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Citation Information: JCI Insight. 2025. https://doi.org/10.1172/jci.insight.186890.
Abstract
BACKGROUND. Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related mortality necessitating the exploration of alternate therapeutic approaches. Tumor reactive or activated-by-cytokine killers (TRACK) are PD-L1+ highly cytolytic natural killer (NK) cells derived from umbilical cord blood NK cells and engineered to express soluble IL15 (sIL15), showing promise in preclinical studies against NSCLC. METHODS. We assessed safety, persistence, homing and cytotoxic activity in six patients with advanced, refractory, and progressing NSCLC who received a low dose of unmatched, allogeneic, off-the-shelf sIL15_TRACK NK cells. We evaluated NK cell presence and persistence with droplet digital (dd) PCR, flow cytometry, and immunofluorescent staining. RESULTS. sIL15_TRACK NK cells had peak measurements at one hour and became undetectable four hours after each in fusion. Cognate ligands to activating NK cell receptors were found in NSCLC. sIL15_TRACK NK cells were observed in a lung tumor biopsy seven days after the final infusion, confirming their sustainment and tumor-homing ability. They retained cytolytic function following isolation from the lung tumor. Three out of six patients achieved disease stabilization on repeat imaging, while the others progressed. CONCLUSION. Unmatched, allogeneic, cryopreserved, off-the-shelf sIL15_TRACK NK cells express activating receptors, home to tumor sites that express their cognate ligands, and retain cytolytic activity after infusion, underscoring their potential as a therapeutic approach in solid tumors. At low doses, the therapy was safely administered and showed preliminary evidence of activity in three of six patients with advanced and progressive NSCLC. Additional dose escalation cohorts and co-administration with atezolizumab are planned. TRIAL REGISTRATION. ClinicalTrials.gov NCT05334329 FUNDING. Funding was provided by CytoImmune Therapeutics; CA266457; CA033572; CA210087.
Authors
Miguel A. Villalona-Calero, Lei Tian, Xiaochen Li, Joycelynne M. Palmer, Claudia Aceves, Hans Meisen, Catherine Cortez, Timothy W. Synold, Colt Egelston, Jeffrey VanDeusen, Ivone Bruno, Lei Zhang, Eliezer Romeu-Bonilla, Omer Butt, Stephen J. Forman, Michael A. Caligiuri, Jianhua Yu
Citation Information: JCI Insight. 2025. https://doi.org/10.1172/jci.insight.186456.
Abstract
Induction of podoplanin (PDPN) expression is a critical response of macrophages to LPS stimulation or bacterial infection in sepsis, but how this key process of TLR4-stimulated PDPN upregulation is regulated and the impact of PDPN expression on macrophage function remain elusive. Here, we determined how this process is regulated in vitro and in vivo. PDPN failed to be upregulated in TLR4 stimulated macrophages deficient in adhesion and degranulation-promoting adapter protein (ADAP), which could be rescued by the reconstitution of ADAP. A distinct PDPNhi peritoneal macrophage (PM) subset, which exhibited an M2-like phenotype and enhanced phagocytic activity, was generated in WT but not in ADAP-deficient septic mice. The blockade of PDPNhi PMs mimicked the effect of ADAP deficiency, which exacerbated sepsis. Mechanistically, BTK-mediated ADAP Y571 phosphorylation worked together with mTOR to converge on STAT3 activation for the transactivation of the PDPN promoter. Moreover, agonist activation of STAT3 profoundly potentiated the PDPNhi PM subset generation and alleviated sepsis severity in mice. Together, our findings reveal a mechanism whereby ADAP resets macrophage function by controlling the TLR4-induced upregulation of PDPN as a host innate immune defense during sepsis.
Authors
Pengchao Zhang, Xinning Wang, Xiaodong Yang, Hebin Liu
Citation Information: JCI Insight. 2025. https://doi.org/10.1172/jci.insight.184491.
Abstract
Despite combination antiretroviral therapy (ART), HIV causes persistent gut barrier dysfunction, immune depletion, and dysbiosis. Further, ART interruption results in reservoir reactivation and rebound viremia. Both IL-21 and anti-α4β7 improve gut barrier functions, and we hypothesized combining them would synergize as a dual therapy to improve immunological outcomes in SIV-infected rhesus macaques (RMs). We found no significant differences in CD4+ T-cell reservoir size by intact proviral DNA assay. SIV rebounded in both dual-treated and control RMs following analytical therapy interruption (ATI), with time to rebound and initial rebound viremia comparable between groups; however, dual-treated RMs showed slightly better control of viral replication at the latest time points post-ATI. Additionally, following post-ATI, dual-treated RMs showed immunological benefits, including T-cell preservation and lower PD-1+ central memory T-cell (TCM) frequency. Notably, PD-1+ TCMs were associated with reservoir size, which predicted viral loads (VLs) post-ATI. Finally, 16S rRNA sequencing revealed better recovery from dysbiosis in treated animals, and the butyrate-producing Firmicute Roseburia predicted PD-1-expressing TCMs and VLs after ATI. PD-1+ TCMs and gut dysbiosis represent mechanisms of HIV persistence and pathogenesis, respectively. Therefore, combining IL-21 and anti-α4β7 may be an effective therapeutic strategy to improve immunological outcomes for people with HIV.
Authors
Samuel D. Johnson, Maria Pino, Arpan Acharya, Julien A. Clain, Deepanwita Bose, Kevin Nguyen, Justin Harper, Francois Villinger, Mirko Paiardini, Siddappa N. Byrareddy
Citation Information: JCI Insight. 2025. https://doi.org/10.1172/jci.insight.187899.
Abstract
Lymphangioleiomyomatosis (LAM) is a progressive lung disease with limited treatments, largely due to an incomplete understanding of its pathogenesis. Lymphatic endothelial cells (LECs) invade LAM cell clusters, which include HMB-45-positive epithelioid cells and smooth muscle α-actin-expressing LAM-associated fibroblasts (LAMFs). Recent evidence shows that LAMFs resemble cancer-associated fibroblasts, with LAMF-LEC interactions contributing to disease progression. To explore these mechanisms, we used spatial transcriptomics on LAM lung tissues and identified a gene cluster enriched in kinase signaling pathways linked to myofibroblasts and co-expressed with LEC markers. Kinase arrays revealed elevated PDGFR and FGFR in LAMFs. Using a 3D co-culture spheroid model of primary LAMFs and LECs, we observed increased invasion in LAMF-LEC spheroids compared to non-LAM fibroblasts. Treatment with sorafenib, a multikinase inhibitor, significantly reduced invasion, outperforming Rapamycin. We also confirmed TSC2-deficient renal angiomyolipoma cells (TSC2-null AML) as key VEGF-A secretors, which was suppressed by sorafenib in both TSC2-null AML cells and LAMFs. These findings highlight VEGF-A and bFGF as potential therapeutic targets and suggest multikinase inhibition as a promising strategy for LAM.
Authors
Sinem Koc-Gunel, Emily C. Liu, Lalit K. Gautam, Ben A. Calvert, Shubha Murthy, Noa C. Harriott, Janna C. Nawroth, Beiyun Zhou, Vera P. Krymskaya, Amy L. Ryan
Citation Information: JCI Insight. 2025. https://doi.org/10.1172/jci.insight.189150.
Abstract
BACKGROUND. Lymphopenia and failure of lymphocytes to mount an early IFN-γ response correlate with increased mortality in COVID-19. Given the essential role of CD4 helper and CD8 cytotoxic cells in eliminating viral pathogens, this profound loss in lymphocytes may impair patients’ ability to eliminate the virus. IL-7 is a pleiotropic cytokine that is obligatory for lymphocyte survival and optimal function. METHODS. We conducted a prospective, double-blind, randomized, placebo-controlled trial of CYT107, recombinant human IL-7, in 109 critically-ill lymphopenic COVID-19 patients. The primary endpoint was to assess CYT107’s effect on lymphocyte recovery with secondary clinical endpoints including safety, ICU and hospital length-of-stay, incidence of secondary infections, and mortality. RESULTS. CYT107 was well-tolerated without precipitating a cytokine storm or worsening pulmonary function. Absolute lymphocyte counts increased in both groups without significant difference between CYT107 and placebo. COVID-19 patients receiving CYT107 but not concomitant antiviral medications, known inducers of lymphopenia, had a final lymphocyte count that was 43% greater than placebo (p=0.067). There were significantly fewer treatment-emergent adverse events in CYT107 versus placebo-treated patients (p<0.001), consistent with a beneficial drug effect. Importantly, CYT107 treated patients had 44% fewer hospital-acquired infections versus placebo-treated patients (p=0.014). CONCLUSIONS. Given that hospital-acquired infections are responsible for a large percentage of COVID-19 deaths, this effect of CYT107 to decrease nosocomial infections could substantially reduce late morbidity and mortality in this highly lethal disease. The strong safety profile of CYT107 and its excellent tolerability provide support for trials of CYT107 in other potential pandemic respiratory viral infections. TRIAL REGISTRATION. NCT04379076, NCT04426201, NCT04442178, NCT04407689; NCT04927169
Authors
Manu Shankar-Hari, Bruno Francois, Kenneth E. Remy, Cristina Gutierrez, Stephen Pastores, Thomas Daix, Robin Jeannet, Jane Blood, Andrew H. Walton, Reinaldo Salomao, Georg Auzinger, David Striker, Robert S. Martin, Nitin J. Anand, James Bosanquet, Teresa Blood, Scott Brakenridge, Lyle L. Moldawer, Vidula Vachharajani, Cassian Yee, Felipe Dal-Pizzol, Michel Morre, Frederique Berbille, Marcel van den Brink, Richard Hotchkiss
Citation Information: JCI Insight. 2025. https://doi.org/10.1172/jci.insight.176839.
Abstract
The standard-of-care treatment of locally advanced cervical cancer includes pelvic radiation therapy with concurrent cisplatin-based chemotherapy and is associated with a 30-50% failure rate. New prognostic and therapeutic targets are needed to improve clinical outcomes. The vaginal microbiome has been linked to the pathogenesis of cervical cancer, but little is known about the vaginal microbiome in locally advanced cervical cancer as it relates to chemoradiation. In this pilot study we utilized 16S rRNA gene community profiling to characterize the vaginal microbiomes of 26 postmenopausal women with locally advanced cervical cancer receiving chemoradiation. Our analysis revealed diverse anaerobe-dominated communities whose taxonomic composition, diversity or bacterial abundance did not change with treatment. We hypothesized that characteristics of the microbiome might correlate with treatment response. Pretreatment microbial diversity and bacterial abundance were not associated with disease recurrence. We observed a greater relative abundance of Fusobacterium in patients that later had cancer recurrence, suggesting that Fusobacterium could play a role in modifying treatment response. Taken together, this hypothesis generating pilot study provides insight into the composition and dynamics of the vaginal microbiome, offering proof-of-concept for future study of the microbiome and its relationship with treatment outcomes in locally advanced cervical cancer.
Authors
Brett A. Tortelli, Jessika Contreras, Stephanie Markovina, Li Ding, Kristine M. Wylie, Julie K. Schwarz
Citation Information: JCI Insight. 2025. https://doi.org/10.1172/jci.insight.180507.
Abstract
The mechanisms utilized by differentiating B cells to withstand highly damaging conditions generated during severe infections, like the massive hemolysis that accompanies malaria, are poorly understood. Here we demonstrate that ROCK1 regulates B cells differentiation in hostile environments replete with PAMPs (pathogen-associated molecular patterns) and high levels of heme by controlling two key heme-regulated molecules, BACH2 and Heme-regulated eIF2a kinase (HRI). ROCK1 phosphorylates BACH2 and protects it from heme-driven degradation. As B cells differentiate, furthermore, ROCK1 restrains their proinflammatory potential and helps them handle the heightened stress imparted by the presence of PAMPs and heme by controlling HRI, a key regulator of the integrated stress response and cytosolic proteotoxicity. ROCK1 controls the interplay of HRI with HSP90 and limits the recruitment of HRI and HSP90 to unique p62/SQSTM1 complexes that also contain critical kinases like mTORC1 and TBK1, and proteins involved in RNA metabolism, oxidative damage, and proteostasis like TDP-43. Thus, ROCK1 helps B cells cope with intense pathogen-driven destruction by coordinating the activity of key controllers of B cell differentiation and stress responses. These ROCK1-dependent mechanisms may be widely employed by cells to handle severe environmental stresses, and these findings may be relevant for immune-mediated and age-related neurodegenerative disorders.
Authors
Juan Rivera-Correa, Sanjay Gupta, Edd Ricker, Danny Flores-Castro, Daniel Jenkins, Stephen Vulcano, Swati P. Phalke, Tania Pannellini, Matthew M. Miele, Zhuoning Li, Nahuel Zamponi, Young-Bum Kim, Yurii Chinenov, Eugenia Giannopoulou, Leandro Cerchietti, Alessandra B. Pernis
Citation Information: JCI Insight. 2025. https://doi.org/10.1172/jci.insight.180226.
Abstract
BACKGROUND. We aimed to characterize factors associated with the under-studied complication of cognitive decline in aging people with long-duration type 1 diabetes (T1D). METHODS. Joslin “Medalists” (n = 222; T1D ≥ 50 years) underwent cognitive testing. Medalists (n = 52) and age-matched non-diabetic controls (n = 20) underwent neuro- and retinal imaging. Brain pathology (n = 26) was examined. Relationships amongst clinical, cognitive and neuroimaging parameters were evaluated. RESULTS. Compared to controls, Medalists had worse psychomotor function and recall, which associated with female gender, lower visual acuity, reduced physical activity, longer diabetes duration and higher inflammatory cytokines. On neuroimaging, compared to controls, Medalists had significantly lower total and regional brain volumes, equivalent to 9 years of accelerated aging, but small vessel disease markers did not differ. Reduced brain volumes associated with female sex, reduced psychomotor function, worse visual acuity, longer diabetes duration and higher inflammation, but not with glycemic control. Worse cognitive function, lower brain volumes, and diabetic retinopathy correlated with thinning of the outer retinal nuclear layer. Worse baseline visual acuity associated with declining psychomotor function in longitudinal analysis. Brain volume mediated the association between visual acuity and psychomotor function by 57%. Brain pathologies showed decreased volumes, but predominantly mild vascular or Alzheimer’s-related pathology. CONCLUSION. This first comprehensive study of cognitive function, neuroimaging and pathology in aging T1D individuals demonstrated that cognitive decline was related to parenchymal rather than neurovascular abnormalities, unlike type 2 diabetes, suggestive of accelerated aging in T1D. Improving visual acuity could perhaps be an important preventive measure against cognitive decline in people with T1D.
Authors
Hetal S. Shah, Matthew N. DeSalvo, Anastasia Haidar, Surya Vishva Teja Jangolla, Marc Gregory Yu, Rebecca S. Roque, Amanda Hayes, John Gauthier, Nolan Ziemniak, Elizabeth Viebranz, I-Hsien Wu, Kyoungmin Park, Ward Fickweiler, Tanvi J. Chokshi, Tashrif Billah, Lipeng Ning, Atif Adam, Jennifer K. Sun, Lloyd Paul Aiello, Yogesh Rathi, Mel B. Feany, George L. King
Citation Information: JCI Insight. 2025. https://doi.org/10.1172/jci.insight.184468.
Abstract
Renal osteodystrophy is commonly seen in patients with chronic kidney disease (CKD) due to disrupted mineral homeostasis. Given the impaired renal function in these patients, common anti-resorptive agents, including bisphosphonates, must be used with caution or even contraindicated. Therefore, an alternative therapy without renal burden to combat renal osteodystrophy is urgently needed. Here, we report that clinically relevant aerobic exercise significantly prevents high-turnover renal osteodystrophy in CKD mouse and patients without compromising renal function. Mechanistically, 4-week aerobic exercise in CKD mice increased expression of skeletal muscle PPARγ coactivator-1α (PGC-1α) and circulating irisin. Both exercise and irisin administration significantly activated osteoblasts, but not osteoclasts, via integrin αvβ5, thereby conferring bone quality benefits. Removal of irisin-influenced thermogenic adipose tissues or genetic ablation of uncoupling protein 1 did not alter the irisin-conferred anti-osteodystrophy effect. Importantly, in a pilot clinical study, 12-week aerobic exercise in patients with high-grade CKD significantly increased circulating irisin and prevented osteodystrophy progression, without detectable renal burden. The combination of irisin and current anti-resorptive agents effectively rescued renal osteodystrophy in mice. Our work provides mechanistic insights into the role of exercise and irisin in renal osteodystrophy, and highlights a clinically relevant, low-cost, kidney-friendly therapy for patients with this devastating disease.
Authors
Meng Wu, Huilan Li, Xiaoting Sun, Rongrong Zhong, Linli Cai, Ruibo Chen, Madiya Madeniyet, Kana Ren, Zhen Peng, Yujie Yang, Weiqin Chen, Yanling Tu, Miaoxin Lai, Jinxiu Deng, Yuting Wu, Shumin Zhao, Qingyan Ruan, Mei Rao, Sisi Xie, Ying Ye, Jianxin Wan
Citation Information: JCI Insight. 2025. https://doi.org/10.1172/jci.insight.186062.
Abstract
BACKGROUND. Previously, we demonstrated that changes in circulating tumor DNA (ctDNA) are promising biomarkers for early response prediction (ERP) to immune checkpoint inhibitors (ICI) in metastatic urothelial cancer (mUC). In this study, we investigated the value of whole blood immunotranscriptomics for ERP-ICI and integrated both biomarkers into a multimodal model to boost accuracy. METHODS. Blood samples of 93 patients were collected at baseline and after 2-6 weeks of ICI for ctDNA (N=88) and immunotranscriptome (N=79) analyses. ctDNA changes were dichotomized into increase or no increase, the latter including patients with undetectable ctDNA. For RNA model development, the cohort was split into a discovery (N=29), test (N=29) and validation set (N=21). Finally, RNA- and ctDNA-based predictions were integrated in a multimodal model. Clinical benefit (CB) was defined as progression-free survival beyond 6 months. RESULTS. Sensitivity (SN) and specificity (SP) of ctDNA increase for predicting non-CB (N-CB) was 59% and 92%, respectively. Immunotranscriptome analysis revealed upregulation of T-cell activation, proliferation and interferon signalling during treatment in the CB group, contrary to N-CB patients. Based on these differences a 10-gene RNA model was generated, reaching a SN and SP of 73% and 79% in the test and 67% and 67% in the validation set for predicting N-CB. Multimodal model integration led to superior performance with a SN and SP of 79% and 100% in the validation cohort. CONCLUSION. The combination of whole blood immunotranscriptome and ctDNA in a multimodal model showed promise for ERP-ICI in mUC and accurately identified patients with N-CB. TRIAL REGISTRATION. 2016-3060, 2020-6778 FUNDING. Eurostars grant E! 114908 - PRECISE, Paul Speth Foundation (Bullseye project)
Authors
Sandra van Wilpe, Davide Croci, Sara S. Fonseca Costa, Iris B.A.W. te Paske, Sofie H. Tolmeijer, Jolique van Ipenburg, Leonie I. Kroeze, Simona Pavan, Sylvain Monnier-Benoit, Guido Coccia, Noushin Hadadi, Irma M. Oving, Tineke J. Smilde, Theo van Voorthuizen, Marieke Berends, Mira D. Franken, Marjolijn J.L. Ligtenberg, Sahar Hosseinian Ehrensberger, Laura Ciarloni, Pedro Romero, Niven Mehra
Citation Information: JCI Insight. 2025. https://doi.org/10.1172/jci.insight.187825.
Abstract
Skeletal muscle regeneration in adults is predominantly driven by satellite cells. Loss of satellite cell pool and function leads to skeletal muscle wasting in many conditions and disease states. Here, we demonstrate that the levels of fibroblast growth factor-inducible 14 (Fn14) were increased in satellite cells after muscle injury. Conditional ablation of Fn14 in Pax7-expressing satellite cells drastically reduced their expansion and skeletal muscle regeneration following injury. Fn14 was required for satellite cell self-renewal and proliferation as well as to prevent precocious differentiation. Targeted deletion of Fn14 inhibited Notch signaling but led to the spurious activation of STAT3 signaling in regenerating skeletal muscle and in cultured muscle progenitor cells. Silencing of STAT3 improved proliferation and inhibited premature differentiation of Fn14-deficient satellite cells. Furthermore, conditional ablation of Fn14 in satellite cells exacerbated myopathy in the mdx mouse model of Duchenne muscular dystrophy (DMD) whereas its overexpression improved the engraftment of exogenous muscle progenitor cells into the dystrophic muscle of mdx mice. Altogether, our study highlights the crucial role of Fn14 in the regulation of satellite cell fate and function and suggests that Fn14 can be a potential molecular target to improve muscle regeneration in muscular disorders.
Authors
Meiricris Tomaz da Silva, Aniket S. Joshi, Ashok Kumar
Citation Information: JCI Insight. 2025. https://doi.org/10.1172/jci.insight.185181.
Abstract
Somatic activating mutations in KRAS can cause complex lymphatic anomalies (CLAs). However, the specific processes that drive KRAS-mediated CLAs have yet to be fully elucidated. Here, we used single-cell RNA sequencing to construct an atlas of normal and KrasG12D-malformed lymphatic vessels. We identified six subtypes of lymphatic endothelial cells (LECs) in the lungs of adult wild-type mice (Ptx3, capillary, collecting, valve, mixed, and proliferating). To determine when the LEC subtypes were specified during development, we integrated our data with data from four stages of development. We found that proliferating and Ptx3 LECs were prevalent during early lymphatic development and that collecting and valve LECs emerged later in development. Additionally, we discovered that the proportion of Ptx3 LECs decreased as the lymphatic network matured but remained high in KrasG12D mice. We also observed that the proportion of collecting and valve LECs was lower in KrasG12D mice than in wild-type mice. Last, we found that immature lymphatic vessels in young mice were more sensitive to the pathologic effects of KrasG12D than mature lymphatic vessels in older mice. Together, our results expand the current model for the development of the lymphatic system and suggest that KRAS mutations impair the maturation of lymphatic vessels.
Authors
Lorenzo M. Fernandes, Danielle Griswold-Wheeler, Jeffrey D. Tresemer, Angelica Vallejo, Neda Vishlaghi, Benjamin Levi, Abigail Shapiro, Joshua P. Scallan, Michael T. Dellinger
Citation Information: JCI Insight. 2025. https://doi.org/10.1172/jci.insight.180867.
Abstract
CD8+ T cells are critical for immune protection against severe COVID-19 during acute infection with SARS-CoV-2. However, the induction of antiviral CD8+ T cell responses varies substantially among infected people, and a better understanding of the mechanisms that underlie such immune heterogeneity is required for pandemic preparedness and risk stratification. In this study, we analyzed SARS-CoV-2-specific CD4+ and CD8+ T cell responses in relation to age, clinical status, and inflammation among patients infected primarily during the initial wave of the pandemic in France or Japan. We found that age-related contraction of the naive lymphocyte pool and systemic inflammation were associated with suboptimal SARS-CoV-2-specific CD4+ and, even more evidently, CD8+ T cell immunity in patients with acute COVID-19. No such differences were observed for humoral immune responses targeting the spike protein of SARS-CoV-2. We also found that the proinflammatory cytokine IL-18, concentrations of which were significantly elevated among patients with severe disease, suppressed the de novo induction and memory recall of antigen-specific CD8+ T cells, including those directed against SARS-CoV-2. These results potentially explain the vulnerability of older adults to infections that elicit a profound inflammatory response, exemplified by acute COVID-19.
Authors
Gaëlle Autaa, Laura Papagno, Takuto Nogimori, Andrea Boizard-Moracchini, Daniil Korenkov, Maeva Roy, Koichiro Suzuki, Yuji Masuta, Eoghann White, Sian Llewellyn-Lacey, Yasuo Yoshioka, Francesco Nicoli, David A. Price, Julie Dechanet-Merville, Takuya Yamamoto, Isabelle Pellegrin, Victor Appay
Citation Information: JCI Insight. 2025. https://doi.org/10.1172/jci.insight.187008.
Abstract
Urinary obstruction causes injury to the renal medulla, impairing the ability to concentrate urine, and increasing the risk of progressive kidney disease. However, the regenerative capacity of the renal medulla after reversal of obstruction is poorly understood. To investigate this, we developed a mouse model of reversible urinary obstruction. Despite robust regeneration and complete histological recovery of the renal medulla, these mice exhibited a permanent defect in urinary concentrating capacity. However, there were lasting changes in the composition, organization, and transcriptional profiles of epithelial, endothelial, and interstitial cells. Persistent inflammatory responses were also seen in patients with renal stone disease, but there were also adaptive responses to the increasingly hypoxic environment of the renal medulla that only occurred after reversal of obstruction. These findings indicate that while partial repair occurs after reversal of urinary obstruction, there are lasting structural and functional changes across all major cellular compartments of the renal medulla. These changes reflect shared and distinct responses to different renal medullary injuries in humans and mice.
Authors
Thitinee Vanichapol, Alex Gonzalez, Rachel Delgado, Maya Brewer, Kelly A. Clouthier, Anna A. Menshikh, William E. Snyder, Teebro Rahman, Veronika Sander, Haichun Yang, Alan Davidson, Mark Caestecker
Citation Information: JCI Insight. 2025. https://doi.org/10.1172/jci.insight.184457.
Abstract
Chronic wounds have emerged as a tough clinical challenge. An improved understanding of wound healing mechanisms is paramount. Collagen XVII (COL17), a pivotal constituent of hemidesmosomes, holds considerable promise for regulating epidermal cell adhesion to the basement membrane, as well as for epidermal cell motility and self-renewal of epidermal stem cells. However, the precise role of COL17 in wound repair remains elusive, and the upstream regulatory mechanisms involved have not been fully elucidated. In this study, we delineated the temporal and spatial expression patterns of COL17 at the epidermal wound edge. Subsequently, we investigated the indispensable role of COL17 in keratinocyte activation and re-epithelialization during wound healing, demonstrating the restoration of the normal repair process by COL17 overexpression in diabetic wounds. Notably, we identified a key transcriptional signaling pathway for COL17, wherein PKM2 (Pyruvate kinase isozyme M2) promotes phosphorylation of STAT3, leading to its activation and subsequent induction of COL17 expression upon injury. Ultimately, by manipulating this pathway using the PKM2 nuclear translocator SAICAR, we revealed a promising therapeutic strategy for enhancing the healing of chronic wounds.
Authors
Yangdan Liu, Chia-kang Ho, Dongsheng Wen, Jiaming Sun, Yuxin Liu, Qing-Feng Li, Yifan Zhang, Ya Gao
Citation Information: JCI Insight. 2025. https://doi.org/10.1172/jci.insight.182376.
Abstract
The impact of remdesivir on SARS-CoV-2 diversity and evolution in vivo has remained unclear. In this single-center, retrospective cohort study, we assessed SARS-CoV-2 diversification and diversity over time in a cohort of hospitalized patients who did or did not receive remdesivir. Whole genome sequencing was performed on 98 paired specimens collected from 49 patients before and after remdesivir administration. Genetic divergence between paired specimens was not significantly different from what was observed in paired specimens from patients who did not receive the drug. However, when comparing minority variants, several positions showed preferential diversification after remdesivir treatment, several of which were associated with different variants of concern. Most notably, remdesivir administration resulted in strong selection for a nonsynonymous mutation in nsp12, G671S, previously associated with enhanced viral fitness. This same mutation was found enriched in a second cohort of 143 inpatients with specimens collected after remdesivir administration compared to controls. Only one other mutation previously implicated in remdesivir resistance (nsp12:V792I) was found to be preferentially selected for after remdesivir administration. These data suggest that SARS-CoV-2 variants with enhanced replicative fitness may be selected for in the presence of antiviral therapy as an indirect means to overcome this selective pressure.
Authors
Ted Ling-Hu, Lacy M. Simons, Estefany Rios-Guzman, Alexandre M. Carvalho, Maria Francesca R. Agnes, Arghavan Alisoltanidehkordi, Egon A. Ozer, Ramon Lorenzo-Redondo, Judd F. Hultquist
Citation Information: JCI Insight. 2025. https://doi.org/10.1172/jci.insight.186263.
Abstract
Surgery of the tracheobronchial tree carries high morbidity, with over half of the complications occurring at the anastomosis. Although fibroblasts are crucial in airway wound healing, the underlying cellular and molecular mechanisms in airway reconstruction remain unknown. We hypothesized that airway reconstruction initiates a surgery-induced stress (SIS) response, altering fibroblast communication within airway tissues. Using single-cell RNAseq, we analyzed native and reconstructed airways and identified five fibroblast subpopulations, each with distinct spatial distributions across anastomotic, submucosal, perichondrial, and paratracheal areas. During homeostasis, Adventitial and Airway fibroblasts (Adventitial Fb and Airway Fb, respectively) maintained tissue structure and created cellular niches by regulating ECM turnover. Under SIS, Perichondrial fibroblasts (PC-Fb) exhibited chondroprogenitor-like gene signatures, and Immune-recruiting fibroblasts (IR-Fb) facilitated cell infiltration. Cthrc1 activated fibroblasts (Cthrc1+ Fb), mainly derived from Adventitial Fb, primarily contributed to fibrotic scar formation and collagen production, mediated by TGFβ. Furthermore, repeated SIS created an imbalance in fibroblast states favoring emergence of CTHRC1+ Fb and leading to impaired fibroblasts-basal cell crosstalk. Collectively, these data identify PC, IR, and Cthrc1+ Fb as a signaling hub, with SIS emerging as a mechanism initiating airway remodeling after reconstruction that, if not controlled, may lead to complications such as stenosis or anastomotic breakdown.
Authors
Jazmin Calyeca, Zakarie Hussein, Zheng Hong Tan, Lumei Liu, Sayali Dharmadhikari, Kimberly M. Shontz, Tatyana A. Vetter, Christopher K. Breuer, Susan D. Reynolds, Tendy Chiang
Citation Information: JCI Insight. 2025. https://doi.org/10.1172/jci.insight.186133.
Abstract
Endometriosis is a chronic gynecological disease that affects 1 in 10 reproductive-aged women. Most studies investigate established disease; however, the initiation and early events in endometriotic lesion development remain poorly understood. Our study used neutrophils from human menstrual effluent from subjects with and without endometriosis for immunophenotyping, and a mouse model of endometriosis and a mouse endometriosis cell line to determine the role of neutrophils in the initiating events of endometriosis, including attachment and survival of minced endometrial pieces. In menstrual effluent from women with endometriosis, the ratio of aged and pro-angiogenic neutrophils increased compared to controls, indicating a potentially permissive pro-inflammatory microenvironment. In our endometriosis mouse model, knocking-down neutrophil recruitment with α-CXCR2 into the peritoneum decreased endometrial tissue adhesion—supported by decreased levels of myeloperoxidase and neutrophil elastase in both developing lesions and peritoneal fluid. Fibrinogen was identified as the preferred substrate for endometrial cell adhesion in an in vitro adhesion assay and in developing lesions in vivo. Together, aged and pro-angiogenic neutrophils and their secretions likely promote attachment and formation of endometriotic lesions by releasing neutrophil extracellular traps and upregulating fibrinogen expression as a provisional matrix to establish attachment and survival in the development of endometriosis lesions.
Authors
Taylor R. Wilson, Kurt R. Peterson, Stephanie A. Morris, Damaris Kuhnell, Susan Kasper, Katherine A. Burns
Citation Information: JCI Insight. 2025. https://doi.org/10.1172/jci.insight.187315.
Abstract
Aortic dissection or rupture is a major cause of mortality in vascular Ehlers-Danlos Syndrome (vEDS), a connective tissue disorder caused by heterozygous mutations in the COL3A1 gene. C57BL6/J (BL6) mice carrying the Col3a1 G938D/+ mutation recapitulate the vEDS vascular phenotype and die suddenly of aortic rupture/dissection. However, 129S6/SvEvTac (129) mice expressing the same Col3a1 G938D/+ mutation show near-complete life-long protection from vascular rupture. To identify genetic modifiers of vascular risk in vEDS, we performed genome-wide genotyping of intercrossed BL6/129 vEDS mice stratified by survival and identified a significant protective locus encompassing a variant in Map2k6, encoding Mitogen-Activated Protein Kinase Kinase 6 (M2K6), a p38-activating kinase. Genetic ablation of Map2k6 rendered previously protected 129 vEDS mice susceptible to aortic rupture, in association with reduced protein phosphatase 1 activity and increased PKC and ERK phosphorylation. Accelerated vascular rupture in vEDS mice treated with a pharmacological inhibitor of p38 was rescued by concomitant ERK antagonism, supporting an opposing role for ERK and p38 in the modification of aortic rupture risk in vEDS. These results suggest that pharmacologic strategies aimed at mimicking the effect of this natural protective pathway may improve prevention of aortic rupture risk in vEDS.
Authors
Caitlin J. Bowen, Rebecca Sorber, Juan F. Calderon Giadrosic, Jefferson J. Doyle, Graham Rykiel, Zachary Burger, Xiaoyan Zhang, Wendy A. Espinoza Camejo, Nicole K. Anderson, Simone Sabnis, Chiara Bellini, Elena MacFarlane, Harry C. Dietz
Citation Information: JCI Insight. 2025. https://doi.org/10.1172/jci.insight.188710.
Abstract
Elevation of intraocular pressure (IOP) due to trabecular meshwork (TM) dysfunction, leading to neurodegeneration, is the pathological hallmark of primary open-angle glaucoma (POAG). Impaired axonal transport is an early and critical feature of glaucomatous neurodegeneration. However, a robust mouse model that accurately replicates these human POAG features has been lacking. We report the development and characterization of a novel Cre-inducible mouse model expressing a DsRed-tagged Y437H mutant of human myocilin (Tg.CreMYOCY437H). A single intravitreal injection of HAd5-Cre induced selective MYOC expression in the TM, causing TM dysfunction, reducing the outflow facility, and progressively elevating IOP in Tg.CreMYOCY437H mice. Sustained IOP elevation resulted in significant loss of retinal ganglion cells (RGCs) and progressive axonal degeneration in Cre-induced Tg.CreMYOCY437H mice. Notably, impaired anterograde axonal transport was observed at the optic nerve head before RGC degeneration, independent of age, indicating that impaired axonal transport contributes to RGC degeneration in Tg.CreMYOCY437H mice. In contrast, axonal transport remained intact in ocular hypertensive mice injected with microbeads, despite significant RGC loss. Our findings indicate that Cre-inducible Tg.CreMYOCY437H mice replicate all glaucoma phenotypes, providing an ideal model for studying early events of TM dysfunction and neuronal loss in POAG.
Authors
Balasankara Reddy Kaipa, Ramesh Kasetti, Yogapriya Sundaresan, Linya Li, Sam Yacoub, J. Cameron Millar, William Cho, Dorota Skowronska-Krawczyk, Prabhavathi Maddineni, Krzysztof Palczewski, Gulab S. Zode
