Inflammation
Abstract
Current therapies to treat autoimmune disease focus mainly on downstream targets of autoimmune responses, including effector cells and cytokines. A potentially more effective approach would entail targeting autoreactive T cells that initiate the disease cascade and break self tolerance. The murine MHC class Ib molecule Qa-1b (HLA-E in humans) exhibits limited polymorphisms and binds to 2 dominant self peptides: Hsp60p216 and Qdm. We found that peptide-induced expansion of tetramer-binding CD8+ Tregs that recognize Qa-1–Hsp60p216 but not Qa-1–Qdm strongly inhibited collagen-induced arthritis, an animal model of human rheumatoid arthritis. Perforin-dependent elimination of autoreactive follicular Th (TFH) and Th17 cells by CD8+ Tregs inhibited disease development. Infusion of in vitro–expanded CD8+ Tregs increased the efficacy of methotrexate treatment and halted disease progression after clinical onset, suggesting an alternative approach to this first-line treatment. Moreover, infusion of small numbers of Qa-1–Hsp60p216–specific CD8+ Tregs resulted in robust inhibition of autoimmune arthritis, confirming the inhibitory effects of Hsp60p216 peptide immunization. These results suggest that strategies designed to expand Qa-1–restricted (HLA-E–restricted), peptide-specific CD8+ Tregs represent a promising therapeutic approach to autoimmune disorders.
Authors
Jianmei W. Leavenworth, Xiaolei Tang, Hye-Jung Kim, Xiaoyang Wang, Harvey Cantor
Abstract
Milk fat globule-EGF 8 (MFGE8) plays important, nonredundant roles in several biological processes, including apoptotic cell clearance, angiogenesis, and adaptive immunity. Several recent studies have reported a potential role for MFGE8 in regulation of the innate immune response; however, the precise mechanisms underlying this role are poorly understood. Here, we show that MFGE8 is an endogenous inhibitor of inflammasome-induced IL-1β production. MFGE8 inhibited necrotic cell–induced and ATP-dependent IL-1β production by macrophages through mediation of integrin β3 and P2X7 receptor interactions in primed cells.
Authors
Nicolas Deroide, Xuan Li, Dominique Lerouet, Emily Van Vré, Lauren Baker, James Harrison, Marine Poittevin, Leanne Masters, Lina Nih, Isabelle Margaill, Yoichiro Iwakura, Bernhard Ryffel, Marc Pocard, Alain Tedgui, Nathalie Kubis, Ziad Mallat
Abstract
Low-grade chronic inflammation is a major characteristic of obesity and results from deregulated white adipose tissue function. Consequently, there is interest in identifying the underlying regulatory mechanisms and components that drive adipocyte inflammation. Here, we report that expression of the transcriptional corepressor complex subunits GPS2 and SMRT was significantly reduced in obese adipose tissue, inversely correlated to inflammatory status, and was restored upon gastric bypass surgery–induced weight loss in morbid obesity. These alterations correlated with reduced occupancy of the corepressor complex at inflammatory promoters, providing a mechanistic explanation for elevated inflammatory transcription. In support of these correlations, RNAi-mediated depletion of GPS2 and SMRT from cultured human adipocytes promoted derepression of inflammatory transcription and elevation of obesity-associated inflammatory markers, such as IL-6 and MCP-1. Furthermore, we identified a regulatory cascade containing PPARγ and TWIST1 that controlled the expression of GPS2 and SMRT in human adipocytes. These findings were clinically relevant, because treatment of diabetic obese patients with pioglitazone, an antidiabetic and antiinflammatory PPARγ agonist, restored expression of TWIST1, GPS2, and SMRT in adipose tissue. Collectively, our findings identify alterations in a regulatory transcriptional network in adipocytes involving the dysregulation of a specific corepressor complex as among the initiating events promoting adipose tissue inflammation in human obesity.
Authors
Amine Toubal, Karine Clément, Rongrong Fan, Patricia Ancel, Veronique Pelloux, Christine Rouault, Nicolas Veyrie, Agnes Hartemann, Eckardt Treuter, Nicolas Venteclef
Abstract
Influenza causes substantial morbidity and mortality, and highly pathogenic and drug-resistant strains are likely to emerge in the future. Protease-activated receptor 1 (PAR1) is a thrombin-activated receptor that contributes to inflammatory responses at mucosal surfaces. The role of PAR1 in pathogenesis of virus infections is unknown. Here, we demonstrate that PAR1 contributed to the deleterious inflammatory response after influenza virus infection in mice. Activating PAR1 by administering the agonist TFLLR-NH2 decreased survival and increased lung inflammation after influenza infection. Importantly, both administration of a PAR1 antagonist and PAR1 deficiency protected mice from infection with influenza A viruses (IAVs). Treatment with the PAR1 agonist did not alter survival of mice deficient in plasminogen (PLG), which suggests that PLG permits and/or interacts with a PAR1 function in this model. PAR1 antagonists are in human trials for other indications. Our findings suggest that PAR1 antagonism might be explored as a treatment for influenza, including that caused by highly pathogenic H5N1 and oseltamivir-resistant H1N1 viruses.
Authors
Khaled Khoufache, Fatma Berri, Wolfgang Nacken, Annette B. Vogel, Marie Delenne, Eric Camerer, Shaun R. Coughlin, Peter Carmeliet, Bruno Lina, Guus F. Rimmelzwaan, Oliver Planz, Stephan Ludwig, Béatrice Riteau
Abstract
Bacterial LPS (endotoxin) has been implicated in the pathogenesis of acute liver disease through its induction of the proinflammatory cytokine TNF-α. TNF-α is a key determinant of the outcome in a well-established mouse model of acute liver failure during septic shock. One possible mechanism for regulating TNF-α expression is through the control of protein elongation during translation, which would allow rapid cell adaptation to physiological changes. However, the regulation of translational elongation is poorly understood. We found that expression of p38γ/δ MAPK proteins is required for the elongation of nascent TNF-α protein in macrophages. The MKK3/6-p38γ/δ pathway mediated an inhibitory phosphorylation of eukaryotic elongation factor 2 (eEF2) kinase, which in turn promoted eEF2 activation (dephosphorylation) and subsequent TNF-α elongation. These results identify a new signaling pathway that regulates TNF-α production in LPS-induced liver damage and suggest potential cell-specific therapeutic targets for liver diseases in which TNF-α production is involved.
Authors
Bárbara González-Terán, José R. Cortés, Elisa Manieri, Nuria Matesanz, Ángeles Verdugo, María E. Rodríguez, Águeda González-Rodríguez, Ángela Valverde, Pilar Martín, Roger J. Davis, Guadalupe Sabio
Abstract
Exaggerated contraction of airway smooth muscle is the major cause of symptoms in asthma, but the mechanisms that prevent exaggerated contraction are incompletely understood. Here, we showed that integrin α9β1 on airway smooth muscle localizes the polyamine catabolizing enzyme spermidine/spermine N1-acetyltransferase (SSAT) in close proximity to the lipid kinase PIP5K1γ. As PIP5K1γ is the major source of PIP2 in airway smooth muscle and its activity is regulated by higher-order polyamines, this interaction inhibited IP3-dependent airway smooth muscle contraction. Mice lacking integrin α9β1 in smooth muscle had increased airway responsiveness in vivo, and loss or inhibition of integrin α9β1 increased in vitro airway narrowing and airway smooth muscle contraction in murine and human airways. Contraction was enhanced in control airways by the higher-order polyamine spermine or by cell-permeable PIP2, but these interventions had no effect on airways lacking integrin α9β1 or treated with integrin α9β1–blocking antibodies. Enhancement of SSAT activity or knockdown of PIP5K1γ inhibited airway contraction, but only in the presence of functional integrin α9β1. Therefore, integrin α9β1 appears to serve as a brake on airway smooth muscle contraction by recruiting SSAT, which facilitates local catabolism of polyamines and thereby inhibits PIP5K1γ. Targeting key components of this pathway could thus lead to new treatment strategies for asthma.
Authors
Chun Chen, Makoto Kudo, Florentine Rutaganira, Hiromi Takano, Candace Lee, Amha Atakilit, Kathryn S. Robinett, Toshimitsu Uede, Paul J. Wolters, Kevan M. Shokat, Xiaozhu Huang, Dean Sheppard
Abstract
Allergic asthma is the most common form of asthma, affecting more than 10 million Americans. Although it is clear that mast cells have a key role in the pathogenesis of allergic asthma, the mechanisms by which they regulate airway narrowing in vivo remain to be elucidated. Here we report that mice lacking αvβ6 integrin are protected from exaggerated airway narrowing in a model of allergic asthma. Expression microarrays of the airway epithelium revealed mast cell proteases among the most prominent differentially expressed genes, with expression of mouse mast cell protease 1 (mMCP-1) induced by allergen challenge in WT mice and expression of mMCP-4, -5, and -6 increased at baseline in β6-deficient mice. These findings were most likely explained by loss of TGF-β activation, since the epithelial integrin αvβ6 is a critical activator of latent TGF-β, and in vitro–differentiated mast cells showed TGF-β–dependent expression of mMCP-1 and suppression of mMCP-4 and -6. In vitro, mMCP-1 increased contractility of murine tracheal rings, an effect that depended on intact airway epithelium, whereas mMCP-4 inhibited IL-13–induced epithelial-independent enhancement of contractility. These results suggest that intraepithelial activation of TGF-β by the αvβ6 integrin regulates airway responsiveness by modulating mast cell protease expression and that these proteases and their proteolytic substrates could be novel targets for improved treatment of allergic asthma.
Authors
Kotaro Sugimoto, Makoto Kudo, Aparna Sundaram, Xin Ren, Katherine Huang, Xin Bernstein, Yanli Wang, Wilfred W. Raymond, David J. Erle, Magnus Åbrink, George H. Caughey, Xiaozhu Huang, Dean Sheppard
Abstract
Current paradigms suggest that two macrophage subsets, termed M1 and M2, are involved in inflammation and host defense. While the distinct functions of M1 and M2 macrophages have been intensively studied — the former are considered proinflammatory and the latter antiinflammatory — the determinants of their speciation are incompletely understood. Here we report our studies that identify Krüppel-like factor 4 (KLF4) as a critical regulator of macrophage polarization. Macrophage KLF4 expression was robustly induced in M2 macrophages and strongly reduced in M1 macrophages, observations that were recapitulated in human inflammatory paradigms in vivo. Mechanistically, KLF4 was found to cooperate with Stat6 to induce an M2 genetic program and inhibit M1 targets via sequestration of coactivators required for NF-κB activation. KLF4-deficient macrophages demonstrated increased proinflammatory gene expression, enhanced bactericidal activity, and altered metabolism. Furthermore, mice bearing myeloid-specific deletion of KLF4 exhibited delayed wound healing and were predisposed to developing diet-induced obesity, glucose intolerance, and insulin resistance. Collectively, these data identify KLF4 as what we believe to be a novel regulator of macrophage polarization.
Authors
Xudong Liao, Nikunj Sharma, Fehmida Kapadia, Guangjin Zhou, Yuan Lu, Hong Hong, Kaavya Paruchuri, Ganapati H. Mahabeleshwar, Elise Dalmas, Nicolas Venteclef, Chris A. Flask, Julian Kim, Bryan W. Doreian, Kurt Q. Lu, Klaus H. Kaestner, Anne Hamik, Karine Clément, Mukesh K. Jain
Abstract
The regulation of neutrophil lifespan by induction of apoptosis is critical for maintaining an effective host response and preventing excessive inflammation. The hypoxia-inducible factor (HIF) oxygen-sensing pathway has a major effect on the susceptibility of neutrophils to apoptosis, with a marked delay in cell death observed under hypoxic conditions. HIF expression and transcriptional activity are regulated by the oxygen-sensitive prolyl hydroxylases (PHD1–3), but the role of PHDs in neutrophil survival is unclear. We examined PHD expression in human neutrophils and found that PHD3 was strongly induced in response to hypoxia and inflammatory stimuli in vitro and in vivo. Using neutrophils from mice deficient in Phd3, we demonstrated a unique role for Phd3 in prolonging neutrophil survival during hypoxia, distinct from other hypoxia-associated changes in neutrophil function and metabolic activity. Moreover, this selective defect in neutrophil survival occurred in the presence of preserved HIF transcriptional activity but was associated with upregulation of the proapoptotic mediator Siva1 and loss of its binding target Bcl-xL. In vivo, using an acute lung injury model, we observed increased levels of neutrophil apoptosis and clearance in Phd3-deficient mice compared with WT controls. We also observed reduced neutrophilic inflammation in an acute mouse model of colitis. These data support what we believe to be a novel function for PHD3 in regulating neutrophil survival in hypoxia and may enable the development of new therapeutics for inflammatory disease.
Authors
Sarah R. Walmsley, Edwin R. Chilvers, Alfred A. Thompson, Kathryn Vaughan, Helen M. Marriott, Lisa C. Parker, Gary Shaw, Selina Parmar, Martin Schneider, Ian Sabroe, David H. Dockrell, Marta Milo, Cormac T. Taylor, Randall S. Johnson, Christopher W. Pugh, Peter J. Ratcliffe, Patrick H. Maxwell, Peter Carmeliet, Moira K.B. Whyte
Abstract
Uncontrolled macrophage activation is now considered to be a critical event in the pathogenesis of chronic inflammatory diseases such as atherosclerosis, multiple sclerosis, and chronic venous leg ulcers. However, it is still unclear which environmental cues induce persistent activation of macrophages in vivo and how macrophage-derived effector molecules maintain chronic inflammation and affect resident fibroblasts essential for tissue homeostasis and repair. We used a complementary approach studying human subjects with chronic venous leg ulcers, a model disease for macrophage-driven chronic inflammation, while establishing a mouse model closely reflecting its pathogenesis. Here, we have shown that iron overloading of macrophages — as was found to occur in human chronic venous leg ulcers and the mouse model — induced a macrophage population in situ with an unrestrained proinflammatory M1 activation state. Via enhanced TNF-α and hydroxyl radical release, this macrophage population perpetuated inflammation and induced a p16INK4a-dependent senescence program in resident fibroblasts, eventually leading to impaired wound healing. This study provides insight into the role of what we believe to be a previously undescribed iron-induced macrophage population in vivo. Targeting this population may hold promise for the development of novel therapies for chronic inflammatory diseases such as chronic venous leg ulcers.
Authors
Anca Sindrilaru, Thorsten Peters, Stefan Wieschalka, Corina Baican, Adrian Baican, Henriette Peter, Adelheid Hainzl, Susanne Schatz, Yu Qi, Andrea Schlecht, Johannes M. Weiss, Meinhard Wlaschek, Cord Sunderkötter, Karin Scharffetter-Kochanek
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ISSN: 0021-9738 (print), 1558-8238 (online)