Kallikrein–Kinin System Suppresses Type I Interferon Responses: A Novel Pathway of Interferon Regulation

AbstractType I interferon (IFN) dysregulation is a major contributory factor in the development of several autoimmune diseases, termed type I interferonopathies, and is thought to be the pathogenic link with chronic inflammation in these conditions. Anti-neutrophil cytoplasmic antibody (ANCA)-Associated Vasculitis (AAV) is an autoimmune disease characterised by necrotising inflammation of small blood vessels. The underlying biology of AAV is not well understood, however several studies have noted abnormalities in type I IFN responses. We hypothesised that type I IFN responses are systemically dysregulated in AAV, consistent with features of a type I interferonopathy. To investigate this, we measured the expression of seven interferon regulated genes (IRGs) (ISG15, SIGLEC1, STAT1, RSAD2, IFI27, IFI44L and IFIT1) in peripheral blood samples, as well as three type I IFN regulated proteins (CXCL10, MCP-1 and CCL19) in serum samples from AAV patients, healthy controls and disease controls. We found no difference in type I IFN regulated gene or protein expression between AAV patients and healthy controls. Furthermore, IRG and IFN regulated protein expression did not correlate with clinical measurements of disease activity in AAV patients. Thus, we conclude that systemic type I IFN responses are not key drivers of AAV pathogenesis and AAV should not be considered a type I interferonopathy.

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435 Autocrine IFN-k maintains baseline type I interferon responses in keratinocytes in a Tyk2 dependent manner

Journal of Investigative Dermatology ◽

10.1016/j.jid.2016.06.455 ◽

2016 ◽

Vol 136 (9) ◽

pp. S234

Author(s):

M. Sarkar ◽

L.C. Tsoi ◽

X. Xing ◽

L. Yun ◽

P. Harms ◽

...

Keyword(s):

Type I Interferon ◽

Type I ◽

Dependent Manner ◽

Interferon Responses

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Type I interferon responses to ischemic injury begin in the bone marrow of mice and humans and depend on Tet2, Nrf2, and Irf3

10.1101/765404 ◽

2019 ◽

Cited By ~ 1

Author(s):

David M. Calcagno ◽

Richard P. Ng ◽

Avinash Toomu ◽

Claire Zhang ◽

Kenneth Huang ◽

...

Keyword(s):

Bone Marrow ◽

Type I Interferon ◽

Tissue Injury ◽

Type I ◽

Blood Neutrophils ◽

Clinical Biomarker ◽

Acute Mi ◽

Molecular Patterns ◽

Interferon Responses ◽

Myeloid Progenitors

AbstractSterile tissue injury locally activates innate immune responses via interactions with damage associated molecular patterns (DAMPs). Here, by analyzing ∼120K single cell transcriptomes after myocardial infarction (MI) in mice and humans, we show neutrophil and monocyte subsets induce type I interferon (IFN) stimulated genes (ISGs) in myeloid progenitors of the bone marrow, far from the site of injury. In patients with acute MI, peripheral blood neutrophils and monocytes express ISGs at levels far beyond healthy individuals and comparable to patients with lupus. In the bone marrow of Tet2-/- mice, ISGs are spontaneously induced in myeloid progenitors and their progeny. In the heart, IFN responses are negatively regulated by Ccr2- resident macrophages in a Nrf2-dependent fashion. Our results show post-MI IFN signaling begins in the bone marrow, implicate multiple transcription factors in its regulation (Tet2, Irf3, Nrf2), and provide a clinical biomarker (ISG score) for studying post-MI IFN signaling in patients.

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Hereditary angioedema: Pathophysiology (HAE type I, HAE type II, and HAE nC1-INH)

Allergy and Asthma Proceedings ◽

10.2500/aap.2020.41.200081 ◽

2020 ◽

Vol 41 (6) ◽

pp. S14-S17 ◽

Cited By ~ 4

Author(s):

H. James Wedner

Keyword(s):

Serine Protease ◽

Hereditary Angioedema ◽

Normal Activity ◽

Genetic Alterations ◽

Type I ◽

Factor Xii ◽

Kinin System ◽

Major Pathway ◽

Major Mechanism ◽

Kallikrein Kinin System

The pathophysiology of hereditary angioedema (HAE) in virtually all cases is the result of the uncontrolled production of the vasoactive peptide bradykinin. C1 inhibitor (C1-INH) is a serine protease inhibitor, which, under normal circumstances, is the regulator of critical enzymes that are active in the cascades that result in bradykinin generation. In the classic forms of HAE, C1-INH is not produced in sufficient quantities (<40% of normal) or the function is <40% of normal activity. The major pathway for the production of bradykinin is the “contact system,” also known as the kallikrein-kinin system. This system begins with the activation of factor XII (FXII) to FXIIa, by a variety of physiologic and pathologic stimuli. FXIIa is a serine protease that binds to surfaces and cleaves prekallikrein to the active serine protease kallikrein. Kallikrein then cleaves high-molecular-weight kininogen to release the nonapeptide bradykinin. Bradykinin binds to the bradykinin β2 receptor, which increases vascular permeability and allows the flow of fluids into the extracellular space and results in angioedema. The two major enzymes generated in this cascade FXIIa and kallikrein are inhibited by C1-INH, which is the major regulator of this cascade. Failure to adequately control the production of bradykinin is thus the major mechanism for HAE. Several other types of HAE in which C1-INH is not decreased (HAE nlC1-INH) have been described. The alterations in FXII and plasminogen (also a serine protease inhibited by C1-INH) like with classic HAE are the result of dysregulation of bradykinin generation. Only genetic alterations in angiopoietin-1 may not be related to bradykinin generation, rather related to the control of the effect of bradykinin on the vascular endothelium.

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P200 family protein IFI204 negatively regulates type I interferon responses by targeting IRF7 in nucleus

PLoS Pathogens ◽

10.1371/journal.ppat.1008079 ◽

2019 ◽

Vol 15 (10) ◽

pp. e1008079 ◽

Cited By ~ 3

Author(s):

Liu Cao ◽

Yanxi Ji ◽

Lanyi Zeng ◽

Qianyun Liu ◽

Zhen Zhang ◽

...

Keyword(s):

Type I Interferon ◽

Type I ◽

Family Protein ◽

Interferon Responses

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Synthetic rewiring and boosting type I interferon responses for visualization and counteracting viral infections

Nucleic Acids Research ◽

10.1093/nar/gkaa961 ◽

2020 ◽

Vol 48 (20) ◽

pp. 11799-11811

Author(s):

Natascha Gödecke ◽

Jan Riedel ◽

Sabrina Herrmann ◽

Sara Behme ◽

Ulfert Rand ◽

...

Keyword(s):

Positive Feedback ◽

Viral Infections ◽

Type I Interferon ◽

Type I ◽

First Line ◽

Initial Stimulus ◽

Sensor Actuator ◽

Actuator System ◽

Interferon Responses ◽

Robust Sensing

Abstract Mammalian first line of defense against viruses is accomplished by the interferon (IFN) system. Viruses have evolved numerous mechanisms to reduce the IFN action allowing them to invade the host and/or to establish latency. We generated an IFN responsive intracellular hub by integrating the synthetic transactivator tTA into the chromosomal Mx2 locus for IFN-based activation of tTA dependent expression modules. The additional implementation of a synthetic amplifier module with positive feedback even allowed for monitoring and reacting to infections of viruses that can antagonize the IFN system. Low and transient IFN amounts are sufficient to trigger these amplifier cells. This gives rise to higher and sustained—but optionally de-activatable—expression even when the initial stimulus has faded out. Amplification of the IFN response induced by IFN suppressing viruses is sufficient to protect cells from infection. Together, this interfaced sensor/actuator system provides a toolbox for robust sensing and counteracting viral infections.

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