney and urinary tract and Wilms tumor. We conclude by discussing the utility of miRNAs as potentially novel biomarkers and therapeutic agents.

Authors

Débora Malta Cerqueira, Maliha Tayeb, Jacqueline Ho

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Human inhibitory leukocyte Ig-like receptors: from immunotolerance to immunotherapy
Calvin D. De Louche, Ali Roghanian
Calvin D. De Louche, Ali Roghanian
Published January 25, 2022
Citation Information: JCI Insight. 2022;7(2):e151553. https://doi.org/10.1172/jci.insight.151553.
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Human inhibitory leukocyte Ig-like receptors: from immunotolerance to immunotherapy

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Abstract

In recent decades, immunotherapeutic strategies have been used to treat a wide range of pathologies, many of which were previously incurable, such as cancer and autoimmune disorders. Despite this unprecedented success, a considerable number of patients fail to respond to currently approved immunotherapies or develop resistance over time. Therefore, there is an urgent need to develop the next generation of immune-targeted therapies. Various members of the Ig superfamily play essential roles in regulating leukocyte functions. One such group, the leukocyte Ig-like receptors (LILRs), have been implicated in both innate and adaptive immune regulation. Human inhibitory LILRs (LILRBs) are primarily expressed on leukocytes and mediate their signaling through multiple cytoplasmic immunoreceptor tyrosine-based inhibitory motifs. Engagement of LILRBs by endogenous and pathogenic ligands can markedly suppress immune responses, leading to tolerance or immunoevasion, whereas blocking these inhibitory receptors can potentiate immune responses. In this Review, we discuss the immunoregulatory functions of human LILRBs and the potential of targeting them to manipulate immune responses in various pathologies.

Authors

Calvin D. De Louche, Ali Roghanian

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Targeting the undruggable oncogenic KRAS: the dawn of hope
Hande Asimgil, … , Güralp Onur Ceyhan, Ihsan Ekin Demir
Hande Asimgil, … , Güralp Onur Ceyhan, Ihsan Ekin Demir
Published January 11, 2022
Citation Information: JCI Insight. 2022;7(1):e153688. https://doi.org/10.1172/jci.insight.153688.
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Targeting the undruggable oncogenic KRAS: the dawn of hope

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Abstract

KRAS mutations are the drivers of various cancers, including non–small cell lung cancer, colon cancer, and pancreatic cancer. Over the last 30 years, immense efforts have been made to inhibit KRAS mutants and oncogenic KRAS signaling using inhibitors. Recently, specific targeting of KRAS mutants with small molecules revived the hopes for successful therapies for lung, pancreatic, and colorectal cancer patients. Moreover, advances in gene editing, protein engineering, and drug delivery formulations have revolutionized cancer therapy regimens. New therapies aim to improve immune surveillance and enhance antitumor immunity by precisely targeting cancer cells harboring oncogenic KRAS. Here, we review recent KRAS-targeting strategies, their therapeutic potential, and remaining challenges to overcome. We also highlight the potential synergistic effects of various combinatorial therapies in preclinical and clinical trials.

Authors

Hande Asimgil, Utku Ertetik, Nedim Can Çevik, Menar Ekizce, Alper Doğruöz, Muazzez Gökalp, Elif Arık-Sever, Rouzanna Istvanffy, Helmut Friess, Güralp Onur Ceyhan, Ihsan Ekin Demir

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