Inflammation
Abstract
BACKGROUND. Infection is an important complication of implanted devices and prosthetics. Identifying infections sufficiently early to salvage implants and avoid reconstructive failure is a persistent medical challenge. METHODS. Two female cohorts >21 years undergoing breast implant reconstruction were recruited. Seroma fluid (82 breasts, 70 patients) was collected upon implant removal for infectious or non-infectious causes. Post-implantation drain fluid (100 samples, 44 breasts, 32 patients) was collected at routine visits prior to implant removal. A liquid-chromatography/mass spectrometry-based metabolomic approach was used to identify infection correlates. RESULTS. In seroma fluid specimens, infection was associated with a diverse set of small molecules including acetylated polyamines, defensins, glucosyl-sphingosine, and several peptide-like features (all P<0.001, diagnostic areas under the receiver operating curve 0.82-0.93). Notably, a subset of these markers were significantly elevated (p<0.05) in post-implantation drain fluid before recorded infection symptoms and diagnosis. Pseudomonas aeruginosa and its specialized exometabolites in drain specimens were also associated with subsequent P. aeruginosa infections. CONCLUSION. Tissue fluid from infected patients has a distinctive metabolome reflecting human and bacterial physiologic processes that often precede clinical diagnoses. A diagnostic based on these findings has potential to improve patient outcomes through early recognition of infection. TRIAL REGISTRATION. Not applicable. FUNDING. Work was supported by U54CK000609 from the CDC and an unencumbered research gift to TMM from Sientra. Metabolomic approaches were supported by RO1DK125860 and RO1DK111930 to JPH. The contents are solely the responsibility of the authors and do not necessarily represent the official views of CDC.
Authors
John A. Wildenthal, Margaret A. Olsen, Hung D. Tran, John I. Robinson, Terence M. Myckatyn, David K. Warren, Keith E. Brandt, Marissa M. Tenenbaum, Joani M Christensen, Thomas H. Tung, Justin M. Sacks, Rachel A. Anolik, Katelin B. Nickel, Hideji Fujiwara, Peter J. Mucha, Jeffrey P. Henderson
Abstract
Neutrophils play a critical role in sepsis-induced acute lung injury (ALI). Extracellular cold-inducible RNA-binding protein (eCIRP), a damage-associated molecular pattern, promotes neutrophil heterogeneity. While delta-like ligand 4 (DLL4) expression has been studied in various cell populations, its expression in neutrophils and impact on inflammation remain unknown. Here, we discovered that eCIRP induces DLL4+ neutrophils. These neutrophils trigger PANoptosis, a novel proinflammatory form of cell death initiated by Z-DNA–binding protein-1 (ZBP1) in pulmonary vascular endothelial cells (PVECs). In sepsis, DLL4+ neutrophils increase in the blood and lungs, upregulating ZBP1, cleaved gasdermin D, cleaved caspase-3, and phosphorylated MLKL, all of which are markers of PANoptosis, exacerbating ALI. DLL4 binds to Notch1 on PVECs and activates Notch1 intracellular domain to increase ZBP1-mediated endothelial PANoptosis. We discovered what we believe to be a novel Notch1-DLL4 inhibitor (NDI), derived from Notch1 to specifically block this interaction. Our findings reveal that NDI reduced endothelial PANoptosis in vitro and in vivo, attenuated pulmonary injury induced by DLL4+ neutrophils, and decreased lung water content and permeability, indicating improved barrier function. NDI also reduced serum injury and inflammatory markers and improved survival rate in sepsis. These findings underscore the Notch1-DLL4 pathway’s critical role in DLL4+ neutrophil–mediated ALI. Targeting the Notch1-DLL4 interaction with an NDI represents a promising therapeutic strategy for sepsis-induced ALI.
Authors
Hui Jin, Saoirse Holland, Alok Jha, Gaifeng Ma, Jingsong Li, Atsushi Murao, Monowar Aziz, Ping Wang
Abstract
Periodontal disease, a bacterial infection affecting a large percentage of the world's population, is an important risk factor for several systemic diseases and is significantly worsened by diabetes. To investigate how diabetes exacerbates the inflammatory response to bacteria in this disease, we combined insights from murine and human studies. Through single-cell RNA sequencing, we identified a compelling hyperglycemia-driven molecular pathway: the upregulation of CD137L in dendritic cells and increased expression of its receptor, CD137, in γδ T-cells. The CD137L-CD137 axis emerged as a pivotal mediator of diabetes-induced inflammatory tissue destruction. Antibody-mediated inhibition of CD137L markedly reduced the diabetes-driven bone loss, neutrophil recruitment, expansion of γδ T-cells, and excessive infiltration by IL17A+ cells. In vitro studies further validated these findings and established that high glucose-mediated dysregulation of dendritic cells dramatically altered γδ T-cell activity in co-culture systems via CD137L. The essential role of dendritic cells as CD137L producers in vivo was definitively established through lineage-specific Akt1 deletion, which abrogated CD137L expression in these cells and reversed the adverse effects of hyperglycemia on leukocyte responses to bacterial pathogens in vivo. Conversely, activation of CD137 with an agonist in normal animals recapitulated diabetes-induced abnormalities in the inflammatory response and accelerated bone loss. These findings elucidate a key mechanism underlying diabetes-induced immune dysregulation and inflammatory damage, and point to the CD137L-CD137 pathway as a promising therapeutic target, offering potential insights into mitigating other diabetes-associated complications linked to inflammatory changes.
Authors
Xin Huang, Min Liu, Michael V. Gonzalez, Rahul Debnath, Hamideh Afzali, Yongwon Choi, Su Ah Kim, Kang I. Ko, Dana T. Graves
Abstract
BACKGROUND. Among antiretroviral therapy (ART)-suppressed people with HIV (PWH), women have higher levels of some inflammatory markers than men, but the broader effect of sex on the inflammatory proteome, and whether these differences are modified by age, remains unclear. METHODS. 363 plasma inflammatory protein levels (Olink Inflammation Explore) were assessed in ART-suppressed PWH sampled from the Center for AIDS Research Network of Integrated Clinical Systems (CNICS). The relationship between sex and 363 plasma proteins – including 22 in the interferon-α response pathway – was assessed with linear regression models adjusting for confounders, assessing interactions by age. FINDINGS. Of 922 participants, 162 (18%) were female. The median age was 47, above which the majority of women had undetectable plasma anti-Müllerian hormone levels, a biomarker of ovarian reserve. Age impacted the influence of sex on the inflammatory proteome. Older age (>47) was associated with greater increases among women than men in 194 proteins. Interferon-α response proteins were higher in men in those ≤ 47 (P = 0.024), but higher in women in those > 47 (P = 0.005, p-interaction < 0.001). Among the 131 proteins associated with mortality risk (q < 0.05), only 5 differed by sex among those ≤ 47, while 79 differed by sex in those > 47, with nearly all being higher in women . Women had decreased mortality than men ≤47 (P < 0.001) but had similar mortality > 47 (P = 0.84). INTERPRETATION. The menopausal transition appears to have a dramatic effect on systemic Type I interferon responses and the broader inflammatory proteome in women with HIV. Among older PWH, women have greater inflammation than men, including the majority of proteins linked with mortality risk.
Authors
Rebecca A. Abelman, Samuel R. Schnittman, Natalia Faraj Murad, Adam Olshen, Gabriele B. Beck-Engeser, Noah Aquino, Gabrielle C. Ambayec, Edward R. Cachay, Joseph J. Eron, Michael Saag, Robin M. Nance, Joseph A. Delaney, Stephanie A. Ruderman, Richard D. Moore, Kenneth H. Mayer, Jeffrey M. Jacobson, Heidi M. Crane, Peter W. Hunt
Abstract
BACKGROUND. Critically ill patients with acute respiratory distress syndrome (ARDS) and sepsis exhibit distinct inflammatory phenotypes with divergent clinical outcomes, but the underlying molecular mechanisms remain poorly understood. These phenotypes, derived from clinical data and protein biomarkers, were associated with metabolic differences in a pilot study. METHODS. We performed integrative multi-omics analysis of blood samples from 160 ARDS patients in the ROSE trial, randomly selecting 80 patients from each latent class analysis-defined inflammatory phenotype (Hyperinflammatory and Hypoinflammatory) with phenotype probability >0.9. Untargeted plasma metabolomics and whole blood transcriptomics at Day 0 and Day 2 were analyzed using multi-modal factor analysis (MEFISTO). The primary outcome was 90-day mortality, with validation in an independent critically ill sepsis cohort (EARLI). RESULTS. Multi-omics integration revealed four molecular signatures associated with mortality: (1) enhanced innate immune activation coupled with increased glycolysis (associated with Hyperinflammatory phenotype), (2) hepatic dysfunction and immune dysfunction paired with impaired fatty acid beta-oxidation (associated with Hyperinflammatory phenotype), (3) interferon program suppression coupled with altered mitochondrial respiration (associated with Hyperinflammatory phenotype), and (4) redox impairment and cell proliferation pathways (not associated with inflammatory phenotype). These signatures persisted through Day 2 of trial enrollment. Within-phenotype analysis revealed distinct mortality-associated pathways in each group. All molecular signatures were validated in the independent EARLI cohort. CONCLUSIONS. Inflammatory phenotypes of ARDS reflect distinct underlying biological processes with both phenotype-specific and phenotype-independent pathways influencing patient outcomes, all characterized by mitochondrial dysfunction. These findings suggest potential therapeutic targets for precise treatment strategies in critical illness. FUNDING. This work is the result of NIH funding.
Authors
Narges Alipanah-Lechner, Lucile Neyton, Pratik Sinha, Carolyn Leroux, Kim Bardillon, Sidney A. Carrillo, Suzanna Chak, Olivia Chao, Taarini Hariharan, Carolyn Hendrickson, Kirsten Kangelaris, Charles R. Langelier, Deanna Lee, Chelsea Lin, Kathleen Liu, Liam Magee, Angelika Ringor, Aartik Sarma, Emma Schmiege, Natasha Spottiswoode, Kathryn Sullivan, Melanie F. Weingart, Andrew Willmore, Hanjing Zhuo, Angela J. Rogers, Kathleen A. Stringer, Michael A. Matthay, Carolyn S. Calfee
Abstract
Clonal hematopoiesis due to TET2-driver mutations (CH) is associated with coronary heart disease and worse prognosis among patients with aortic valve stenosis (AVS). However, it is unknown what role CH plays in the pathogenesis of AVS. In a meta-analysis of All Of Us, BioVU, and the UK Biobank, patients with CHIP exhibited an increased risk of AVS, with a higher risk among patients with TET2 or ASXL1 mutations. Single-cell RNA-sequencing of immune cells from AVS patients harboring TET2 CH-driver mutations revealed monocytes with heightened pro-inflammatory signatures and increased expression of pro-calcific paracrine signaling factors, most notably Oncostatin M (OSM). Secreted factors from TET2-silenced macrophages increased in vitro calcium deposition by mesenchymal cells, which was ablated by OSM silencing. Atheroprone Ldlr–/– mice receiving CH-mimicking Tet2–/– bone marrow transplants displayed greater calcium deposition in aortic valves. Together, these results demonstrate that monocytes with CH promote aortic valve calcification, and that patients with CH are at increased risk of AVS.
Authors
Wesley T. Abplanalp, Michael A. Raddatz, Bianca Schuhmacher, Silvia Mas-Peiro, María A. Zuriaga, Nuria Matesanz, José J. Fuster, Yash Pershad, Caitlyn Vlasschaert, Alexander J. Silver, Eric H. Farber-Eger, Yaomin Xu, Quinn S. Wells, Delara Shahidi, Sameen Fatima, Xiao Yang, Adwitiya A.P. Boruah, Akshay Ware, Maximilian Merten, Moritz von Scheidt, David John, Mariana Shumliakivska, Marion Muhly-Reinholz, Mariuca Vasa-Nicotera, Stefan Guenter, Michael R. Savona, Brian R. Lindman, Stefanie Dimmeler, Alexander G. Bick, Andreas M. Zeiher
Abstract
Influenza and other respiratory viral pathogens remain leading causes of mortality and morbidity. Circadian rhythms play a critical role in regulating immune responses and can confer temporal protection from influenza infection. Here, we investigated whether this protection requires rhythmic function after the initial infection by manipulating environmental cycles. We found that disrupting environmental lighting cues within a critical window of vulnerability abrogated the time-of-day-specific protection. This poor outcome was mediated by a dysregulated immune response, as evidenced by the accumulation of inflammatory monocytes and CD8+ T cells in the lungs and a transcriptomic profile indicative of an exaggerated inflammation. Disruption of the light cycle did not affect outcomes in a clock mutant, indicating that it acts through the host’s circadian clock. Importantly, rhythmic meal timing mitigated the adverse effects of disrupted light cycles, supporting the idea that external cues acting through different body clocks can compensate for one another. Together, these findings underscore the critical interplay between environmental timing cues and endogenous circadian rhythms in determining influenza outcomes and offer translational insight into optimizing care for critically ill patients with respiratory viral infections.
Authors
Oindrila Paul, Thomas G. Brooks, Alisha Shetty, Y. Jane Choi, Martina Towers, Lora J. Assi, James P. Garifallou, Kaitlyn Forrest, Alecia Cameron, Amita Sehgal, Gregory Grant, Shaon Sengupta
Abstract
Demyelination associated microglia (DMAM) orchestrate the regenerative response to demyelination by clearing myelin debris and promoting oligodendrocyte maturation. Peroxisomal metabolism has emerged as a candidate regulator of DMAMs, though the cell-intrinsic contribution in microglia remains undefined. Here we elucidate the role of peroxisome integrity in DMAMs using cuprizone mediated demyelination coupled with conditional knockout of peroxisome biogenesis factor 5 (PEX5) in microglia. Absent demyelination, PEX5 conditional knockout (PEX5cKO) had minimal impact on homeostatic microglia. However, during cuprizone-induced demyelination, the emergence of DMAMs unmasked a critical requirement for peroxisome integrity. At peak demyelination, PEX5cKO DMAMs exhibited increased lipid droplet burden and reduced lipophagy suggestive of impaired lipid catabolism. Although lipid droplet burden declined during the remyelination phase, PEX5cKO DMAMs accumulated intralysosomal crystals and curvilinear profiles, which features were largely absent in controls. Aberrant lipid processing was accompanied by elevated lysosomal damage markers and downregulation of the lipid exporter gene Apoe, consistent with defective lipid clearance. Furthermore, the disruptions in PEX5cKO DMAMs were associated with defective myelin debris clearance and impaired remyelination. Together, these findings delineate a stage-specific role for peroxisomes in coordinating lipid processing pathways essential to DMAM function and necessary for enabling a pro-remyelinating environment.
Authors
Joseph A. Barnes-Vélez, Xiaohong Zhang, Yaren L. Peña Señeriz, Kiersten A. Scott, Yinglu Guan, Jian Hu
Abstract
Colitis-associated cancer (CAC) arises from a complex interplay between host and environmental factors. In this report, we investigated the role of the gut microbiome using Winnie mice, a UC-like model with a missense mutation in the Muc2 gene. Upon rederivation from a conventional (CONV) to a specific-pathogen-free (SPF) facility, Winnie mice developed severe colitis and, notably, spontaneous CAC that progressively worsened over time. In contrast, CONV Winnie showed only mild colitis but no tumorigenesis. By comparison, when rederived into germ-free (GF) conditions, SPF Winnie mice were protected from colitis and colon tumors, indicating an essential role for the gut microbiome in the development of CAC in these mice. Using shotgun metagenomics, metabolomics, and lipidomics, we identified a distinct pro-inflammatory microbial and metabolic signature that potentially drives the transition from colitis to CAC. Fecal microbiota transplantation (FMT), using either SPF Winnie or WT (Bl/6) donors into GF Winnie recipients, demonstrated that while colitis developed regardless of the donor, only FMT from SPF Winnie donors resulted in CAC. Our studies present a relevant model of CAC, providing strong evidence that the microbiome plays a key role in its pathogenesis, thereby challenging the concept of colon cancer as a strictly non-transmissible disease.
Authors
Giulio Verna, Stefania De Santis, Bianca N. Islam, Eduardo M. Sommella, Danilo Licastro, Liangliang Zhang, Fabiano De Almelda Celio, Emily N. Miller, Fabrizio Merciai, Vicky Caponigro, Wei Xin, Pietro Campiglia, Theresa T. Pizarro, Marcello Chieppa, Fabio Cominelli
Abstract
Chronic inflammation leads to tissue fibrosis which can disrupt the function of the parenchyma of the organ and ultimately lead to organ failure. The most prevalent form of this occurs in chronic hepatitis which leads to liver fibrosis and, ultimately, cirrhosis and hepatic failure. Although there is no specific treatment for fibrosis, the phosphodiesterase 4 (PDE4) competitive inhibitors have been shown to ameliorate fibrosis in rodent models. However, competitive inhibitors of PDE4 have shown significantly reduced effectiveness due to severe gastrointestinal side effects. The PDE4 family is composed of four genes (PDE4A–D) with each having up to 9 differentially spliced isoforms. Here, we report that PDE4D expression is specifically elevated during the hepatic fibrosis stage of liver disease progression. Furthermore, the expression of the long isoforms of PDE4D is selectively elevated in activated hepatic stellate cells, leading to the enhanced accumulation of extracellular matrix components. In a mouse model of liver fibrosis, genetic ablation of PDE4D or pharmacological inhibition using D159687, a selective allosteric inhibitor targeting the long isoforms of PDE4D, suppresses the expression of inflammatory and profibrogenic genes. These findings establish the long isoforms of PDE4D as key drivers of liver fibrosis and highlight their potential as therapeutic targets to ameliorate liver fibrosis.
Authors
Jeonghan Kim, Heeeun Yoon, Seoung Chan Joe, Antoine Smith, Jinsung Park, Geunhye Hong, Ji Myeong Ha, Eun Bae Kim, Ekihiro Seki, Myung K. Kim, Hae-Ock Lee, Ho-Shik Kim, Jay H. Chung
No posts were found with this tag.
Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)