Inflammation
Abstract
The inability of mature retinal ganglion cells (RGCs) to regenerate axons after optic nerve injury can be partially reversed by manipulating cell-autonomous and/or -non-autonomous factors. Although manipulations of cell-non-autonomous factors could have higher translational potential than genetic manipulations of RGCs, they have generally produced lower levels of optic nerve regeneration. Here we report that preconditioning resulting from mild lens injury (conditioning LI, cLI) prior to optic nerve damage induces far greater regeneration than LI after nerve injury or the pro-inflammatory agent zymosan given either before or after nerve damage. Unlike zymosan-induced regeneration, cLI is unaltered by depleting mature neutrophils or T cells or blocking receptors for known inflammation-derived growth factors (Oncomodulin, SDF1, CCL5), and is only partly diminished by suppressing CCR2+ monocyte recruitment. Repeated episodes of LI lead to full-length optic nerve regeneration, and pharmacological removal of local resident macrophages with the colony stimulating factor 1 receptor (CSF1R) inhibitor PLX5622 enables some axons to re-innervate the brain in just 6 weeks, comparable to the results obtained with the most effective genetic manipulations of RGCs. Thus, cell-non-autonomous interventions can induce high levels of optic nerve regeneration, paving the way to uncover potent, translatable therapeutic targets for CNS repair.
Authors
Qian Feng, Kimberly A. Wong, Larry I. Benowitz
Abstract
Macrophages intimately interact with intestinal epithelial cells, but the consequences of defective macrophage–epithelial cell interactions for protection against enteric pathogens are poorly understood. Here, we show that in mice with a deletion in protein tyrosine phosphatase nonreceptor type 2 (PTPN2) in macrophages, infection with Citrobacter rodentium, a model of enteropathogenic and enterohemorrhagic E. coli infection in humans, promoted a strong type 1/IL-22–driven immune response, culminating in accelerated disease but also faster clearance of the pathogen. In contrast, deletion of PTPN2 specifically in epithelial cells rendered the epithelium unable to upregulate antimicrobial peptides and consequently resulted in a failure to eliminate the infection. The ability of PTPN2-deficient macrophages to induce faster recovery from C. rodentium was dependent on macrophage-intrinsic IL-22 production, which was highly increased in macrophages deficient in PTPN2. Our findings demonstrate the importance of macrophage-mediated factors, and especially macrophage-derived IL-22, for the induction of protective immune responses in the intestinal epithelium, and show that normal PTPN2 expression in the epithelium is crucial to allow for protection against enterohemorrhagic E. coli and other intestinal pathogens.
Authors
Marianne R. Spalinger, Vinicius Canale, Anica Becerra, Ali Shawki, Meli’sa Crawford, Alina N. Santos, Pritha Chatterjee, Jiang Li, Meera G. Nair, Declan F. McCole
Abstract
As a hallmark for inflammatory bowel disease (IBD), elevated intestinal epithelial cell (IEC) death compromises the gut barrier, activating inflammatory response and triggering more IEC death. However, the precise intracellular machinery that prevents IEC death and break this vicious feedback remains largely unknown. Here, we report that Gab1 expression is decreased in patients with IBD and inversely correlated with IBD severity. Gab1 deficiency in intestinal epithelial cells accounts for the exacerbated colitis induced by dextran sodium sulfate (DSS) owing to sensitizing IECs to RIPK3-mediated necroptosis, which irreversibly disrupted homeostasis of the epithelial barrier and promoted intestinal inflammation. Mechanistically, Gab1 negatively regulates necroptosis signaling through inhibiting the formation of RIPK1/RIPK3 complex in response to TNF-α. Importantly, administration of RIPK3 inhibitor reveals a curative effect in epithelial Gab1-deficient mice. Further analysis indicates mice with Gab1 deletion are prone to inflammation associated colorectal tumorigenesis. Collectively, our study defines a protective role for Gab1 in colitis and colitis-driven colorectal cancer through negatively regulating RIPK3-dependent necroptosis, in which may serve as an important target to fine-tune necroptosis and intestinal inflammation-related disease.
Authors
Jiaqi Xu, Shihao Li, Wei Jin, Hui Zhou, Tingting Zhong, Xiaoqing Cheng, Yujuan Fu, Peng Xiao, Hongqiang Cheng, Di Wang, Yuehai Ke, Zhinong Jiang, Xue Zhang
Abstract
Low CC16 plasma levels are linked to accelerated lung function decline in COPD patients. Cigarette smoke (CS)-exposed Cc16-/- mice have exaggerated COPD-like disease associated with increased NF-kB activation in their lungs. It is unclear whether CC16 augmentation can reverse exaggerated COPD in CS-exposed Cc16-/- mice and whether increased NF-kB activation contributes to the exaggerated COPD in CS-exposed Cc16-/- lungs. CS-exposed WT and Cc16-/- mice were treated with recombinant human CC16 protein solution (rhCC16) or a NF-kB inhibitor (IMD0354) versus vehicle beginning at the mid-point of the exposures. COPD-like disease and NF-kB activation were measured in the lungs. RhCC16 limited the progression of emphysema, small airway fibrosis, and chronic-bronchitis-like disease in WT and Cc16-/- mice partly by reducing pulmonary inflammation (reducing myeloid leukocytes and/or increasing regulatory T and/or B cells) and alveolar septal cell apoptosis, reducing NF-kB activation in CS-exposed Cc16-/- lungs, and rescuing the reduced Foxj1 expression in CS-exposed Cc16-/- lungs. IMD0354 treatment reduced exaggerated lung inflammation and rescued the reduced Foxj1 expression in CS-exposed Cc16-/- mice. rhCC16 treatment reduced NF-kB activation in luciferase reporter A549 cells. Thus, rhCC16 treatment limits COPD progression in CS-exposed Cc16-/- mice partly by inhibiting NF-kB activation and represents a novel therapeutic approach for COPD.
Authors
Joselyn Rojas-Quintero, Maria E. Laucho-Contreras, Xiaoyun Wang, Quynh-Anh Fucci, Patrick R. Burkett, Se-Jin Kim, Duo Zhang, Yohannes Tesfaigzi, Yuhong Li, Abhiram R. Bhashyam, Li Zhang, Haider Khamas, Bartolome Celli, Aprile L. Pilon, Francesca Polverino, Caroline A. Owen
Abstract
Keloid is considered as a fibro-proliferative disease characterized by chronic inflammation that is induced following skin injury. Deciphering the underlying mechanism of keloid formation is essential for improving treatment outcomes. Here, we found that more macrophages were activated towards M2 subtype in keloid dermis when compared to normal dermis. Western Blot revealed that the level of phosphorylated STAT6, a known inducer of M2 polarization, was higher in keloid fibroblasts as opposed to fibroblasts from normal dermis. Moreover, keloid fibrosis was shown to be positively correlated with the level of phosphorylated STAT6. Further, we identified downregulation of IL13RA2, a ‘decoy’ receptor of IL13, in keloid fibroblasts compared to fibroblasts from normal dermis. Ectopic expression of IL13RA2 in keloid fibroblasts resulted in inhibition of STAT6 phosphorylation, cell proliferation, migration, invasion, extracellular matrix secretion and myofibroblast marker expression, as well as an increase in apoptosis. Consistently, knockdown of IL13RA2 in normal fibroblasts induced a ‘keloidal’ status. Furthermore, both in vitro application and intra-tumoral injection of pSTAT6 inhibitor AS1517499 in a PDX keloid-implantation mouse model, resulted in proliferation inhibition, tissue necrosis, apoptosis and myofibroblast marker reduction. Collectively, this study elucidates the key role of IL13RA2 in keloid pathology and inspire further translational research of keloid treatment concerning JAK/STAT6 inhibition.
Authors
Hua Chao, Lisheng Zheng, Pojui Hsu, Jinyun He, Ridong Wu, Shuqia Xu, Ruixi Zeng, Yuan Zhou, Huisi Ma, Haibo Liu, Qing Tang
Abstract
Neutrophils (PMN) are the first immune responders to infection/injury playing a critical role in clearing invading microbes and promoting tissue repair. However, dysregulated trafficking of PMNs across mucosal surfaces is a pathological hallmark of numerous diseases characterized by persistent or intermittent bursts of mucosal inflammation. The critical final step in PMN trafficking into mucosal lined organs (including the lungs, kidneys, skin and gut) involves transepithelial migration (TEpM). The glycoprotein CD11b/CD18 is the predominant β2 integrin that mediates PMN TEpM. Furthermore, CD11b/CD18 also regulates key PMN inflammatory effector functions that are implicated in the pathogenesis of chronic mucosal inflammation including superoxide release and degranulation. Recent studies have shown that terminal Fucose and GlcNAc glycans on CD11b/CD18 can be targeted to reduce PMN trafficking across intestinal epithelium, highlighting the importance of glycosylation in regulating PMN inflammatory function in mucosal settings. Previous studies have also demonstrated that the most abundant terminal glycan on human and murine PMN is sialic acid (Sia). However, the role of Sia in regulating PMN epithelial influx and mucosal inflammatory function is not well understood. Here we demonstrate that inhibiting sialidase mediated removal of α2-3 linked Sia from CD11b/CD18 inhibits PMN migration across intestinal epithelium in vitro and in vivo. Sialylation was also found to regulate critical PMN inflammatory effector functions including degranulation and superoxide release. Finally, we demonstrate that sialidase inhibition reduces bacterial peptide mediated CD11b/CD18 activation in PMN and blocks downstream intracellular signaling mediated by Spleen tyrosine kinase (Syk) and p38 MAP kinase. Taken together, these data demonstrate that sialylated glycans on CD11b/CD18 represent novel targets for ameliorating PMN mediated tissue damage and reducing inflammation in mucosal inflammatory disorders.
Authors
Veronica Azcutia, Matthias Kelm, Dylan Fink, Richard D. Cummings, Asma Nusrat, Charles A. Parkos, Jennifer C. Brazil
Abstract
Rosacea is a common chronic inflammatory skin disease with a fluctuating course of excessive inflammation and apparent neovascularization. Microbial dysbiosis with high density of B. oleronius and increased activity of kallikrein 5, which cleaves cathelicidin antimicrobial peptide, are key pathogenic triggers in rosacea. However, how these events are linked to the disease remains unknown. Here, we show that type I interferons produced by plasmacytoid dendritic cells represent the pivotal link between dysbiosis, the aberrant immune response, and neovascularization. Compared to other commensal bacteria, B. oleronius is highly susceptible and preferentially killed by cathelicidin antimicrobial peptides leading to enhanced generation of complexes with bacterial DNA. These bacterial DNA-complexes but not DNA-complexes derived from host cells are required for cathelicidin-induced activation of plasmacytoid dendritic cells and type I interferon production. Moreover, kallikrein 5 cleaves cathelicidin into peptides with heightened DNA-binding and type I interferon-inducing capacities. In turn, excessive type I interferon expression drives neoangiogenesis via IL22 induction and upregulation of the IL22 receptor on endothelial cells. These findings unravel a novel pathomechanism, which directly links hallmarks of rosacea to the killing of dysbiotic commensal bacteria with induction of a pathogenic type I interferon-driven and IL22-mediated angiogenesis.
Authors
Alessio A. Mylonas, Heike C. Hawerkamp, Yichen Wang, Jiaqi Chen, Francesco Messina, Olivier Demaria, Stephan Meller, Bernhard Homey, Jeremy Di Domizio, Lucia Mazzolai, Alain Hovnanian, Michel Gilliet, Curdin Conrad
Abstract
Newborns are at high risk of developing neonatal sepsis, particularly if born prematurely. This has been linked to divergent requirements the immune system has to fulfill during intrauterine compared to extrauterine life. By transcriptomic analysis of fetal and adult neutrophils we set out to shed new light on the molecular mechanisms of neutrophil maturation and functional adaption during fetal ontogeny. We identified an accumulation of differentially regulated genes within the non-canonical NF-κB signaling pathway accompanied by constitutive nuclear localization of RelB and increased surface expression of TNFRII in fetal neutrophils as well as elevated levels of LT-α in fetal serum. Furthermore, we found strong upregulation of the negative inflammatory regulator A20 (Tnfaip3) in fetal neutrophils, which was accompanied by a pronounced downregulation of the canonical NF-κB pathway. Functionally, overexpressing A20 in Hoxb8 cells led to reduced adhesion of these neutrophil-like cells under flow. Conversely, mice with a neutrophil specific A20 deletion displayed increased inflammation in vivo. Taken together, we have uncovered constitutive activation of the non-canonical NF-κB pathway with concomitant upregulation of A20 in fetal neutrophils. This offers perfect adaption of neutrophil function during intrauterine fetal life, but also restricts appropriate immune responses particularly in prematurely born infants.
Authors
Ina Rohwedder, Lou Martha Wackerbarth, Kristina Heinig, Annamaria Ballweg, Johannes Altstätter, Myriam Ripphahn, Claudia Nussbaum, Melanie Salvermoser, Susanne Bierschenk, Tobias Straub, Matthias Gunzer, Marc Schmidt-Supprian, Thomas Kolben, Christian Schulz, Averil Ma, Barbara Walzog, Matthias Heinig, Markus Sperandio
Abstract
The molecular mediators of cell death and inflammation in Alzheimer’s disease (AD) have yet to be fully elucidated. Caspase-8 is a critical regulator of several cell death and inflammatory pathways; however, its role in AD pathogenesis has not yet been examined in detail. In the absence of Caspase-8, mice are embryonic lethal due to excessive RIPK3-dependent necroptosis. Compound RIPK3 and Caspase-8 mutants rescue embryonic lethality, which we leveraged to examine the roles of these pathways in an amyloid beta (Aβ)-mediated mouse model of AD. We find that combined deletion of Caspase-8 and RIPK3, but not RIPK3 alone, leads to diminished Aβ deposition and microgliosis in the 5xFAD mouse model of AD. Despite its well-known role in cell death, Caspase-8 does not appear to impact cell loss in the 5xFAD model. In contrast, we found that Caspase-8 is a critical regulator of Aβ-driven inflammasome gene expression and IL-1β release. Interestingly, loss of RIPK3 had only a modest effect on disease progression suggesting that inhibition of necroptosis or RIPK3-mediated cytokine pathways are not critical during mid stages of Aβ amyloidosis. These findings suggest that therapeutics targeting Caspase-8 may represent a novel strategy to limit Aꞵ amyloidosis and neuroinflammation in AD.
Authors
Sushanth Kumar, Sakar Budhathoki, Christopher B. Oliveira, August D. Kahle, O. Yipkin Calhan, John R. Lukens, Christopher D. Deppmann
Abstract
Although air pollutants such as fine particulate matter (PM2.5) are associated with acute and chronic lung inflammation, the etiology of PM2.5-induced airway inflammation remains poorly understood. Here we report that PM2.5 triggered airway hyperreactivity (AHR) and neutrophilic inflammation with concomitant increases in Th1 and Th17 responses and epithelial cell apoptosis. We found that γδ T cells promoted neutrophilic inflammation and AHR through IL-17A. Unexpectedly, we found that invariant natural killer T (iNKT) cells played a protective role in PM2.5-induced pulmonary inflammation. Specifically, PM2.5 activated a suppressive CD4– iNKT cell subset that coexpressed Tim-1 and programmed cell death ligand 1 (PD-L1). Activation of this suppressive subset was mediated by Tim-1 recognition of phosphatidylserine on apoptotic cells. The suppressive iNKT subset inhibited γδ T cell expansion and intrinsic IL-17A production, and the inhibitory effects of iNKT cells on the cytokine-producing capacity of γδ T cells were mediated in part by PD-1/PD-L1 signaling. Taken together, our findings underscore a pathogenic role for IL-17A–producing γδ T cells in PM2.5-elicited inflammation and identify PD-L1+Tim-1+CD4– iNKT cells as a protective subset that prevents PM2.5-induced AHR and neutrophilia by inhibiting γδ T cell function.
Authors
Christina Li-Ping Thio, Alan Chuan-Ying Lai, Jo-Chiao Wang, Po-Yu Chi, Ya-Lin Chang, Yu-Tse Ting, Shih-Yu Chen, Ya-Jen Chang
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