Injury-Induced Type I IFN Signaling Regulates Inflammatory Responses in the Central Nervous System

Khorooshi, Reza; Owens, Trevor

doi:10.4049/jimmunol.0901753

Cited by 76 publications

(78 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We now confirm a previous report (11) that production of type I IFN is one maladaptive response. These data are consistent with the maladaptive role of type I IFN in hepatic ischemia (59) and sterile injury of the brain (20). Although a role for type I IFN during ischemia-reperfusion injury has been established, which cells produce type I IFNs during ischemic AKI and what regulates IFN production were not known.…”

Section: Discussionsupporting

confidence: 79%

Reactive oxygen species and IRF1 stimulate IFNα production by proximal tubules during ischemic AKI

Winterberg

Wang

Lin

et al. 2013

American Journal of Physiology-Renal Physiology

View full text Add to dashboard Cite

ously reported that expression of the transcription factor interferon regulatory factor 1 (IRF1) is an early, critical maladaptive signal expressed by renal tubules during murine ischemic acute kidney injury (AKI). We now show that IRF1 mediates signals from reactive oxygen species (ROS) generated during ischemic AKI and that these signals ultimately result in production of ␣-subtypes of type I interferons (IFN␣s). We found that genetic knockout of the common type I IFN receptor (IFNARI Ϫ/Ϫ ) improved kidney function and histology during AKI. There are major differences in the spatial-temporal production of the two major IFN subtypes, IFN␤ and IFN␣s: IFN␤ expression peaks at 4 h, earlier than IFN␣s, and continues at the same level at 24 h; expression of IFN␣s also increases at 4 h but continues to increase through 24 h. The magnitude of the increase in IFN␣s relative to baseline is much greater than that of IFN␤. We show by immunohistology and study of isolated cells that IFN␤ is produced by renal leukocytes and IFN␣s are produced by renal tubules. IRF1, IFN␣s, and IFNARI were found on the same renal tubules during ischemic AKI. Furthermore, we found that ROS induced IFN␣ expression by renal tubules in vitro. This expression was inhibited by small interfering RNA knockdown of IRF1. Overexpression of IRF1 resulted in the production of IFN␣s. Furthermore, we found that IFN␣ stimulated production of maladaptive proinflammatory CXCL2 by renal tubular cells. Altogether our data support the following autocrine pathway in renal tubular cells:AKI; innate immunity; type I interferon ISCHEMIC ACUTE KIDNEY INJURY (AKI) causes significant shortterm morbidity and mortality (33) and, over the long-term, may contribute to the increasing incidence of end-stage renal disease (15,41,55). Despite these major clinical implications, there is currently no specific therapy beyond supportive care (33). A major insight into pathogenesis was the recognition that the initial ischemic insult elicits maladaptive responses that exacerbate the injury (31). In other words, the ultimate amount of renal injury is determined not only by the direct effects of hypoxia but also by the ensuing maladaptive responses. Understanding the latter may reveal novel therapeutic targets for the treatment of AKI.One maladaptive response is the production of type I interferons (IFNs). Knockout of the gene for the ␣-chain (IFNAR1) of the type I interferon (IFN) receptor heterodimer ameliorated ischemic AKI and decreased renal inflammation in mice (11). Such receptor knockout prevents signaling by, and thus the biological effects of, all type I IFNs (32, 37). These include IFN-, IFN-, IFNε, about which little is known, and also the better understood IFN␤ and the IFN␣ family (which has 13 members in humans, 14 in mice).1 Their biological effects include increasing inflammation and increasing apoptosis (11). These effects should increase injury during ischemic AKI and are in addition to the more widely known antiviral effects of type I IFNs (36, 54).Despite their im...

show abstract

Section: Discussionsupporting

confidence: 79%

Reactive oxygen species and IRF1 stimulate IFNα production by proximal tubules during ischemic AKI

Winterberg

Wang

Lin

et al. 2013

American Journal of Physiology-Renal Physiology

View full text Add to dashboard Cite

show abstract

“…This would include patients that are about to undergo major cardiac [32,33] or carotid artery [34] surgery, as well as possibly patients with subarachnoid hemorrhage that are at high risk of developing cerebral vasospasm and accompanying delayed cerebral ischemia [35,36]. The pioneering papers in the RIPC field suggest that neuroprotection is induced rapidly [30,31,37]; however, the duration of protection has not been determined [37,38]. Molecular determinants behind the phenomenon of RIPC have not been fully elucidated, but there is some evidence of overlap with molecular mediators of ischemic and LPS preconditioning, including hypoxiainducible factor (HIF)-1α [39], and inflammatory factors [40][41][42][43].…”

Section: Hif-1mentioning

confidence: 99%

Neuroimmune Response in Ischemic Preconditioning

McDonough

Weinstein

2016

Neurotherapeutics

View full text Add to dashboard Cite

Ischemic preconditioning (IPC) is a robust neuroprotective phenomenon in which a brief period of cerebral ischemia confers transient tolerance to subsequent ischemic challenge. Research on IPC has implicated cellular, molecular, and systemic elements of the immune response in this phenomenon. Potent molecular mediators of IPC include innate immune signaling pathways such as Toll-like receptors and type 1 interferons. Brain ischemia results in release of proand anti-inflammatory cytokines and chemokines that orchestrate the neuroinflammtory response, resolution of inflammation, and transition to neurological recovery and regeneration. Cellular mediators of IPC include microglia, the resident central nervous system immune cells, astrocytes, and neurons. All of these cell types engage in cross-talk with each other using a multitude of signaling pathways that modulate activation/ suppression of each of the other cell types in response to ischemia. As the postischemic neuroimmune response evolves over time there is a shift in function toward provision of trophic support and neuroprotection. Peripheral immune cells infiltrate the central nervous system en masse after stroke and are largely detrimental, with a few subtypes having beneficial, protective effects, though the role of these immune cells in IPC is largely unknown. The role of neural progenitor cells in IPC-mediated neuroprotection is another active area of investigation as is the role of microglial proliferation in this setting. A mechanistic understanding of these molecular and cellular mediators of IPC may not only facilitate more effective direct application of IPC to specific clinical scenarios, but also, more broadly, reveal novel targets for therapeutic intervention in stroke.

show abstract

“…Axonal transection of entorhinal afferents in the hippocampus induces IFN-stimulated genes and inhibits MMP9 in the hippocampal macrophages and microglia. The local IFN prevents macrophage infiltration into these damaged areas (Khorooshi and Owens 2010).…”

Section: Ifn-b Enhances Cognition In Ms (Pliskin and Others 1996; Ebementioning

confidence: 99%

How Type I Interferons Work in Multiple Sclerosis and Other Diseases: Some Unexpected Mechanisms

Reder

Feng

2014

Journal of Interferon & Cytokine Research

View full text Add to dashboard Cite

Type I interferons (IFNs) are important in innate and adaptive immunity. They are used to treat virus infections, cancer, and multiple sclerosis (MS). There are 5 type I IFN families in humans-IFN-a with 13 subtypes, plus IFN-b, e, k, and o. Because their receptor binding affinities vary, these IFNs have different gene induction profiles and quite variable therapeutic effects. IFN-a subtypes may each be specific for certain viruses, but can be neurotoxic. IFN-b induces IFN-a, plus has additional direct effects on target cells. IFN-b was the first therapy approved that could change the course of MS. It has broader specificity than IFN-a, enhances cognition in MS, and may be neuroprotective and can potentially enhance fertility in women. IFNs have tissue-specific and gene-specific roles that are dependent on a balance of the different IFN subtypes, the timing of exposure, and interactions with drugs and environmental factors. The *1,000 genes that are controlled by these IFNs are critical for antiviral immunity and also impact cell proliferation, immune regulation, cytoprotection, and possibly fertility.In multiple sclerosis (MS), cells from the innate and adaptive arms of the immune system cause central nervous system (CNS) inflammation. Adaptive immunity is prominent in the earlier, relapsing/remitting phase of MS (RRMS). Innate immune responses appear to underlie the later secondary progressive (SPMS) phase but are likely to contribute to brain damage at all times. IFN-b therapy for MS prevents and shortens relapses and also reduces new magnetic resonance imaging (MRI) brain lesions, MRI T1 black hole formation, progression, and cognitive loss (Lacy and others 2013). Long-term therapy induces neuroprotectant proteins such as BDNF, NGF, Nrf2, and NCOA7-AS (Croze and others 2013). Five years of IFN-b-1b therapy, begun 8 years after the first symptoms, reduces the death rate by 47% (Goodin and others 2012). The survival benefit is based on less all-cause mortality, but is predominantly from less MS-related death. Its method of action is complex, with dose-dependent changes in different cells and tissues, and variation at different phases of MS. Type I IFNs Differ from Each Other: Implications for Therapy of MS and Other Diseases Different effects of IFN-a and IFN-b on MS, cancer, and virus infectionsMultiple sclerosis. IFN-b is used to treat MS, whereas IFNa is an approved therapy to treat virus infections and cancer. The rationale for these applications is a mix of scientific evidence and tradition. In MS, early small studies showed that moderate to high doses of IFN-b-1b (4-16 M units every other day) reduced relapses (Knobler and others 1993).With human leukocyte IFN-a, however, there were no or minimal benefits (Frith and the AUSTIMS Research Group 1989). Magnetic resonance imaging was still in its infancy and was not performed in this early study. Other small studies of human leukocyte IFN-a, which is composed of multiple subtypes of IFN-a, showed trends for benefit (Knobler and others 1984; Squillacote and ...

show abstract

Injury-Induced Type I IFN Signaling Regulates Inflammatory Responses in the Central Nervous System

Cited by 76 publications

References 47 publications

Reactive oxygen species and IRF1 stimulate IFNα production by proximal tubules during ischemic AKI

Reactive oxygen species and IRF1 stimulate IFNα production by proximal tubules during ischemic AKI

Neuroimmune Response in Ischemic Preconditioning

How Type I Interferons Work in Multiple Sclerosis and Other Diseases: Some Unexpected Mechanisms

Contact Info

Product

Resources

About