Inflammation
Abstract
In response to viral pathogens, the host upregulates antiviral genes that suppress translation of viral mRNAs. However, induction of such antiviral responses may not be exclusive to viruses, as the pathways lie at the intersection of broad inflammatory networks that can also be induced by bacterial pathogens. Using a model of Gram-negative sepsis, we show that propagation of kidney damage initiated by a bacterial origin ultimately involves antiviral responses that result in host translation shutdown. We determined that activation of the eukaryotic translation initiation factor 2-α kinase 2/eukaryotic translation initiation factor 2α (Eif2ak2/Eif2α) axis is the key mediator of translation initiation block in late-phase sepsis. Reversal of this axis mitigated kidney injury. Furthermore, temporal profiling of the kidney translatome revealed that multiple genes involved in formation of the initiation complex were translationally altered during bacterial sepsis. Collectively, our findings imply that translation shutdown is indifferent to the specific initiating pathogen and is an important determinant of tissue injury in sepsis.
Authors
Takashi Hato, Bernhard Maier, Farooq Syed, Jered Myslinski, Amy Zollman, Zoya Plotkin, Michael T. Eadon, Pierre C. Dagher
Abstract
Pyrin is an inflammasome sensor that promotes caspase-1–mediated pyroptotic cell death and maturation of proinflammatory cytokines IL-1β and IL-18. Familial Mediterranean fever (FMF), an autoinflammatory disorder, is associated with mutations in the gene encoding pyrin (MEFV). FMF-knockin (FMF-KI) mice that express chimeric pyrin protein with FMF mutation (MefvV726A/V726A) exhibit an autoinflammatory disorder mediated by autoactivation of the pyrin inflammasome. Increase in the levels of TNF are observed in FMF-KI mice, and many features of FMF overlap with the autoinflammatory disorder associated with TNF receptor signaling. In this study, we assessed the contribution of TNF signaling to pyrin inflammasome activation and its consequent role in distinct FMF pathologies. TNF signaling promoted the expression of pyrin in response to multiple stimuli and was required for inflammasome activation in response to canonical pyrin stimuli and in myeloid cells from FMF-KI mice. TNF signaling promoted systemic wasting, anemia, and neutrophilia in the FMF-KI mice. Further, TNF-induced pathology was induced specifically through the TNFR1 receptor, while TNFR2-mediated signaling was distinctly protective in colitis and ankle joint inflammation. Overall, our data show that TNF is a critical modulator of pyrin expression, inflammasome activation, and pyrin-inflammasomopathy. Further, specific blockade of TNFR1 or activation of TNFR2 could provide substantial protection against FMF pathologies.
Authors
Deepika Sharma, Ankit Malik, Clifford Guy, Peter Vogel, Thirumala-Devi Kanneganti
Abstract
NLRP3 inflammasome plays a critical spatiotemporal role in the pathogenesis of experimental autoimmune encephalomyelitis (EAE). This study reports a mechanistic insight into noncanonical NLRP3 inflammasome activation in microglia for the effector stage of EAE. Microglia-specific deficiency of ASC (apoptosis-associated speck-like protein containing a C-terminal caspase-activation and recruitment [CARD] domain) attenuated T cell expansion and neutrophil recruitment during EAE pathogenesis. Mechanistically, TLR stimulation led to IRAKM–caspase-8–ASC complex formation, resulting in the activation of caspase-8 and IL-1β release in microglia. Noncanonical inflammasome-derived IL-1β produced by microglia in the CNS helped to expand the microglia population in an autocrine manner and amplified the production of inflammatory cytokines/chemokines. Furthermore, active caspase-8 was markedly increased in the microglia in the brain tissue from patients with multiple sclerosis. Taken together, our study suggests that microglia-derived IL-1β via noncanonical caspase-8–dependent inflammasome is necessary for microglia to exert their pathogenic role during CNS inflammation.
Authors
Cun-Jin Zhang, Meiling Jiang, Hao Zhou, Weiwei Liu, Chenhui Wang, Zizhen Kang, Bing Han, Quanri Zhang, Xing Chen, Jianxin Xiao, Amanda Fisher, William J. Kaiser, Masanori A. Murayama, Yoichiro Iwakura, Ji Gao, Julie Carman, Ashok Dongre, George Dubyak, Derek W. Abbott, Fu-Dong Shi, Richard M. Ransohoff, Xiaoxia Li
Abstract
Dysregulated intestinal epithelial apoptosis initiates gut injury, alters the intestinal barrier, and can facilitate bacterial translocation leading to a systemic inflammatory response syndrome (SIRS) and/or multi-organ dysfunction syndrome (MODS). A variety of gastrointestinal disorders, including inflammatory bowel disease, have been linked to intestinal apoptosis. Similarly, intestinal hyperpermeability and gut failure occur in critically ill patients, putting the gut at the center of SIRS pathology. Regulation of apoptosis and immune-modulatory functions have been ascribed to Thirty-eight-negative kinase 1 (TNK1), whose activity is regulated merely by expression. We investigated the effect of TNK1 on intestinal integrity and its role in MODS. TNK1 expression induced crypt-specific apoptosis, leading to bacterial translocation, subsequent septic shock, and early death. Mechanistically, TNK1 expression in vivo resulted in STAT3 phosphorylation, nuclear translocation of p65, and release of IL-6 and TNF-α. A TNF-α neutralizing antibody partially blocked development of intestinal damage. Conversely, gut-specific deletion of TNK1 protected the intestinal mucosa from experimental colitis and prevented cytokine release in the gut. Finally, TNK1 was found to be deregulated in the gut in murine and porcine trauma models and human inflammatory bowel disease. Thus, TNK1 might be a target during MODS to prevent damage in several organs, notably the gut.
Authors
Milena Armacki, Anna Katharina Trugenberger, Ann K. Ellwanger, Tim Eiseler, Christiane Schwerdt, Lucas Bettac, Dominik Langgartner, Ninel Azoitei, Rebecca Halbgebauer, Rüdiger Groß, Tabea Barth, André Lechel, Benjamin M. Walter, Johann M. Kraus, Christoph Wiegreffe, Johannes Grimm, Annika Scheffold, Marlon R. Schneider, Kenneth Peuker, Sebastian Zeißig, Stefan Britsch, Stefan Rose-John, Sabine Vettorazzi, Eckhart Wolf, Andrea Tannapfel, Konrad Steinestel, Stefan O. Reber, Paul Walther, Hans A. Kestler, Peter Radermacher, Thomas F.E. Barth, Markus Huber-Lang, Alexander Kleger, Thomas Seufferlein
Abstract
Allergic asthma is characterized by airway hyperresponsiveness, inflammation, and a cellular infiltrate dominated by eosinophils. Numerous epidemiological studies have related the exacerbation of allergic asthma with an increase in ambient inhalable particulate matter from air pollutants. This is because inhalable particles efficiently deliver airborne allergens deep into the airways, where they can aggravate allergic asthma symptoms. However, the cellular mechanisms by which inhalable particulate allergens (pAgs) potentiate asthmatic symptoms remain unknown, in part because most in vivo and in vitro studies exploring the pathogenesis of allergic asthma use soluble allergens (sAgs). Using a mouse model of allergic asthma, we found that, compared with their sAg counterparts, pAgs triggered markedly heightened pulmonary eosinophilia in allergen-sensitized mice. Mast cells (MCs) were implicated in this divergent response, as the differences in airway inflammatory responses provoked by the physical nature of the allergens were attenuated in MC-deficient mice. The pAgs were found to mediate MC-dependent responses by enhancing retention of pAg/IgE/FcεRI complexes within lipid raft–enriched, CD63+ endocytic compartments, which prolonged IgE/FcεRI-initiated signaling and resulted in heightened cytokine responses. These results reveal how the physical attributes of allergens can co-opt MC endocytic circuitry and signaling responses to aggravate pathological responses of allergic asthma in mice.
Authors
Cong Jin, Christopher P. Shelburne, Guojie Li, Kristina J. Riebe, Gregory D. Sempowski, W. Michael Foster, Soman N. Abraham
Abstract
The E3 ubiquitin ligase Pellino 1 (Peli1) is a microglia-specific mediator of autoimmune encephalomyelitis. Its role in neurotropic flavivirus infection is largely unknown. Here, we report that mice deficient in Peli1 (Peli1–/–) were more resistant to lethal West Nile virus (WNV) infection and exhibited reduced viral loads in tissues and attenuated brain inflammation. Peli1 mediates chemokine and proinflammatory cytokine production in microglia and promotes T cell and macrophage infiltration into the CNS. Unexpectedly, Peli1 was required for WNV entry and replication in mouse macrophages and mouse and human neurons and microglia. It was also highly expressed on WNV-infected neurons and adjacent inflammatory cells from postmortem patients who died of acute WNV encephalitis. WNV passaged in Peli1–/– macrophages or neurons induced a lower viral load and impaired activation in WT microglia and thereby reduced lethality in mice. Smaducin-6, which blocks interactions between Peli1 and IRAK1, RIP1, and IKKε, did not inhibit WNV-triggered microglia activation. Collectively, our findings suggest a nonimmune regulatory role for Peli1 in promoting microglia activation during WNV infection and identify a potentially novel host factor for flavivirus cell entry and replication.
Authors
Huanle Luo, Evandro R. Winkelmann, Shuang Zhu, Wenjuan Ru, Elizabeth Mays, Jesus A. Silvas, Lauren L. Vollmer, Junling Gao, Bi-Hung Peng, Nathen E. Bopp, Courtney Cromer, Chao Shan, Guorui Xie, Guangyu Li, Robert Tesh, Vsevolod L. Popov, Pei-Yong Shi, Shao-Cong Sun, Ping Wu, Robyn S. Klein, Shao-Jun Tang, Wenbo Zhang, Patricia V. Aguilar, Tian Wang
Abstract
The resolution of inflammation is an active process that is coordinated by endogenous mediators. Previous studies have demonstrated the immunomodulatory properties of the axonal guidance proteins in the initial phase of acute inflammation. We hypothesized that the neuronal guidance protein neogenin (Neo1) modulates mechanisms of inflammation resolution. In murine peritonitis, Neo1 deficiency (Neo1–/–) resulted in higher efficacies in reducing neutrophil migration into injury sites, increasing neutrophil apoptosis, actuating PMN phagocytosis, and increasing the endogenous biosynthesis of specialized proresolving mediators, such as lipoxin A4, maresin-1, and protectin DX. Neo1 expression was limited to Neo1-expressing Ly6Chi monocytes, and Neo1 deficiency induced monocyte polarization toward an antiinflammatory and proresolving phenotype. Signaling network analysis revealed that Neo1–/– monocytes mediate their immunomodulatory effects specifically by activating the PI3K/AKT pathway and suppressing the TGF-β pathway. In a cohort of 59 critically ill, intensive care unit (ICU) pediatric patients, we found a strong correlation between Neo1 blood plasma levels and abdominal compartment syndrome, Pediatric Risk of Mortality III (PRISM-III) score, and ICU length of stay and mortality. Together, these findings identify a crucial role for Neo1 in regulating tissue regeneration and resolution of inflammation, and determined Neo1 to be a predictor of morbidity and mortality in critically ill children affected by clinical inflammation.
Authors
Martin Schlegel, Andreas Körner, Torsten Kaussen, Urs Knausberg, Carmen Gerber, Georg Hansmann, Hulda Soffia Jónasdóttir, Martin Giera, Valbona Mirakaj
Abstract
Inflammation occurs in all tissues in response to injury or stress and is the key process underlying hepatic fibrogenesis. Targeting chronic and uncontrolled inflammation is one strategy to prevent liver injury and fibrosis progression. Here, we demonstrate that triggering receptor expressed on myeloid cells-1 (TREM-1), an amplifier of inflammation, promotes liver disease by intensifying hepatic inflammation and fibrosis. In the liver, TREM-1 expression is limited to liver macrophages and monocytes and is highly upregulated on Kupffer cells, circulating monocytes, and monocyte-derived macrophages in a mouse model of chronic liver injury and fibrosis induced by carbon tetrachloride (CCl4) administration. TREM-1 signaling promotes pro-inflammatory cytokine production and mobilization of inflammatory cells to the site of injury. Deletion of Trem1 reduced liver injury, inflammatory cell infiltration, and fibrogenesis. Reconstitution of Trem1-deficient mice with Trem1-sufficient Kupffer cells restored recruitment of inflammatory monocytes and severity of liver injury. Markedly increased infiltration of liver fibrotic areas with TREM-1-positive Kupffer cells and monocytes/macrophages was found in patients with hepatic fibrosis. Our data support a role of TREM-1 in liver injury and hepatic fibrogenesis and suggests that TREM-1 is a master regulator of Kupffer cell activation, which escalates chronic liver inflammatory responses, activates hepatic stellate cells, and reveals a novel mechanism of promotion of liver fibrosis.
Authors
Anh Thu Nguyen-Lefebvre, Ashwin Ajith, Vera Portik-Dobos, Daniel David Horuzsko, Ali Syed Arbab, Amiran Dzutsev, Ramses Sadek, Giorgio Trinchieri, Anatolij Horuzsko
Abstract
The mechanisms of pain induction by inflammation have been extensively studied. However, the mechanisms of pain resolution are not fully understood. Here, we report that GPR37, expressed by macrophages (MΦs) but not microglia, contributes to the resolution of inflammatory pain. Neuroprotectin D1 (NPD1) and prosaptide TX14 increase intracellular Ca2+ (iCa2+) levels in GPR37-transfected HEK293 cells. NPD1 and TX14 also bind to GPR37 and cause GPR37-dependent iCa2+ increases in peritoneal MΦs. Activation of GPR37 by NPD1 and TX14 triggers MΦ phagocytosis of zymosan particles via calcium signaling. Hind paw injection of pH-sensitive zymosan particles not only induces inflammatory pain and infiltration of neutrophils and MΦs, but also causes GPR37 upregulation in MΦs, phagocytosis of zymosan particles and neutrophils by MΦs in inflamed paws, and resolution of inflammatory pain in WT mice. Mice lacking Gpr37 display deficits in MΦ phagocytic activity and delayed resolution of inflammatory pain. Gpr37-deficient MΦs also show dysregulations of proinflammatory and antiinflammatory cytokines. MΦ depletion delays the resolution of inflammatory pain. Adoptive transfer of WT but not Gpr37-deficient MΦs promotes the resolution of inflammatory pain. Our findings reveal a previously unrecognized role of GPR37 in regulating MΦ phagocytosis and inflammatory pain resolution.
Authors
Sangsu Bang, Ya-Kai Xie, Zhi-Jun Zhang, Zilong Wang, Zhen-Zhong Xu, Ru-Rong Ji
Abstract
Induction of TLR2 activation depends on its association with adapter protein MyD88. We have found that levels of TLR2 and MyD88 are elevated in the hippocampus and cortex of Alzheimer’s disease (AD) patients and 5XFAD mouse model of AD. Since there is no specific inhibitor of TLR2, to target induced TLR2 from therapeutic angle, we engineered a peptide corresponding to the TLR2-interacting domain of MyD88 (TIDM) that binds to the BB loop of only TLR2, but not other TLRs. Interestingly, wild type (wt) TIDM peptide inhibited microglial activation induced by fibrillar Aβ1-42 and lipoteichoic acid, but not 1-methyl-4-phenylpyridinium, double-stranded RNA, bacterial lipopolysaccharide, flagellin, and CpG DNA. After intranasal administration, wtTIDM peptide reached the hippocampus, reduced hippocampal glial activation, lowered Aβ burden, attenuated neuronal apoptosis, and improved memory and learning in 5XFAD mice. However, wtTIDM peptide was not effective in 5XFAD mice lacking TLR2. In addition to 5XFAD mice, wtTIDM peptide also suppressed the disease process in mice with experimental allergic encephalomyelitis and collagen-induced arthritis. Therefore, selective targeting of activated status of one component of the innate immune system by wtTIDM peptide may be beneficial in AD as well as other disorders in which TLR2-MyD88 signaling plays a role in disease pathogenesis.
Authors
Suresh B. Rangasamy, Malabendu Jana, Avik Roy, Grant T. Corbett, Madhuchhanda Kundu, Sujyoti Chandra, Susanta Mondal, Sridevi Dasarathi, Elliott J. Mufson, Rama K. Mishra, Chi-Hao Luan, David A. Bennett, Kalipada Pahan
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Copyright © 2018 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)