Skin microbiome and dermatologic disorders

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Abstract

Human skin acts as a physical barrier to prevent the entry of pathogenic microbes while simultaneously providing a home for commensal bacteria and fungi. Microbiome sequencing studies have demonstrated the unappreciated diversity and selectivity of these microbes. Functional studies have demonstrated the impact of specific strains to tune the immune system, sculpt the microbial community, provide colonization resistance, and promote epidermal barrier integrity. Recent studies have integrated the microbiome, immunity, and tissue integrity to understand their interplay in common disorders such as atopic dermatitis. In this Review, we explore microbiome shifts associated with cutaneous disorders with an eye toward how the microbiome can be mined to identify new therapeutic opportunities.

Authors

Tiffany C. Scharschmidt, Julia A. Segre

The gut microbiome and cancer response to immune checkpoint inhibitors

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Abstract

Immune checkpoint inhibitors (ICIs) are widely used for cancer immunotherapy, yet only a fraction of patients respond. Remarkably, gut bacteria impact the efficacy of ICIs in fighting tumors outside of the gut. Certain strains of commensal gut bacteria promote antitumor responses to ICIs in a variety of preclinical mouse tumor models. Patients with cancer who respond to ICIs have a different microbiome compared with that of patients who don’t respond. Fecal microbiota transplants (FMTs) from patients into mice phenocopy the patient tumor responses: FMTs from responders promote response to ICIs, whereas FMTs from nonresponders do not promote a response. In patients, FMTs from patients who have had a complete response to ICIs can overcome resistance in patients who progress on treatment. However, the responses to FMTs are variable. Though emerging studies indicate that gut bacteria can promote antitumor immunity in the absence of ICIs, this Review will focus on studies that demonstrate relationships between the gut microbiome and response to ICIs. We will explore studies investigating which bacteria promote response to ICIs in preclinical models, which bacteria are associated with response in patients with cancer receiving ICIs, the mechanisms by which gut bacteria promote antitumor immunity, and how microbiome-based therapies can be translated to the clinic.

Authors

Francesca S. Gazzaniga, Dennis L. Kasper

HMGA1 is a crucial mediator of colon tumorigenesis driven by the loss of APC

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Abstract

Colorectal cancer is the second leading cause of cancer death in the United States. The adenomatous polyposis coli (APC) pathway plays a critical role in colorectal tumorigenesis, but the mechanism is not fully understood. In this issue of the JCI, Luo and colleagues used genetically engineered mouse models to show that high mobility group A (HMGA1) is a critical mediator in the development of colon tumors driven by the loss of the Apc gene. HMGA1 activated the transcription of Achaete-Scute Family BHLH Transcription Factor 2 (ASCL2), which regulated intestinal stemness and promoted colon tumorigenesis.

Authors

Yuxiang Wang, Mikayla Ybarra, Zhenghe Wang

Gene-replacement therapy in neurodevelopmental disorders: progress and challenges

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Abstract

Heterozygous loss-of-function variants in the SLC6A1 gene, encoding GAT1, which is the main GABA transporter in the brain, lead to a broad spectrum of neuropsychiatric and neurodevelopmental disorders including epilepsy, developmental delay, intellectual disability, and autism. Gene-replacement strategies involving adeno-associated viruses (AAV) require the delivery of genes to specific types of neurons or areas in the brain, likely during certain developmental time points. In this issue of the JCI, Guo and colleagues from the Gray lab evaluated two promoters, three injection modalities, and various timing strategies for replacement of GAT1 via AAV type 9 in heterozygous and homozygous knockout mouse models. Intrathecal administration of vectors containing either promoter at postnatal day 5 achieved high expression and was the best tolerated approach. Notably, gene-replacement therapy failed at later disease stages, suggesting the importance of early gene reconstitution and confirming the importance of GABA metabolism in early brain development.

Authors

Holger Lerche, Ulrike B.S. Hedrich, Thomas V. Wuttke

A deafness-blindness syndrome results from ATF6-based disruption of the unfolded protein response

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Abstract

Sensorineural hearing loss (SNHL) is the most prevalent form of permanent hearing impairment, arising from factors such as aging, exposure to loud noise, disease, ototoxic medications, and genetic mutations. Despite extensive research, effective treatments or cures for SNHL remain elusive. In this issue of the JCI, Lee et al. reveal a link between mutations in ATF6 and SNHL in patients with achromatopsia. The study also shows that Atf6-deficient (Atf6–/–) mice exhibit disorganized stereocilia and age-related loss of outer hair cells. Additionally, the researchers show that Atf6 is critical for cochlear hair cell function. Mice lacking Atf6 expression experienced ER stress, which ultimately led to SNHL. Collectively, these findings enhance our understanding of the emerging role of protein homeostasis and ER stress in the pathogenesis of SNHL.

Authors

Yuvraj Joshi, Jeffrey N. Savas

Blood pressure regulation through circadian variation: PRDM16 as a target in vascular smooth muscle cells

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Abstract

The precise mechanisms of blood pressure (BP) regulation are not fully elucidated, and understanding BP regulation is crucial for managing hypertension and improving outcomes for cardiovascular disease. In this issue of the JCI, Wang et al. identified the transcription factor PR domain–containing protein 16 (PRDM16) as a regulator of both vascular smooth muscle cell contraction and the circadian response to BP control. PRDM16 directly transcriptionally controlled the expression of the adrenergic receptor α 1d and several clock genes crucial for BP circadian regulation. These findings identify a mechanism of how molecular pathways govern circadian BP variation, highlighting PRDM16 as a potential target for hypertension.

Authors

M. Adriana Cuibus, Omar Abdel-Wahab

A deep intronic mutation causes RAD50 deficiency through an unusual mechanism of distant exon activation

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Abstract

Authors

Kristine Bousset, Stefano Donega, Najim Ameziane, Tabea Fleischhammer, Dhanya Ramachandran, Miriam Poley-Gil, Detlev Schindler, Ingrid M. van de Laar, Franco Pagani, Thilo Dörk

Metalloproteinase inhibitors regulate biliary progenitor cells through sDLK1 in organoid models of liver injury

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Abstract

Understanding cell fate regulation in the liver is necessary to advance cell therapies for hepatic disease. Liver progenitor cells (LPCs) contribute to tissue regeneration after severe hepatic injury, yet signals instructing progenitor cell dynamics and fate are largely unknown. Tissue inhibitor of metalloproteinases 1 (TIMP1) and TIMP3 control the sheddases ADAM10 and ADAM17, key for NOTCH activation. Here we uncover the role of the TIMP/ADAM/NOTCH/DLK1 axis in LPC maintenance and cholangiocyte specification. Combined TIMP1/TIMP3 loss in vivo caused abnormal portal triad stoichiometry accompanied by collagen deposits, dysregulated Notch signaling, and increased soluble DLK1. The MIC1-1C3+CD133+CD26– biliary progenitor population was reduced following acute CCl4 or chronic DDC liver injury and in aged TIMP-deficient livers. Single-cell RNA sequencing data interrogation and RNAscope identified portal mesenchymal cells coexpressing ADAM17/DLK1 as enzymatically equipped to process DLK1 and direct LPC differentiation. Specifically, TIMP-deficient biliary fragment–derived organoids displayed increased propensity for cholangiocyte differentiation. ADAM17 inhibition reduced Sox9-mediated cholangiocyte differentiation, prolonging organoid growth and survival, whereas WT organoids treated with soluble DLK1 triggered Sox9 expression and cholangiocyte specification in mouse and patient-derived liver organoids. Thus, metalloproteinase inhibitors regulate instructive signals for biliary cell differentiation and LPC preservation within the portal niche, providing a new basis for cell therapy strategies.

Authors

Virginie Defamie, Kazeera Aliar, Soumili Sarkar, Foram Vyas, Ronak Shetty, Swami Reddy Narala, Hui Fang, Sanjay Saw, Pirashaanthy Tharmapalan, Otto Sanchez, Jennifer J. Knox, Paul D. Waterhouse, Rama Khokha

Translational regulation of SND1 governs endothelial homeostasis during stress

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Abstract

Translational control shapes the proteome and is particularly important in regulating gene expression under stress. A key source of endothelial stress is treatment with tyrosine kinase inhibitors (TKIs), which lowers cancer mortality but increases cardiovascular mortality. Using a human induced pluripotent stem cell–derived endothelial cell (hiPSC-EC) model of sunitinib-induced vascular dysfunction combined with ribosome profiling, we assessed the role of translational control in hiPSC-ECs in response to stress. We identified staphylococcal nuclease and tudor domain–containing protein 1 (SND1) as a sunitinib-dependent translationally repressed gene. SND1 translational repression was mediated by the mTORC1/4E-BP1 pathway. SND1 inhibition led to endothelial dysfunction, whereas SND1 OE protected against sunitinib-induced endothelial dysfunction. Mechanistically, SND1 transcriptionally regulated UBE2N, an E2-conjugating enzyme that mediates K63-linked ubiquitination. UBE2N along with the E3 ligases RNF8 and RNF168 regulated the DNA damage repair response pathway to mitigate the deleterious effects of sunitinib. In silico analysis of FDA-approved drugs led to the identification of an ACE inhibitor, ramipril, that protected against sunitinib-induced vascular dysfunction in vitro and in vivo, all while preserving the efficacy of cancer therapy. Our study established a central role for translational control of SND1 in sunitinib-induced endothelial dysfunction that could potentially be therapeutically targeted to reduce sunitinib-induced vascular toxicity.

Authors

Zhenbo Han, Gege Yan, Jordan Jousma, Sarath Babu Nukala, Mehdi Amiri, Stephen Kiniry, Negar Tabatabaei, Youjeong Kwon, Sen Zhang, Jalees Rehman, Sandra Pinho, Sang-Bing Ong, Pavel V. Baranov, Soroush Tahmasebi, Sang-Ging Ong

NEDD4L mediates intestinal epithelial cell ferroptosis to restrict inflammatory bowel diseases and colorectal tumorigenesis

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Various factors play key roles in maintaining intestine homeostasis. Disruption of the balance may lead to inflammatory bowel diseases 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 downregulated 4–like protein (NEDD4L, or 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, ulcerative colitis, and CRC. Global KO of NEDD4L or its deficiency in IECs exacerbated colitis induced by dextran sulfate sodium (DSS) and 2,4,6-trinitrobenzene sulfonic acid (TNBS) and CRC induced by azoxymethane and DSS. Mechanistically, NEDD4L deficiency in IECs inhibited expression of the key ferroptosis regulator glutathione peroxidase 4 (GPX4) 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 CRC. Thus, NEDD4L is 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

Lactobacillus rhamnosus GG induces STING-dependent IL-10 in intestinal monocytes and alleviates inflammatory colitis in mice

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Abstract

Preclinical and clinical observations indicate that the probiotic Lactobacillus rhamnosus GG (LGG) can modulate colonic inflammation. However, the underlying mechanisms have not been explored in depth. Here, we demonstrate that oral administration of live LGG alleviated inflammatory colitis by increasing IL-10 expression in intestinal Ly6C+ monocytes. Mechanistically, LGG induced IL-10 production via the stimulator of IFN genes (STING)/TBK1/NF-κB (RELA) signaling pathway in intestinal Ly6C+ monocytes, enhancing their immune-suppressive function. Elevated IL-10 subsequently activated IL-10 signaling in Ly6C+ monocytes, resulting in an IL-10–based autocrine regulatory loop and inhibition of proinflammatory cytokine production. Furthermore, LGG shifted the gut microbial community and its metabolic functions, leading to intestinal immune responses against colitis. Fecal microbiota transplantation from LGG-colonized mice alleviated immune checkpoint blockade–associated colitis. Our findings highlight the importance of STING signaling in IL-10–dependent antiinflammatory immunity and establish an empirical basis for developing oral administration of live LGG as an efficient and safe therapeutic strategy against inflammatory colitis.

Authors

Wei Si, Xin Zhao, Ruitong Li, Yaopeng Li, Cui Ma, Xiaohan Zhao, Jason Bugno, Yuchang Qin, Junmin Zhang, Hongwei Liu, Liangliang Wang

Mutations in unfolded protein response regulator ATF6 cause hearing and vision loss syndrome

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Abstract

Activating transcription factor 6 (ATF6) is a key regulator of the unfolded protein response (UPR) and is important for ER function and protein homeostasis in metazoan cells. Patients carrying loss-of-function ATF6 disease alleles develop the cone dysfunction disorder achromatopsia. The effect of loss of ATF6 function on other cell types, organs, and diseases in people remains unclear. Here, we report that progressive sensorineural hearing loss was a notable complaint in some patients carrying ATF6 disease alleles and that Atf6–/– mice also showed progressive auditory deficits affecting both sexes. In mice with hearing deficits, we found disorganized stereocilia on hair cells and focal loss of outer hair cells. Transcriptomics analysis of Atf6–/– cochleae revealed a marked induction of the UPR, especially through the protein kinase RNA-like endoplasmic reticulum kinase (PERK) arm. These findings identify ATF6 as an essential regulator of cochlear health and function. Furthermore, they support the idea that ATF6 inactivation in people causes progressive sensorineural hearing loss as part of a blindness-deafness genetic syndrome targeting hair cells and cone photoreceptors. Last, our genetic findings indicate that ER stress is an important pathomechanism underlying cochlear damage and hearing loss, with clinical implications for patient lifestyle modifications that minimize environmental and physiological sources of ER stress to the ear.

Authors

Eun-Jin Lee, Kyle Kim, Monica Sophia Diaz-Aguilar, Hyejung Min, Eduardo Chavez, Korina J. Steinbergs, Lance A. Safarta, Guirong Zhang, Allen F. Ryan, Jonathan H. Lin

Postischemic inactivation of HIF prolyl hydroxylases in endothelium promotes maladaptive kidney repair by inducing glycolysis

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Abstract

Ischemic acute kidney injury (AKI) is common in hospitalized patients and increases the risk for chronic kidney disease (CKD). Impaired endothelial cell (EC) functions are thought to contribute in AKI to CKD transition, but the underlying mechanisms remain unclear. Here, we identify a critical role for endothelial oxygen sensing prolyl hydroxylase domain (PHD) enzymes 1–3 in regulating postischemic kidney repair. In renal endothelium, we observed compartment-specific differences in the expression of the 3 PHD isoforms in both mice and humans. Postischemic concurrent inactivation of endothelial PHD1, PHD2, and PHD3 but not PHD2 alone promoted maladaptive kidney repair characterized by exacerbated tissue injury, fibrosis, and inflammation. scRNA-Seq analysis of the postischemic endothelial PHD1, PHD2, and PHD3-deficient (PHDTiEC) kidney revealed an endothelial hypoxia and glycolysis-related gene signature, also observed in human kidneys with severe AKI. This metabolic program was coupled to upregulation of the SLC16A3 gene encoding the lactate exporter monocarboxylate transporter 4 (MCT4). Strikingly, treatment with the MCT4 inhibitor syrosingopine restored adaptive kidney repair in PHDTiEC mice. Mechanistically, MCT4 inhibition suppressed proinflammatory EC activation, reducing monocyte-EC interaction. Our findings suggest avenues for halting AKI to CKD transition based on selectively targeting the endothelial hypoxia-driven glycolysis/MCT4 axis.

Authors

Ratnakar Tiwari, Rajni Sharma, Ganeshkumar Rajendran, Gabriella S. Borkowski, Si Young An, Michael Schonfeld, James O’Sullivan, Matthew J. Schipma, Yalu Zhou, Guillaume Courbon, Benjamin R. Thomson, Valentin David, Susan E. Quaggin, Edward B. Thorp, Navdeep S. Chandel, Pinelopi P. Kapitsinou

Beclin 1 prevents ISG15-mediated cytokine storms to secure fetal hematopoiesis and survival

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Abstract

Proper control of inflammatory responses is essential for embryonic development, but the underlying mechanism is poorly understood. Here, we show that under physiological conditions, inactivation of ISG15, an inflammation amplifier, is associated with the interaction of Beclin 1 (Becn1), via its evolutionarily conserved domain, with STAT3 in the major fetal hematopoietic organ of mice. Conditional loss of Becn1 caused sequential dysfunction and exhaustion of fetal liver hematopoietic stem cells, leading to lethal inflammatory cell–biased hematopoiesis in the fetus. Molecularly, the absence of Becn1 resulted in the release of STAT3 from Becn1 tethering and subsequent phosphorylation and translocation to the nucleus, which in turn directly activated the transcription of ISG15 in fetal liver hematopoietic cells, coupled with increased ISGylation and production of inflammatory cytokines, whereas inactivating STAT3 reduced ISG15 transcription and inflammation but improved hematopoiesis potential, and further silencing ISG15 mitigated the above collapse in the Becn1-null hematopoietic lineage. The Becn1/STAT3/ISG15 axis remains functional in autophagy-disrupted fetal hematopoietic organs. These results suggest that Becn1, in an autophagy-independent manner, secures hematopoiesis and survival of the fetus by directly inhibiting STAT3/ISG15 activation to prevent cytokine storms. Our findings highlight a previously undocumented role of Becn1 in governing ISG15 to safeguard the fetus.

Authors

Wen Wei, Xueqin Gao, Jiawei Qian, Lei Li, Chen Zhao, Li Xu, Yanfei Zhu, Zhenzhen Liu, Nengrong Liu, Xueqing Wang, Zhicong Jin, Bowen Liu, Lan Xu, Jin Dong, Suping Zhang, Jiarong Wang, Yumu Zhang, Yao Yu, Zhanjun Yan, Yanjun Yang, Jie Lu, Yixuan Fang, Na Yuan, Jianrong Wang

Structural characterization of human monoclonal antibodies targeting uncommon antigenic sites on spike glycoprotein of SARS-CoV

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Abstract

The function of the spike protein N terminal domain (NTD) in coronavirus (CoV) infections is poorly understood. However, some rare antibodies that target the SARS-CoV-2 NTD potently neutralize the virus. This finding suggests the NTD may contribute, in part, to protective immunity. Pansarbecovirus antibodies are desirable for broad protection, but the NTD region of SARS-CoV and SARS-CoV-2 exhibit a high level of sequence divergence; therefore, cross-reactive NTD-specific antibodies are unexpected, and there is no structure of a SARS-CoV NTD-specific antibody in complex with NTD. Here, we report a monoclonal antibody COV1-65, encoded by the IGHV1-69 gene, that recognizes the NTD of SARS-CoV S protein. A prophylaxis study showed the mAb COV1-65 prevented disease when administered before SARS-CoV challenge of BALB/c mice, an effect that requires intact fragment crystallizable region (Fc) effector functions for optimal protection in vivo. The footprint on the S protein of COV1-65 is near to functional components of the S2 fusion machinery, and the selection of COV1-65 escape mutant viruses identified critical residues Y886H and Q974H, which likely affect the epitope through allosteric effects. Structural features of the mAb COV1-65–SARS-CoV antigen interaction suggest critical antigenic determinants that should be considered in the rational design of sarbecovirus vaccine candidates.

Authors

Naveenchandra Suryadevara, Nurgun Kose, Sandhya Bangaru, Elad Binshtein, Jennifer Munt, David R. Martinez, Alexandra Schäfer, Luke Myers, Trevor D. Scobey, Robert H. Carnahan, Andrew B. Ward, Ralph S. Baric, James E. Crowe Jr

Fusobacterium nucleatum promotes colorectal cancer through neogenesis of tumor stem cells

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Abstract

Intestinal stem cells are crucial for maintaining intestinal homeostasis, yet their transformation into tumor stem cells in the context of microbial infection remains poorly understood. Fusobacterium nucleatum is frequently associated with the onset and progression of colorectal cancer (CRC). In this study, we uncovered that F. nucleatum colonized the depths of gut crypts in both patients with CRC and mouse models. Through single-cell sequencing analysis, we demonstrated that F. nucleatum infection reprogrammed crypt cells and activated lymphocyte antigen 6 complex, locus A+ ( LY6A+, also known as stem cell antigen 1 [Sca-1]) revival stem cells (RSCs), promoting their hyperproliferation and subsequent transformation into tumor stem cells, which accelerated intestinal carcinogenesis. Mechanistically, we identified LY6A as a glycosylphosphatidylinositol-anchored (GPI-anchored) membrane receptor for F. nucleatum. Upon binding, F. nucleatum induced the upregulation of ribosomal protein S14 (RPS14) via the LY6A receptor, driving RSC hyperactivity and tumorigenic conversion. Functional studies showed that genetic ablation of Ly6a in intestinal epithelial cells or Rps14 in LY6A+ RSCs substantially reduced F. nucleatum colonization and tumorigenesis. Moreover, analysis of clinical CRC cohorts revealed a strong correlation between F. nucleatum infection, RSC expansion, and elevated RPS14 expression in tumor tissues. These findings highlight an alternative F. nucleatum/LY6A/RPS14 signaling axis as a critical driver of CRC progression and propose potential therapeutic targets for effective CRC intervention.

Authors

Qinying Wang, Tingting Hu, Qinyuan Zhang, Yichi Zhang, Xiaoxu Dong, Yutao Jin, Jinming Li, Yangyang Guo, Fanying Guo, Ziying Chen, Peijie Zhong, Yongzhi Yang, Yanlei Ma

AAV9/SLC6A1 gene therapy rescues abnormal EEG patterns and cognitive behavioral deficiencies in Slc6a1^–/– mice

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Abstract

The solute carrier family 6 member 1 (SLC6A1) gene encodes the γ-aminobutyric acid (GABA) transporter GAT-1, the deficiency of which is associated with infantile encephalopathy with intellectual disability. We designed 2 AAV9 vectors, with either the JeT or MeP promoter, and conducted preclinical gene therapy studies using heterozygous and homozygous Slc6a1-KO mice at different developmental ages and various routes of administration. Neonatal intracerebroventricular administration of either vector resulted in significantly normalized EEG patterns in Slc6a1–/– or Slc6a1+/– mice as well as improvement in several behavioral phenotypes of Slc6a1–/– mice. However, some mortality and adverse effects were observed in neonatal-treated mice. Intrathecal administration of either vector at P5 normalized EEG patterns in Slc6a1+/– mice, but in Slc6a1–/– mice, the treatment only rescued nest building without impact on EEG. Both vectors were well tolerated in all mice treated at P5 or later (including WT mice), up to 1 year after injection. Overall, our data demonstrate compelling efficacy when mice are treated at an early development age. We also identified that outside of the neonatal treatment window, the severe homozygous KO model is more refractory to treatment, whereas our treatments in the heterozygous mice, which genotypically match human patients, have resulted in stronger benefits.

Authors

Weirui Guo, Matthew Rioux, Frances Shaffo, Yuhui Hu, Ze Yu, Chao Xing, Steven J. Gray

Vascular smooth muscle cell PRDM16 regulates circadian variation in blood pressure

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Abstract

Disruptions of blood pressure (BP) circadian variation are closely associated with an increased risk of cardiovascular disease. Thus, gaining insights into the molecular mechanisms of BP circadian variation is essential for comprehending BP regulation. Human genetic analyses suggest that PR domain–containing protein 16 (PRDM16), a transcription factor highly expressed in vascular smooth muscle cells (VSMCs), is significantly associated with BP-related traits. However, the roles of PRDM16 in BP regulation are largely unknown. Here, we demonstrate that BP in VSMC-specific Prdm16-KO (Prdm16SMKO) mice was significantly lower than that in control mice during the active period, resulting in aberrant BP circadian variation. Mesenteric artery rings from Prdm16SMKO mice showed a reduced response to phenylephrine. Mechanistically, we identified adrenergic receptor α 1d (Adra1d) as a transcriptional target of PRDM16. Notably, PRDM16 exhibited a remarkable circadian expression pattern and regulated the expression of clock genes, particularly Npas2, which is crucial for BP circadian variation regulation. Consequently, PRDM16 deficiency in VSMCs caused disrupted BP circadian variation through a reduced response to adrenergic signaling and clock gene regulation. Our findings provide insights into the intricate molecular pathways that govern circadian fluctuations in BP.

Authors

Zhenguo Wang, Wenjuan Mu, Juan Zhong, Ruiyan Xu, Yaozhong Liu, Guizhen Zhao, Yanhong Guo, Jifeng Zhang, Ida Surakka, Y. Eugene Chen, Lin Chang

Ferumoxytol nanozymes effectively target chronic biofilm infections in apical periodontitis

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Abstract

Bacterial biofilms are pervasive and recalcitrant to current antimicrobials, causing numerous infections. Iron oxide nanozymes, including an FDA-approved formulation, ferumoxytol (FMX), show potential against biofilm infections via catalytic activation of hydrogen peroxide (H2O2). However, clinical evidence regarding the efficacy and therapeutic mechanisms of FMX is lacking. Here, we investigate whether FMX nanozymes can treat chronic biofilm infections and compare their bioactivity to that of the gold standard sodium hypochlorite (NaOCl), a potent but caustic disinfectant. Clinical performance was assessed in patients with apical periodontitis, an intractable endodontic infection affecting half of the global adult population. Data show robust antibiofilm activity by a single application of FMX with H2O2 achieving results comparable to those seen with NaOCl without adverse effects. FMX binds efficiently to the bacterial pathogens Enterococcus faecalis and Fusobacterium nucleatum and remains catalytically active without being affected by dental tissues. This allows for effective eradication of endodontic biofilms via on-site free radical generation without inducing cytotoxicity. Unexpectedly, FMX promotes growth of stem cells of the apical papilla (SCAPs), with transcriptomic analyses revealing upregulation of proliferation-associated pathways and downregulation of cell cycle suppressor genes. Notably, FMX activates SCAP pluripotency and WNT/NOTCH signaling that induces its osteogenic capacity. Together, these results show that FMX nanozymes are clinically effective against severe chronic biofilm infection with pathogen targeting and unique stem cell–stimulatory properties, offering a regenerative approach to antimicrobial therapy.

Authors

Alaa Babeer, Yuan Liu, Zhi Ren, Zhenting Xiang, Min Jun Oh, Nil Kanatha Pandey, Aurea Simon-Soro, Ranran Huang, Bekir Karabucak, David P. Cormode, Chider Chen, Hyun Koo

HMGA1 acts as an epigenetic gatekeeper of ASCL2 and Wnt signaling during colon tumorigenesis

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Mutated tumor cells undergo changes in chromatin accessibility and gene expression, resulting in aberrant proliferation and differentiation, although how this occurs is unclear. HMGA1 chromatin regulators are abundant in stem cells and oncogenic in diverse tissues; however, their role in colon tumorigenesis is only beginning to emerge. Here, we uncover a previously unknown epigenetic program whereby HMGA1 amplifies Wnt signaling during colon tumorigenesis driven by inflammatory microbiota and/or Adenomatous polyposis coli (Apc) inactivation. Mechanistically, HMGA1 “opens” chromatin to upregulate the stem cell regulator, Ascl2, and downstream Wnt effectors, promoting stem and Paneth-like cell states while depleting differentiated enterocytes. Loss of just one Hmga1 allele within colon epithelium restrains tumorigenesis and Wnt signaling driven by mutant Apc and inflammatory microbiota. However, HMGA1 deficiency has minimal effects in colon epithelium under homeostatic conditions. In human colon cancer cells, HMGA1 directly induces ASCL2 by recruiting activating histone marks. Silencing HMGA1 disrupts oncogenic properties, whereas reexpression of ASCL2 partially rescues these phenotypes. Further, HMGA1 and ASCL2 are coexpressed and upregulated in human colorectal cancer. Together, our results establish HMGA1 as an epigenetic gatekeeper of Wnt signals and cell state under conditions of APC inactivation, illuminating HMGA1 as a potential therapeutic target in colon cancer.

Authors

Li Z. Luo, Jung-Hyun Kim, Iliana Herrera, Shaoguang Wu, Xinqun Wu, Seong-Sik Park, Juyoung Cho, Leslie Cope, Lingling Xian, Bailey E. West, Julian Calderon-Espinosa, Joseph Kim, Zanshé Thompson, Isha Maloo, Tatianna Larman, Karen L. Reddy, Ying Feng, Eric R. Fearon, Cynthia L. Sears, Linda Resar

Cathelicidin antimicrobial peptide expression in neutrophils and neurons antagonistically modulates neuroinflammation

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Abstract

Multiple sclerosis (MS) is an autoimmune disease that affects the CNS, the pathophysiology of which remains unclear and for which there is no definitive cure. Antimicrobial peptides (AMPs) are immunomodulatory molecules expressed in various tissues, including the CNS. Here, we investigated whether the cathelicidin-related AMP (CRAMP) modulated the development of experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. We showed that, at an early stage, CNS-recruited neutrophils produced neutrophil extracellular traps (NETs) rich in CRAMP that were required for EAE initiation. NET-associated CRAMP stimulated IL-6 production by dendritic cells via the cGAS/STING pathway, thereby promoting encephalitogenic Th17 response. However, at a later disease stage, neurons also expressed CRAMP that reduced EAE severity. Camp knockdown in neurons led to disease exacerbation, while local injection of CRAMP1–39 at the peak of EAE promoted disease remission. In vitro, CRAMP1–39 regulated the activation of microglia and astrocytes through the formyl peptide receptor (FPR) 2. Finally, administration of butyrate, a gut microbiota-derived metabolite, stimulated the expression of neural CRAMP via the free fatty acids receptors 2/3 (FFAR2/3), and prevented EAE. This study shows that CRAMP produced by different cell types has opposing effects on neuroinflammation, offering therapeutic opportunities for MS and other neuroinflammatory disorders.

Authors

Subash Chand Verma, Emmanuelle Enée, Kanchanadevi Manasse, Feriel Rebhi, Axelle Penc, David Romeo-Guitart, Cuc Bui Thi, Matthias Titeux, Franck Oury, Simon Fillatreau, Roland Liblau, Julien Diana