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IL-1β Signaling Promotes CNS-Intrinsic Immune Control of West Nile Virus Infection  [PDF]
Hilario J. Ramos,Marion C. Lanteri,Gabriele Blahnik,Amina Negash,Mehul S. Suthar,Margaret M. Brassil,Khushbu Sodhi,Piper M. Treuting,Michael P. Busch,Philip J. Norris,Michael Gale Jr.
PLOS Pathogens , 2012, DOI: 10.1371/journal.ppat.1003039
Abstract: West Nile virus (WNV) is an emerging flavivirus capable of infecting the central nervous system (CNS) and mediating neuronal cell death and tissue destruction. The processes that promote inflammation and encephalitis within the CNS are important for control of WNV disease but, how inflammatory signaling pathways operate to control CNS infection is not defined. Here, we identify IL-1β signaling and the NLRP3 inflammasome as key host restriction factors involved in viral control and CNS disease associated with WNV infection. Individuals presenting with acute WNV infection displayed elevated levels of IL-1β in their plasma over the course of infection, suggesting a role for IL-1β in WNV immunity. Indeed, we found that in a mouse model of infection, WNV induced the acute production of IL-1β in vivo, and that animals lacking the IL-1 receptor or components involved in inflammasome signaling complex exhibited increased susceptibility to WNV pathogenesis. This outcome associated with increased accumulation of virus within the CNS but not peripheral tissues and was further associated with altered kinetics and magnitude of inflammation, reduced quality of the effector CD8+ T cell response and reduced anti-viral activity within the CNS. Importantly, we found that WNV infection triggers production of IL-1β from cortical neurons. Furthermore, we found that IL-1β signaling synergizes with type I IFN to suppress WNV replication in neurons, thus implicating antiviral activity of IL-1β within neurons and control of virus replication within the CNS. Our studies thus define the NLRP3 inflammasome pathway and IL-1β signaling as key features controlling WNV infection and immunity in the CNS, and reveal a novel role for IL-1β in antiviral action that restricts virus replication in neurons.
Exacerbation of CNS inflammation and neurodegeneration by systemic LPS treatment is independent of circulating IL-1β and IL-6
Carol L Murray, Donal T Skelly, Colm Cunningham
Journal of Neuroinflammation , 2011, DOI: 10.1186/1742-2094-8-50
Abstract: ME7 animals, at 18-19 weeks post-inoculation, were challenged with LPS (500 μg/kg) in the presence or absence of dexamethasone-21-phosphate (2 mg/kg) and effects on core-body temperature and systemic and CNS cytokine production and apoptosis were examined.LPS induced hypothermia and decreased exploratory activity. Dexamethasone-21-phosphate prevented this hypothermia, markedly suppressed systemic IL-1β and IL-6 secretion but did not prevent decreased exploration. Furthermore, robust transcription of cytokine mRNA occurred in the hippocampus of both ME7 and NBH (normal brain homogenate) control animals despite the effective blocking of systemic cytokine synthesis. Microglia primed by neurodegeneration were not blocked from the robust synthesis of IL-1β protein and endothelial COX-2 was also robustly synthesized. We injected biotinylated LPS at 100 μg/kg and even at this lower dose this could be detected in blood plasma. Apoptosis was acutely induced by LPS, despite the inhibition of the systemic cytokine response.These data suggest that LPS can directly activate the brain endothelium even at relatively low doses, obviating the need for systemic cytokine stimulation to transduce systemic inflammatory signals into the brain or to exacerbate existing pathology.It is known that chronic neurodegeneration is associated with an inflammatory response, chiefly mediated by the brain macrophage population, the microglia. However it remains unclear how this microglial response contributes to neurodegeneration and, thus far, non-steroidal anti-inflammatory drugs (NSAIDs) have not proved helpful in patients with dementia [1]. We have previously shown that the microglial response in the ME7 model of prion disease is characterised by a muted inflammatory phenotype with very limited synthesis of pro-inflammatory cytokines [2,3]. However these microglia are primed by disease to respond more robustly to subsequent inflammatory challenges either peripherally or centrally [4]. One conseq
Initiation and Regulation of CNS Autoimmunity: Balancing Immune Surveillance and Inflammation in the CNS  [PDF]
Melissa G. Harris, Zsuzsanna Fabry
Neuroscience & Medicine (NM) , 2012, DOI: 10.4236/nm.2012.33026
Abstract: While the central nervous system (CNS) was once thought to be immune privileged, more recent data support that certain areas of the healthy CNS are routinely patrolled by immune cells. Further, antigen drainage is another means by which the adaptive arm of the immune system can gain information about the health of the CNS. Altogether these ensure that the CNS is not beyond the scope of immune protection against viruses and tumors. However, immune surveillance in the CNS has to be tightly regulated, as CNS autoimmune disease and inflammation may arise from increased immune cell infiltration. In this review we discuss the concept and implications of CNS immune surveillance and introduce the CNS antigen-presenting cells (APCs) that potentially regulate neuroinflammation and autoimmunity. We also discuss novel animal models in which CNS disease initiation and the role of APCs in disease regulation can be tested.
Astrocyte Regulation of CNS Inflammation and Remyelination  [PDF]
Kumiko I. Claycomb,Kasey M. Johnson,Paige N. Winokur,Anthony V. Sacino,Stephen J. Crocker
Brain Sciences , 2013, DOI: 10.3390/brainsci3031109
Abstract: Astrocytes regulate fundamentally important functions to maintain central nervous system (CNS) homeostasis. Altered astrocytic function is now recognized as a primary contributing factor to an increasing number of neurological diseases. In this review, we provide an overview of our rapidly developing understanding of the basal and inflammatory functions of astrocytes as mediators of CNS responsiveness to inflammation and injury. Specifically, we elaborate on ways that astrocytes actively participate in the pathogenesis of demyelinating diseases of the CNS through their immunomodulatory roles as CNS antigen presenting cells, modulators of blood brain barrier function and as a source of chemokines and cytokines. We also outline how changes in the extracellular matrix can modulate astrocytes phenotypically, resulting in dysregulation of astrocytic responses during inflammatory injury. We also relate recent studies describing newly identified roles for astrocytes in leukodystrophies. Finally, we describe recent advances in how adapting this increasing breadth of knowledge on astrocytes has fostered new ways of thinking about human diseases, which offer potential to modulate astrocytic heterogeneity and plasticity towards therapeutic gain. In summary, recent studies have provided improved insight in a wide variety of neuroinflammatory and demyelinating diseases, and future research on astrocyte pathophysiology is expected to provide new perspectives on these diseases, for which new treatment modalities are increasingly necessary.
Investigation of the relation between the hypothalamus-pituitary-adrenal (HPA) axis activity, IL-6 and hyperalgesia during chronic inflammation due to rheumatoid arthritis (RA) in male rats.  [cached]
Jala Zaringhalam,Homa Manaheji,Nader Maghsoodi,Babak Farokhi
Physiology and Pharmacology , 2007,
Abstract: Introduction: The activity of Hypothalamus-Pituitary-Adrenal (HPA) axis is increased following inflammation due to its closed relation with immune system. This axis indicates an increased secretion of ACTH, and corticosterone during acute inflammation while little is known about its activity during chronic inflammation such as rheumatoid arthritis (RA). In this study we measured the products of HPA axis and their relation with IL-6 and hyperalgesia during rheumatoid arthritis. Methods: Fourteen Wistar rats were divided in two groups. RA was induced by subcutaneous injection of complete freund’s adjuvant (CFA) to right hind paw of group 1 and the next group was considered as sham control. The levels of ACTH, corticosterone and IL-6 in blood samples were assessed using specific rat ELISA kits on zero, 6th and 21st days. Hyperalgesia was assessed using radiant hit instrument at the same days. Results: The results indicated a significant increase of IL-6 on days 6th and 21st in comparison with day 0. ACTH and corticosterone levels also significantly increased on the 6th day in the RA group in comparison with the control group, but there was no significant increase on the day 21st. Pain threshold was significantly decreased on the 6th day of intervention comparing to the day 0 in the RA group. On the 21st day of intervention, no significant hyperalgesia in the RA group was observed. Conclusion: The activation of HPA axis which is known to respond to IL-6, decreased during RA. ACTH and corticosterone secretion were not modulated during chronic inflammation in this study. On the other hand, long term RA symptoms such as hyperalgesia can be due to the effect of other modulators and independent on HPA axis and immune system.
Type I IFN Promotes IL-10 Production from T Cells to Suppress Th17 Cells and Th17-Associated Autoimmune Inflammation  [PDF]
Lixia Zhang, Shunzong Yuan, Genhong Cheng, Beichu Guo
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0028432
Abstract: Whereas the immune system is essential for host defense against pathogen infection or endogenous danger signals, dysregulated innate and adaptive immune cells may facilitate harmful inflammatory or autoimmune responses. In the CNS, chronic inflammation plays an important role in the pathogenesis of neurodegenerative diseases such as multiple sclerosis (MS). Our previous study has demonstrated a critical role for the type I IFN induction and signaling pathways in constraining Th17-mediated experimental autoimmune encephalomyelitis (EAE), an animal model of human MS. However, it remains unknown if self-reactive Th17 cells can be reprogrammed to have less encephalitogenic activities or even have regulatory effects through modulation of innate pathways. In this study, we investigated the direct effects of type I IFN on Th17 cells. Our data show that IFNβ treatment of T cells cultured under Th17 polarizing conditions resulted in reduced production of IL-17, but increased production of IL-10. We also found that IFNβ induced IL-10 production by antigen specific T cells derived from immunized mice. Furthermore, IFNβ treatment could suppress the encephalitogenic activity of myelin-specific T cells, and ameliorate clinical symptoms of EAE in an adoptive transfer model. Together, results from this study suggest that IFNβ may induce antigen-specific T cells to produce IL-10, which in turn negatively regulate Th17-mediate inflammatory and autoimmune response.
IL-1 and IL-23 Mediate Early IL-17A Production in Pulmonary Inflammation Leading to Late Fibrosis  [PDF]
Paméla Gasse, Nicolas Riteau, Rachel Vacher, Marie-Laure Michel, Alain Fautrel, Franco di Padova, Lizette Fick, Sabine Charron, Vincent Lagente, Gérard Eberl, Marc Le Bert, Valérie F. J. Quesniaux, Fran?ois Huaux, Maria Leite-de-Moraes, Bernhard Ryffel, Isabelle Couillin
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0023185
Abstract: Background Idiopathic pulmonary fibrosis is a devastating as yet untreatable disease. We demonstrated recently the predominant role of the NLRP3 inflammasome activation and IL-1β expression in the establishment of pulmonary inflammation and fibrosis in mice. Methods The contribution of IL-23 or IL-17 in pulmonary inflammation and fibrosis was assessed using the bleomycin model in deficient mice. Results We show that bleomycin or IL-1β-induced lung injury leads to increased expression of early IL-23p19, and IL-17A or IL-17F expression. Early IL-23p19 and IL-17A, but not IL-17F, and IL-17RA signaling are required for inflammatory response to BLM as shown with gene deficient mice or mice treated with neutralizing antibodies. Using FACS analysis, we show a very early IL-17A and IL-17F expression by RORγt+ γδ T cells and to a lesser extent by CD4αβ+ T cells, but not by iNKT cells, 24 hrs after BLM administration. Moreover, IL-23p19 and IL-17A expressions or IL-17RA signaling are necessary to pulmonary TGF-β1 production, collagen deposition and evolution to fibrosis. Conclusions Our findings demonstrate the existence of an early IL-1β-IL-23-IL-17A axis leading to pulmonary inflammation and fibrosis and identify innate IL-23 and IL-17A as interesting drug targets for IL-1β driven lung pathology.
IL-1 signal affects both protection and pathogenesis of virus-induced chronic CNS demyelinating disease  [cached]
Kim Byung S,Jin Young-Hee,Meng Liping,Hou Wanqiu
Journal of Neuroinflammation , 2012, DOI: 10.1186/1742-2094-9-217
Abstract: Background Theiler’s virus infection induces chronic demyelinating disease in mice and has been investigated as an infectious model for multiple sclerosis (MS). IL-1 plays an important role in the pathogenesis of both the autoimmune disease model (EAE) and this viral model for MS. However, IL-1 is known to play an important protective role against certain viral infections. Therefore, it is unclear whether IL-1-mediated signaling plays a protective or pathogenic role in the development of TMEV-induced demyelinating disease. Methods Female C57BL/6 mice and B6.129S7-Il1r1tm1Imx/J mice (IL-1R KO) were infected with Theiler’s murine encephalomyelitis virus (1 x 106 PFU). Differences in the development of demyelinating disease and changes in the histopathology were compared. Viral persistence, cytokine production, and immune responses in the CNS of infected mice were analyzed using quantitative PCR, ELISA, and flow cytometry. Results Administration of IL-1β, thereby rending resistant B6 mice susceptible to TMEV-induced demyelinating disease, induced a high level of Th17 response. Interestingly, infection of TMEV into IL-1R-deficient resistant C57BL/6 (B6) mice also induced TMEV-induced demyelinating disease. High viral persistence was found in the late stage of viral infection in IL-1R-deficient mice, although there were few differences in the initial anti-viral immune responses and viral persistent levels between the WT B6 and IL-1R-deficiecent mice. The initial type I IFN responses and the expression of PDL-1 and Tim-3 were higher in the CNS of TMEV-infected IL-1R-deficient mice, leading to deficiencies in T cell function that permit viral persistence. Conclusions These results suggest that the presence of high IL-1 level exerts the pathogenic role by elevating pathogenic Th17 responses, whereas the lack of IL-1 signals promotes viral persistence in the spinal cord due to insufficient T cell activation by elevating the production of inhibitory cytokines and regulatory molecules. Therefore, the balance of IL-1 signaling appears to be extremely important for the protection from TMEV-induced demyelinating disease, and either too much or too little signaling promotes the development of disease.
IL-6 signaling blockade increases inflammation but does not affect muscle function in the mdx mouse
Matthew Kostek, Kanneboyina Nagaraju, Ed Pistilli, Arpana Sali, San-Hui Lai, Brad Gordon, tadamitsu kishimoto, Yi-Wen Chen
BMC Musculoskeletal Disorders , 2012, DOI: 10.1186/1471-2474-13-106
Abstract: A monoclonal antibody against the IL-6 receptor (IL-6r mAb) that blocks local and systemic IL-6 signaling was administered to mdx and BL-10 mice for 5 weeks and muscle function, histology, and inflammation were examined.IL-6r mAb treatment increased mdx muscle inflammation including total inflammation score and ICAM-1 positive lumens in muscles. There was no significant improvement in muscle strength nor muscle pathology due to IL-6r mAb treatment in mdx mice.These results showed that instead of reducing inflammation, IL-6 signaling blockade for 5 weeks caused an increase in muscle inflammation, with no significant change in indices related to muscle regeneration and muscle function. The results suggest a potential anti-inflammatory instead of the original hypothesized pro-inflammatory role of IL-6 signaling in the mdx mice.
IL-17A/F-Signaling Does Not Contribute to the Initial Phase of Mucosal Inflammation Triggered by S. Typhimurium  [PDF]
Pascal Songhet,Manja Barthel,Till A. R?hn,Laurye Van Maele,Delphine Cayet,Jean-Claude Sirard,Martin Bachmann,Manfred Kopf,Wolf-Dietrich Hardt
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0013804
Abstract: Salmonella enterica subspecies 1 serovar Typhimurium (S. Typhimurium) causes diarrhea and acute inflammation of the intestinal mucosa. The pro-inflammatory cytokines IL-17A and IL-17F are strongly induced in the infected mucosa but their contribution in driving the tissue inflammation is not understood. We have used the streptomycin mouse model to analyze the role of IL-17A and IL-17F and their cognate receptor IL-17RA in S. Typhimurium enterocolitis. Neutralization of IL-17A and IL-17F did not affect mucosal inflammation triggered by infection or spread of S. Typhimurium to systemic sites by 48 h p.i. Similarly, Il17ra?/? mice did not display any reduction in infection or inflammation by 12 h p.i. The same results were obtained using S. Typhimurium variants infecting via the TTSS1 type III secretion system, the TTSS1 effector SipA or the TTSS1 effector SopE. Moreover, the expression pattern of 45 genes encoding chemokines/cytokines (including CXCL1, CXCL2, IL-17A, IL-17F, IL-1α, IL-1β, IFNγ, CXCL-10, CXCL-9, IL-6, CCL3, CCL4) and antibacterial molecules was not affected by Il17ra deficiency by 12 h p.i. Thus, in spite of the strong increase in Il17a/Il17f mRNA in the infected mucosa, IL-17RA signaling seems to be dispensable for eliciting the acute disease. Future work will have to address whether this is attributable to redundancy in the cytokine signaling network.
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