Inflammation
Abstract
2'3'-cGAMP is known as a non-classical 2nd messenger and small immune modulator that possesses potent anti-tumor and antiviral activities through stimulating STING-mediated signaling pathway. However, its function in regulating type 2 immune responses remains unknown. We sought to determine a role of STING activation by 2'3'-cGAMP in type 2 inflammatory reactions in multiple mouse models of eosinophilic asthma. We discovered that 2'3'-cGAMP administration strongly attenuated type 2 lung immunopathology and airway hyperresponsiveness (AHR) induced by IL-33 and a fungal allergen, A. flavus. Mechanistically, upon the respiratory delivery, 2'3'-cGAMP was mainly internalized by alveolar macrophages, in which it activated the STING-IRF3-IFN-I signaling axis to induce the production of inhibitory factors containing IFNα, which blocked the IL-33-mediated activation of group 2 innate lymphoid cells (ILC2) in vivo. We further demonstrated that 2'3'-cGAMP directly suppressed the proliferation and function of both human and mouse ILC2 in vitro. Taken together, our findings suggest that STING activation by 2'3'-cGAMP in alveolar macrophages and ILC2 cells can negatively regulate type 2 immune responses, implying that the respiratory delivery of 2'3'-cGAMP might be further developed as an alternative strategy for treating type 2 immunopathologic diseases such as eosinophilic asthma.
Authors
Li She, Gema D. Barrera, Liping Yan, Hamad Hazzaa Alanazi, Edward G. Brooks, Peter H. Dube, Yilun Sun, Hong Zan, Daniel P. Chupp, Nu Zhang, Xin Zhang, Yong Liu, Xiao-Dong Li
Abstract
Ginger is known to have anti-inflammatory and anti-oxidative effects, and has traditionally been used as an herbal supplement in the treatment of various chronic diseases. Here, we report anti-neutrophil properties of 6-gingerol, the most abundant bioactive compound of ginger root, in models of lupus and antiphospholipid syndrome (APS). Specifically, we demonstrate that 6-gingerol attenuates neutrophil extracellular trap (NET) release in response to lupus- and APS-relevant stimuli through a mechanism that at least partially dependent on inhibition of phosphodiesterases. At the same time, administration of 6-gingerol to mice reduces NET release in various models of lupus and APS, while also improving other disease-relevant endpoints such as autoantibody formation and large-vein thrombosis. In summary, this study is the first to demonstrate a protective role for ginger-derived compounds in the context of lupus, and importantly provides a potential mechanism for these effects via phosphodiesterase inhibition and attenuation of neutrophil hyperactivity.
Authors
Ramadan A. Ali, Alex A. Gandhi, Lipeng Dai, Julia K. Weiner, Shanea K. Estes, Srilakshmi Yalavarthi, Kelsey Gockman, Duxin Sun, Jason S. Knight
Abstract
Aberrant activation of NLRP3 inflammasome has been implicated in a variety of human inflammatory diseases, however currently no pharmacological NLRP3 inhibitor has been approved in clinic. In this study, we showed that echinatin, the ingredient of the traditional herbal medicine licorice, effectively suppresses the activation of NLRP3 inflammasome in vitro and in vivo. Further investigation revealed that echinatin exerts its inhibitory effect on NLRP3 inflammasome by binding to heat-shock protein 90 (HSP90), inhibiting its ATPase activity, and disrupting the association between the cochaperone SGT1 and HSP90-NLRP3. Importantly, in vivo experiments demonstrated that administration of echinatin obviously inhibits NLRP3 inflammasome activation and ameliorates LPS-induced septic shock and DSS-induced colitis in mice. Moreover, echinatin exerted favorable pharmacological effects on liver inflammation and fibrosis in mouse model of non-alcoholic steatohepatitis (NASH). Collectively, our study identified echinatin as a novel inhibitor of NLRP3 inflammasome and may be developed as a potentially therapeutic approach for the treatment of NLRP3-driven diseases.
Authors
Guang Xu, Shubin Fu, Xiaoyan Zhan, Zhilei Wang, Ping Zhang, Wei Shi, Nan Qin, Yuanyuan Chen, Chunyu Wang, Ming Niu, Yuming Guo, Jia-bo Wang, Zhaofang Bai, Xiaohe Xiao
A roadmap from single-cell transcriptome to patient classification for the immune response to trauma
Abstract
Immune dysfunction is an important factor driving mortality and adverse outcomes after trauma but remains poorly understood, especially at cellular level. To deconvolute trauma-induced immune response, we applied single-cell RNA sequencing to circulating and bone marrow mononuclear cells in injured mice and circulating mononuclear cells in trauma patients. In mice, the greatest changes in gene expression were seen in monocytes across both compartments. After systemic injury, the gene expression pattern of monocytes markedly deviated from steady state with corresponding changes in critical transcription factors (TFs), which can be traced back to myeloid progenitors. These changes were largely recapitulated in human single-cell analysis. We generalized the major changes in human CD14+ monocytes into six signatures, which further defined two trauma patient subtypes (SG1 vs. SG2) identified in the whole blood leukocyte transcriptome in the initial 12h after injury. Compared with SG2, SG1 patients exhibited delayed recovery, more severe organ dysfunction and a higher incidence of infection and non-infectious complications. The two patient subtypes were also recapitulated in burn and sepsis patients, revealing a shared pattern of immune response across critical illness. Our data will be broadly useful to further explore the immune response to inflammatory diseases and critical illness.
Authors
Tianmeng Chen, Matthew J. Delano, Kong Chen, Jason L. Sperry, Rami A. Namas, Ashley J. Lamparello, Meihong Deng, Julia Conroy, Lyle L. Moldawer, Philip A. Efron, Patricia A. Loughran, Christopher W. Seymour, Derek C. Angus, Yoram Vodovotz, Wei Chen, Timothy R. Billiar
Abstract
Psychological stress affects maternal gastrointestinal (GI) permeability, leading to low-grade inflammation which can impact negatively on fetal development. We investigated a panel of circulating markers as a biological signature of this stress exposure in pregnant women with and without the stress-related GI disorder irritable bowel syndrome (IBS). Markers of GI permeability and inflammation were measured in plasma from healthy (n = 104) and IBS cohorts (n = 105) of women at 15- and 20-weeks’ gestation. Biomarkers were evaluated with respect to their degree of association to levels of stress, anxiety and depression as indicated by responses from the Perceived Stress Scale, State-Trait Anxiety Inventory and Edinburgh Postnatal Depression Scale. High levels of stress were associated with elevations of soluble CD14, lipopolysaccharide binding protein (LBP) and tumour necrosis factor-α, while anxiety associated with elevated concentrations of C-reactive protein (CRP) in otherwise healthy pregnancies. Prenatal depression was associated with higher levels of soluble CD14, LBP and CRP in the healthy cohort. High levels of prenatal anxiety and depression were also associated with lower concentrations of tryptophan and kynurenine respectively in the IBS cohort. These markers may represent a core maternal biological signature of active prenatal stress which can be used to inform intervention strategies via stress reduction techniques or other lifestyle approaches. Such interventions may need to be tailored to reflect underlying GI conditions such as IBS.
Authors
James M. Keane, Ali S. Khashan, Fergus P. McCarthy, Louise C. Kenny, James M. Collins, Sarah M. O’Donovan, Jillian R.M. Brown, John F. Cryan, Timothy G. Dinan, Gerard Clarke, Siobhain M. O'Mahony
Abstract
Activation of Farnesoid-X-Receptor (FXR) by obeticholic acid (OCA) reduces hepatic inflammation and fibrosis in patients with primary biliary cholangitis (PBC), a life-threatening cholestatic liver failure. Inhibition of bromodomain-containing protein-4 (BRD4) also has anti-inflammatory, anti-fibrotic effects in mice. We determined the role of BRD4 in FXR function in bile acid (BA) regulation and examined whether the known beneficial effects of OCA are enhanced by inhibiting BRD4 in cholestatic mice. Liver-specific downregulation of BRD4 disrupted BA homeostasis in mice, and FXR-mediated regulation of BA-related genes, including Shp and Cyp7a1, was BRD4-dependent. In cholestatic mice, JQ1 or OCA treatment ameliorated hepatotoxicity, inflammation, and fibrosis, but surprisingly, was antagonistic in combination. Mechanistically, OCA increased binding of FXR and the corepressor SMRT, decreased NF-κB binding at inflammatory genes, and repressed the genes in a BRD4-dependent manner. In PBC patients, hepatic expression of FXR and BRD4 was significantly reduced. In conclusion, BRD4 is a novel cofactor of FXR for maintaining BA homeostasis and hepatoprotection. While BRD4 promotes hepatic inflammation and fibrosis in cholestasis, paradoxically, BRD4 is required for the anti-inflammatory, anti-fibrotic actions of OCA-activated FXR. Co-treatment with OCA and JQ1, individually beneficial, may be antagonistic in treatment of liver disease patients with inflammation and fibrosis complications.
Authors
Hyunkyung Jung, Jinjing Chen, Xiangming Hu, Hao Sun, Shwu-Yuan Wu, Cheng-Ming Chiang, Byron Kemper, Lin-Feng Chen, Jongsook Kemper
Abstract
Atherosclerosis develops preferentially in areas of the arterial system, in which blood flow is disturbed. Exposure of endothelial cells to disturbed flow has been shown to induce inflammatory signaling, including NF-κB activation, which leads to the expression of leukocyte adhesion molecules and chemokines. Here, we show that disturbed flow promotes the release of adrenomedullin from endothelial cells, which in turn activates its Gs-coupled receptor calcitonin receptor–like receptor (CALCRL). This induces antiinflammatory signaling through cAMP and PKA, and it results in reduced endothelial inflammation in vitro and in vivo. Suppression of endothelial expression of Gαs, the α subunit of the G-protein Gs; CALCRL; or adrenomedullin leads to increased disturbed flow–induced inflammatory signaling in vitro and in vivo. Furthermore, mice with induced endothelial-specific deficiency of Gαs, CALCRL, or adrenomedullin show increased atherosclerotic lesions. Our data identify an antiinflammatory signaling pathway in endothelial cells stimulated by disturbed flow and suggest activation of the endothelial adrenomedullin/CALCRL/Gs system as a promising approach to inhibit progression of atherosclerosis.
Authors
Akiko Nakayama, Julián Albarrán-Juárez, Guozheng Liang, Kenneth Anthony Roquid, András Iring, Sarah Tonack, Min Chen, Oliver J. Müller, Lee S. Weinstein, Stefan Offermanns
Abstract
Cardiopulmonary bypass (CPB) is required during most cardiac surgeries. CBP drives systemic inflammation and multi-organ dysfunction that is more severe in neonatal patients. Limited understanding of molecular mechanisms underlying CPB-associated inflammation presents a significant barrier to improving clinical outcomes. To better understand these clinical issues, we performed the first mRNA-sequencing on total circulating leukocytes from neonatal patients undergoing CPB. These data identified myeloid cells, particularly monocytes, as the major cell type driving transcriptional responses to CPB. Furthermore, Interleukin-8 (IL8) and Tumor Necrosis Factor-α (TNFα) were inflammatory cytokines robustly upregulated in leukocytes from both patients and piglets exposed to CPB. To delineate a molecular mechanism, we exposed THP-1 human monocytic cells to CPB-like conditions including artificial surfaces, high shear stress, and cooling/rewarming. Here, shear stress was found to drive cytokine upregulation via calcium-dependent signaling pathways. We also observed a subpopulation of THP-1 cells died via TNFα-mediated necroptosis in our model, which we hypothesize contributes to post-CPB inflammation. Together, our study identifies a shear-stress modulated molecular mechanism that drives systemic inflammation in pediatric CPB patients. These are also the first data to demonstrate that shear-stress causes necroptosis. Finally, we observe that calcium and TNFα signaling are novel targets to ameliorate post-CPB inflammation.
Authors
Lan N. Tu, Lance Hsieh, Masaki Kajimoto, Kevin Charette, Nataliya Kibiryeva, Adriana Forero, Sarah E. Hampson, Jennifer Marshall, James O’Brien, Marta Scatena, Michael A. Portman, Ram Savan, Christopher Benner, Alberto Aliseda, Muhammad Nuri, Douglas Bittel, Peter Pastuszko, Vishal Nigam
Abstract
Background. Clostridioides difficile is a major cause of healthcare-associated diarrhea. Severity ranges from mild to life-threatening, but this variability remains poorly understood. Microbiological diagnosis of C. difficile infection (CDI) is straightforward, but offers little insight into the patient's prognosis, nor into pathophysiological determinants of clinical trajectory. The aim of this study was to discover host-derived, CDI-specific, fecal biomarkers involved in disease severity. Methods. Subjects without and with diarrhea were recruited. CDI was established by commercial, diagnostic real-time PCR assay of tcdB. CDI severity was based on IDSA/SHEA criteria. We developed a liquid chromatography tandem mass spectrometry (LC-MS/MS) approach to identify host-derived protein biomarkers from stool and applied it to diagnostic samples for cohort-wise comparison (CDI-negative vs. non-severe CDI vs. severe CDI). Selected biomarkers were orthogonally confirmed and subsequently verified in a CDI mouse model. Results. We identified a protein signature from stool, consisting of alpha-2-macroglobulin (A2M), matrix metalloproteinase-7 (MMP7) and alpha-1-antitrypsin (A1AT), that not only discriminates CDI-positive samples from non-CDI ones, but is potentially associated with disease severity. In the mouse model, this signature with the murine homologs of the corresponding proteins was also identified. Conclusions. A2M, MMP7 and A1AT serve as biomarkers in patients with CDI and define novel components of the host response that may determine disease severity.
Authors
Makan Golizeh, Kaitlin Winter, Lucie Roussel, Marija Landekic, Melanie Langelier, Vivian G. Loo, Momar Ndao, Donald C. Vinh
Abstract
Infection-driven inflammation in pregnancy is a major cause of spontaneous preterm birth (PTB). Both systemic infection and bacterial ascension through the vagina/cervix to the amniotic cavity are strongly associated with PTB. However, the contribution of maternal or fetal inflammatory responses in the context of systemic or localized models of infection-driven PTB is not well defined. Here, using intraperitoneal or intraamniotic LPS challenge, we examined the necessity and sufficiency of maternal and fetal Toll-like receptor (TLR) 4 signaling in induction of inflammatory vigor and PTB. Both systemic and local LPS challenge promoted induction of inflammatory pathways in uteroplacental tissues and induced PTB. Restriction of TLR4 expression to the maternal compartment was sufficient for induction of LPS-driven PTB in either systemic or intraamniotic challenge models. In contrast, restriction of TLR4 expression to the fetal compartment failed to induce LPS-driven PTB. Vav1-Cre–mediated genetic deletion of TLR4 suggested a critical role for maternal immune cells in inflammation-driven PTB. Further, passive transfer of WT in vitro–derived macrophages and dendritic cells to TLR4-null gravid females was sufficient to induce an inflammatory response and drive PTB. Cumulatively, these findings highlight the critical role for maternal regulation of inflammatory cues in induction of inflammation-driven parturition.
Authors
Monica Cappelletti, Jessica R. Doll, Traci E. Stankiewicz, Matthew J. Lawson, Vivien Sauer, Bingqiang Wen, Vladimir V. Kalinichenko, Xiaofei Sun, Tamara Tilburgs, Senad Divanovic
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