An Emerging Role for Type I Interferons as Critical Regulators of Blood Coagulation

Abstract

Type I interferons (IFNs) are central mediators of anti-viral and anti-bacterial host defence. Detection of microbes by innate immune cells via pattern recognition receptors (PRRs), including Toll-like receptors (TLRs) and cGAS-STING, induces the expression of type I IFN-stimulated genes. Primarily comprising the cytokines IFN-α and IFN-β, type I IFNs act via the type I IFN receptor in an autocrine or exocrine manner to orchestrate rapid and diverse innate immune responses. Growing evidence pinpoints type I IFN signalling as a fulcrum that not only induces blood coagulation as a core feature of the inflammatory response but is also activated by components of the coagulation cascade. In this review, we describe in detail recent studies identifying the type I IFN pathway as a modulator of vascular function and thrombosis. In addition, we profile discoveries showing that thrombin signalling via protease-activated receptors (PARs), which can synergize with TLRs, regulates the host response to infection via induction of type I IFN signalling. Thus, type I IFNs can have both protective (via maintenance of haemostasis) and pathological (facilitating thrombosis) effects on inflammation and coagulation signalling. These can manifest as an increased risk of thrombotic complications in infection and in type I interferonopathies such as systemic lupus erythematosus (SLE) and STING-associated vasculopathy with onset in infancy (SAVI). We also consider the effects on coagulation of recombinant type I IFN therapies in the clinic and discuss pharmacological regulation of type I IFN signalling as a potential mechanism by which aberrant coagulation and thrombosis may be treated therapeutically.

Lacticaseibacillus rhamnosus CRL1505 Peptidoglycan Modulates the Inflammation-Coagulation Response Triggered by Poly(I:C) in the Respiratory Tract

“…Some respiratory viruses, such as influenza virus [37] and SARS-CoV-2 [38], can activate coagulation cascade in blood [39,40]. In line with these findings, the intranasal administration of poly(I:C) results in hemostatic activation in mice, with a decrease in prothrombin activity as well as increased platelet counts and vWF levels in peripheral blood.…”

A case report of vaccine-induced immune thrombotic thrombocytopenia (VITT) with genetic analysis

“…Type I IFNs are induced by exposure of cells to pathogen-associated molecular patterns (PAMPs) detected by receptors like toll-like receptors (TLRs). By distinct mechanisms, type I IFN signaling leads to inflammasome activation, pyroptosis, and, lately, the release of proinflammatory molecules and prothrombotic mediators, like TF, initiating the extrinsic coagulation pathway ( 24 ). Due to the involvement of type I IFN response to thrombotic processes, we also evaluated SNPs in the related genes.…”

Toll-like Receptors as Pro-Thrombotic Drivers in Viral Infections: A Narrative Review

“…This increase in TLR-3 activity enhances downstream activities of toll-interleukin receptor (TIR) domain-containing adaptor protein inducing interferon (TRIF), interferon regulatory factor 3 (IRF3), NF-kB and pro-inflammatory cytokines, all of which can induce pro-coagulatory and pro-thrombotic responses [16]. During viral or bacterial infection type I interferon (IFN), signaling is induced upon detection of pathogens (by pathogen-associated molecular patterns) via pattern recognition receptors (PRRs) [17]. IRF3 is activated immediately after viral infection occurs and is a primary activator of IFN genes and the RANTES chemokine gene, finally resulting in the recruitment of leukocytes to sites of inflammation [18].…”