Inflammation
Abstract
Sepsis is a systemic response to infection with life-threatening consequences such as hemolysis, a predictor of mortality risks for the disease. Here, by measuring organism-wide changes in gene expression, we discovered that the secreted phospholipase PLA2G5 is induced in colon cell types during sepsis. The genetic deletion of Pla2g5 and treatment with a PLA2G5 antibody were both associated with protection from lethal sepsis. Treatment with a PLA2G5 antibody during sepsis was associated with increased splenic red pulp macrophages and improved iron homeostasis, linking PLA2G5 to red blood cell homeostasis during sepsis. Mechanistically, bloodborne PLA2G5 led to intravascular hemolysis through its lipolytic activity on red blood cell membranes. In humans with sepsis due to bacterial, fungal, or viral infections, the serum level of PLA2G5 was elevated and predictive of disease severity and mortality. We conclude that sepsis corrupts PLA2G5 into becoming an intravascular hemolytic factor which is toxic for host red blood cells.
Authors
Michihiro Takahama, Krysta S. Wolfe, Gabriella Richey, Madison Plaster, Anna Czapar, Fabian Hernandez, Denis Cipurko, Tatsuki Ueda, Yoshimi Miki, Yuki Nagasaki, Yoshitaka Taketomi, Tatsuya Saitoh, Tadafumi Kawamoto, Steven M. Dudek, Makoto Murakami, Nicolas Chevrier
Abstract
BACKGROUND. Elevated lipoprotein(a) [Lp(a)] is associated with a higher risk of atherosclerotic cardiovascular disease (ASCVD). Although Lp(a) is a genetically determined risk factor, the plasma proteomic features associated with Lp(a) and whether they provide information about ASCVD risk beyond Lp(a) concentration are not well characterized. OBJECTIVE. We sought to identify plasma proteomic features associated with Lp(a) concentration and to evaluate whether an Lp(a)-associated proteomic signature is associated with ASCVD phenotypes in young, healthy adults. METHODS. In the Coronary Artery Risk Development in Young Adults (CARDIA) study, we measured Year 7 Lp(a) and 184 cardiovascular proteins using the Olink proximity extension assay in 3,920 participants without prior coronary heart disease. Lp(a)-associated proteomic signatures were derived using LASSO regression in a split-sample design and tested for association with coronary artery calcification (CAC), incident CHD, and hs-CRP over 27 years of follow-up. External replication was performed in the UK Biobank (n=37,996). RESULTS. Lp(a) was associated with CAC (OR 1.23 [1.13-1.34]; p<0.0001) and incident CHD (HR 1.23 [1.07-1.41]; p=0.004). Lp(a) correlated with proteomic features reflecting immune activation, coagulation, and vascular dysfunction. A quantitative Lp(a) proteomic score was independently associated with incident CAC (standardized beta = 0.40, p<0.0001) and hs-CRP (standardized beta = 0.11, p = 0.00015) after adjustment for Lp(a) concentration. In the UK Biobank, a recalibrated Lp(a)-associated proteomic score was associated with CRP, incident CHD, and all-cause mortality. CONCLUSIONS. In young adults, Lp(a) is associated with distinct proteomic features that independently predict ASCVD phenotypes beyond Lp(a) concentration, generating hypotheses regarding biological pathways linked to Lp(a)-related cardiovascular risk.
Authors
Sascha N. Goonewardena, Shanshan Yao, Tomasz Jurga, Lanyue Zhang, Donald Lloyd-Jones, Dilna Damodaran, Bharat Thyagarajan, David R. Jacobs Jr, Supriya Shore, Eric J. Brandt, Clary Clish, Kahraman Tanriverdi, Jane E. Freedman, Chirag J. Patel, Mark A. Sarzynski, Brian T. Emmer, John T. Wilkins, Ron Do, Vera Bittner, Ravi Shah, Marios K. Georgakis, Robert S. Rosenson, Venkatesh Murthy
Abstract
CD48 is a surface molecule with immunoregulatory functions. Following our initial report of a patient with a de novo heterozygous variant at amino acid S220 in the CD48 gene, we describe a second, unrelated patient with similar features of immune dysregulation and a missense change affecting the same residue. To further elucidate the specific pathogenic mechanisms of the identified variants, we reviewed patient records, analyzed patient-derived cells, and employed complementary in vitro and in vivo model systems, including transfected cell lines and CD48-deficient mice. We demonstrate that the variants are associated with altered distribution of CD48, characterized by diminished CD48 surface expression, intracellular retention, and activation of endoplasmic reticulum stress signaling. Patient T cells display increased susceptibility to apoptosis, reduced antiviral responses, and enhanced inflammation. Both patients exhibit T-cell lymphopenia, a restricted TCR repertoire diversity, and oligoclonal expansions consistent with antigen-driven selection. In parallel, virally-infected CD48-deficient mice recapitulate key aspects of the human phenotype, including delayed antiviral immune responses, impaired viral clearance and pronounced inflammation. We conclude that identified variants compromise CD48 cell-surface localization, impair T-cell survival and function, and predispose to inflammation, thereby highlighting the role of CD48 in immune regulation and the prevention of excessive inflammation.
Authors
Samantha Milanesi, Tiziana Lorenzini, Tommaso Marchetti, Diana Tintor, Raquel Planas, Ola Sabet, Lars Malmström, Sudip Acharya, Carson D. Williams, Zoe E. Manning, Jack H. Roser, Angelica C. Ehler, Michael Huber, Seraina Prader, Stefano Vavassori, Cullen M. Dutmer, Jordan K. Abbott, Jana Pachlopnik Schmid
Abstract
Traumatic brain injury (TBI) disproportionately affects the elderly, yet the underlying mechanisms remain unclear. Here, we demonstrate that aged TBI brains predominantly harbor pro-inflammatory NLRP3+ microglia, in stark contrast to the neuroprotective Lysozyme+ microglia prevalent in young TBI brains. This age-dependent microglial dichotomy correlates with elevated mortality and impaired recovery in aged TBI mice. By leveraging an integrative multi-omics approach combined with metabolomics and epigenome analysis, we identify a previously unrecognized link between enhanced glycolysis and pro-inflammatory chromatin landscape in NLRP3+ microglia. Further investigation identifies ELF1 as a key transcription factor driving NLRP3+ microglia formation. Importantly, ablation of ELF1 reverses age-associated microglial dysfunction and improves TBI outcomes. Finally, we discover that Imeglimin, a clinically approved antihyperglycemic agent capable of crossing the blood brain barrier, inhibits ELF1 and reverses microglial phenotype, reducing acute mortality rate and leading to improved functional recovery of aged TBI mice. Our work elucidates the mechanistic basis of age-dependent TBI outcomes, reveals the crosstalk between metabolic rewiring and epigenetic regulation in microglial aging, and identifies ELF1 as a promising therapeutic target for improving TBI outcome.
Authors
Zhichao Lu, Yi Shuai, Chenxing Wang, Zongheng Liu, Ziheng Wang, Qianqian Liu, Rui Jiang, Jue Zhu, Yongqi Zhu, Weiquan Liao, Xingjia Zhu, Jingwei Zhao, Kaibin Shi, Wei Shi, Peipei Gong
Abstract
Cytokines mediating epithelial and immune cell interactions modulate mucosal healing—a process that goes awry with chronic inflammation as in inflammatory bowel disease. TNFSF13 is a cytokine important for B cell maturation and function, but roles for epithelial TNFSF13 and putative contribution to inflammatory bowel disease are poorly understood. We evaluated functional consequences of a novel monoallelic TNFSF13 variant using biopsies, tissue-derived colonoids and induced pluripotent stem cell (iPSC)-derived colon organoids. TNFSF13 variant colonoids exhibited a >50% reduction in secreted TNFSF13, increased epithelial proliferation, and reduced apoptosis, which was confirmed in iPSC-derived colon organoids. Single cell RNA-sequencing and flow cytometry suggested FAS as the predominant colonic epithelial receptor for TNFSF13, which was confirmed by co-immunoprecipitation and binding assays. Imaging mass cytometry revealed an increase in epithelial-associated B cells in TNFSF13 variant colon tissue sections. Finally, TNFSF13 variant colonoids co-cultured with memory B cells demonstrated a reduction in immunoglobulin-producing plasma cells compared to control colonoid cocultures. Our findings support a role for epithelial TNFSF13 as a regulator of colonic epithelial growth and epithelial crosstalk with B cells.
Authors
Xianghui Ma, Shaneice K. Nettleford, Yuhua Tian, Noor Dawany, Ayano Kondo, Yalan Li, Kelly Maurer, Tatiana A. Karakasheva, Rawan Shraim, Patrick A. Williams, Louis R. Parham, Lauren A. Simon, Charles H. Danan, Maire A. Conrad, David A. Piccoli, Marcella Devoto, Neil Romberg, Kathleen E. Sullivan, Klaus H. Kaestner, Judith R. Kelsen, Kathryn E. Hamilton
Abstract
Understanding susceptibility factors of sepsis is crucial for early diagnosis and development of personalized treatment strategies. However, the genetic determinants for initiation and progression of sepsis remain unclear. Here, we showed that the expression levels of estrogen receptor (ER) β are significantly reduced in the peripheral blood of sepsis patients, which were negatively correlated with disease severity. The results from human samples and experimental animals demonstrated that ERβ deficiency enhances the body's susceptibility to sepsis by inducing macrophage pyroptosis, thereby impairing bacterial clearance. Mechanistically, ERβ deficiency enhanced fatty acid oxidation, increased acetyl-CoA levels, and promoted acetylation of stomatin-like protein 2 (Stoml2) at K221, leading to mitochondrial dysfunction and macrophage pyroptosis. Mutating the Stoml2 K221 site mitigated these effects and improved survival of septic mice. These findings suggest ERβ deficiency as a potential genetic factor in sepsis susceptibility.
Authors
Yanrong Zhu, Gang Li, Yilei Guo, Yue He, Wanyi Zhang, Lei Gao, Jing Zhang, Pengxiang Guo, Haochang Lin, Wenjie Zhang, Zhifeng Wei, Yufeng Xia, Yue Dai
Abstract
The dynamic assembly and regulation of the IκB kinase (IKK) complex in the NF-κB pathway are central to the pathogenesis and progression of inflammatory bowel disease (IBD). We recently reported that the transcription factor hematopoietically-expressed homeobox (HHEX) promotes colitis-associated colorectal cancer, but the potential role of HHEX in intestinal inflammation remains uncharacterized. Here, we found that HHEX is upregulated in inflamed colons in a colitis mouse model and in clinical IBD samples. HHEX overexpression increased inflammatory cytokine expression, and HHEX loss largely abrogated the inflammatory response in vitro and intestinal inflammation in vivo. Mechanistically, IKKα phosphorylates HHEX at S213 to stabilize HHEX in response to TNF-α by inhibiting the interaction of HHEX with the E3 ubiquitin ligase MID2 and subsequent K48-linked ubiquitination and protein degradation. Importantly, HHEX interacts with and stabilizes the IKKα/IKKβ complex via its N-terminal domain, thereby activating the NF-κB pathway and establishing a positive feedback loop that exacerbates intestinal inflammation. Our study reveals a transcription-independent function of HHEX in promoting IKK complex assembly and colitis, identifying HHEX as an IBD susceptibility gene and a potential target for IBD treatment.
Authors
Zhebin Hua, Weimin Xu, Wenjun Ding, Zhuoyue Fu, Yaosheng Wang, Yiqing Yang, Fangyuan Liu, Zhujiang Dai, Wenbo Tang, Weijun Ou, Wensong Ge, YingWei Chen, Zhongchuan Wang, Chen-Ying Liu, Peng Du
Abstract
This study investigated how chronic pelvic pain (CPP) develops using rhesus macaques with naturally occurring endometriosis and a multiple-lesion induction mouse model (MIM), as repeated retrograde menstruation is considered an underlying mechanism of endometriosis pathogenesis. MIM increased lesion numbers and elevated hypersensitivity. Elevated persistent glial cell activation was observed across multiple brain regions and/or spinal cords in MIM and rhesus macaques. Elevated TRPV1, SP, and CGRP expressions in the dorsal root ganglia (DRG) were persistent in MIM. MIM induced the severe disappearance of TIM4hi MHCIIlo residential macrophages and an influx of increased pro-inflammatory TIM4lo MHCIIhi macrophages in the peritoneal cavity. Cytokine levels were persistently elevated in MIM. Furthermore, dienogest (a synthetic progestin) and fingolimod (a selective immunosuppressor) reduced hyperalgesia and neuroinflammation. Our results indicate that recurrent retrograde menstruation can be a peripheral stimulus that induces nociceptive pain and creates a composite chronic inflammatory stimulus, leading to neuroinflammation and sensitization of the central nervous system. The circuits of neuroplasticity and stimulation of peripheral organs via a feedback loop of neuroinflammation may mediate widespread endometriosis-associated CPP. These findings in mice were further supported by results from the spontaneously developed advanced endometriosis in rhesus macaques via recurrent retrograde menstruation.
Authors
Madeleine E. Harvey, Mingxin Shi, Yeongseok Oh, Taylor M. Page, Debra A. Mitchell, Addie Luo, Ov D. Slayden, James A. MacLean, Anjali Sharma, Kanako Hayashi
Abstract
The link between glutaminolysis and osteoarthritis (OA) has only recently begun to be elucidated. Here, we report the association of obesity- and injury-induced cartilage damage with impaired glutaminolysis in chondrocytes. Defective glutaminolysis triggered the onset and progression of OA, with enhanced catabolism and decreased anabolism. Supplementation of α-ketoglutarate (αKG), a key component in glutaminolysis and an epigenetic factor, effectively protected cartilage against degradation in vivo via a TCA cycle– and HIF-1α–independent manner. Mechanistically, OA pathogenic factors increased H3K27me3 deposition on promoters of key glutaminolysis genes, including Slc1a5 and Gls1, leading to impaired glutaminolysis. Conversely, αKG facilitated Kdm6b-dependent H3K27me3 demethylation of not only glutaminolysis genes to rescue Gln metabolism but also Ube2o to reverse OA. Elevated Ube2o expression led to TRAF6 ubiquitination and subsequent inhibition of NF-κB signaling, thereby reversing the pathological reprogramming of glycolysis and oxidative phosphorylation and protecting against cartilage destruction. Collectively, these results demonstrated that OA pathogenic factors impair glutaminolysis through epigenetic regulation, which further exacerbate OA. Moreover, αKG restores metabolic homeostasis and alleviates OA through H3K27me3 demethylation.
Authors
Shuaijun Li, Jiefeng Huang, Ting Shang, Laiya Lu, Orion R. Fan, Peisheng Jin, Xin Zou, Zixin Cai, Wuyan Lu, Shuangmeng Jia, Linxiao Li, Ke Fang, Fengting Niu, Jiaojiao Li, Cheng Zhao, Qian Wang, Ruizhu Sun, Si Shi, Feng Yin, Yun Zhang, Yi Eve Sun, Lei Cui
Abstract
Surgical stress, such as hepatic ischemia-reperfusion (I/R) injury, induces excessive inflammation and adversely affects liver surgery outcomes. Regulatory T cells (Tregs) are crucial for immune homeostasis, yet their protective mechanisms against liver I/R injury remain unclear. In this study, we demonstrated that decreased hepatic Treg abundance correlates with increased liver injury in patients undergoing hepatic hemangioma resections. In murine models, Treg depletion worsened liver I/R injury. Bulk RNA-seq of hepatic Tregs showed enrichment of Toll-like receptor (TLR) signaling pathways, with flow cytometry identifying TLR4 as the most increased TLR after I/R. Treg-specific Tlr4 knockout mice (Treg-Tlr4–/– mice) exhibited exacerbated liver injury following I/R. Adoptive transfer of WT Tregs, but not Tlr4-deficient Tregs, alleviated liver injury in both Treg-depleted and Treg-Tlr4–/– mice. Transcriptomic analysis revealed that IL-10 production was impaired in Tlr4-deficient Tregs. Mechanistically, Tlr4-deficient Tregs showed reduced activation of the MyD88/ERK/CREB pathway, resulting in diminished IL-10 production. Myd88–/– and IL-10–/– Tregs failed to confer protection against liver I/R injury, whereas exogenous IL-10 administration rescued the hepatic dysfunction in Treg-Tlr4–/– mice. Our findings implicate the vital role of TLR4 in Tregs to mitigate liver I/R injury and offer a potential therapeutic option to reduce postoperative complications following liver surgery.
Authors
Hongji Zhang, Yunwei Zhang, Tianxing Ren, Carolyn Tsung, Peng Song, Peng Xu, Guoliang Wang, Chunyan Cao, Changyan Wang, Ping Sun, Qi Zhang, Yanhong Zhu, Xin Zhong, Yong Guan, Xiaofei Zhang, Han Wang, Jinxiang Zhang, Hui Wang
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Copyright © 2026 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)