Emerging Roles of Type-I Interferons in Neuroinflammation, Neurological Diseases, and Long-Haul COVID

Abstract

Interferons (IFNs) are pleiotropic cytokines originally identified for their antiviral activity. IFN-α and IFN-β are both type I IFNs that have been used to treat neurological diseases such as multiple sclerosis. Microglia, astrocytes, as well as neurons in the central and peripheral nervous systems, including spinal cord neurons and dorsal root ganglion neurons, express type I IFN receptors (IFNARs). Type I IFNs play an active role in regulating cognition, aging, depression, and neurodegenerative diseases. Notably, by suppressing neuronal activity and synaptic transmission, IFN-α and IFN-β produced potent analgesia. In this article, we discuss the role of type I IFNs in cognition, neurodegenerative diseases, and pain with a focus on neuroinflammation and neuro-glial interactions and their effects on cognition, neurodegenerative diseases, and pain. The role of type I IFNs in long-haul COVID-associated neurological disorders is also discussed. Insights into type I IFN signaling in neurons and non-neuronal cells will improve our treatments of neurological disorders in various disease conditions.

Keywords: IFN-α; IFN-β; astrocytes; long-haul COVID; microglia; neuroinflammation; neurological disease; pain; primary sensory neurons; spinal cord.

Figure 1

Production of type I IFNs. Type I IFNs are induced by activation of toll-like receptors (TLRs) and stimulator of interferon genes (STING). Abbreviations: CD14, cluster of differentiation 14; LBP, LPS-binding protein; LPS, lipopolysaccharide; MD2, myeloid differentiation factor 2; poly(I:C), polyinosine-deoxycytidylic acid; poly(I:C), polyinosine-deoxycytidylic acid; IRF3/7, interferon regulatory factor 3/7; MYD88, myeloid differentiation primary response 88; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; STING, stimulator of interferon genes; TRIF, TIR-domain-containing adapter-inducing IFN-β.

Figure 2

Type I IFN-induced interferon receptor (IFNAR) signaling and gene expression. IFN-α and IFN-β transmit signals via IFNAR1 and IFNAR2 subunits. TYK2 and JAK1 are distinct components of IFNAR1 and IFNAR2. Through ISRE, GAS, and CRE/SBE, TYK2 and JAK1 activation lead to activation of STAT1/2, STAT homo- or heterodimers, PI3K, and MAPK, which activates transcription of ISGs, including antiviral, type-I IFN, and pro-inflammatory genes. Furthermore, TYK2 may form associations with membrane proteins, such as ion channels, which modulate the activity of cells rapidly. Abbreviations: JAK1, Janus kinase 1; TYK2, tyrosine kinase 2; STAT, signal transducer and activator of transcription; MAPK, mitogen-activated protein kinase; PI3K, phosphoinositide 3-kinase; CRE, cyclic AMP response element; SBE, SMAD binding elements; GAS, IFN-γ-activated sites; ISRE, IFN-stimulated response elements; ISG, IFN-stimulated genes.

Figure 3

Expression of interferon (IFN)-α, interferon receptor (IFNAR) and IFNAR signaling in nociceptive sensory neurons and their central terminals producing antinociceptive effects. (A,B) IFN-α expression in cultured astrocytes (A). (B) Triple staining of IFN-α, GFAP, and nucleus marker DAPI in astrocytes. Scales: 50 μm in A and 10 μm in B. Arrows indicate IFN-α-labeled vesicles in remote astrocyte processes. (C) IFNAR (IFN-α/βR) is colocalized with CGRP in the superficial dorsal horn. Scale: 100 μm. (D–F) IFN-α inhibits synaptic transmission in spinal cord slices. (D) The recorded neuron (somatostatin-positive, shown by white arrow) with an electrode (black arrow). (E) Inhibition of spontaneous excitatory postsynaptic currents (sEPSCs) in lamina II neurons by IFN-α was shown by patch clamp (25 ng/mL, 2 min). a and b indicate traces before and after the treatment. (F) Frequency of sEPSCs, expressed as ratio of baseline. Seven out of nine recorded neurons respond to IFN-α. * p < 0.05, n = 7 neurons. (G) Intrathecal injection of IFN-α produces dose-dependent inhibition of inflammatory pain in rats. IFN-α was given one day after inflammation by complete Freund’s adjuvant (CFA). (H) Type I IFN (IFN-I) activates IFNAR1, resulting in subsequent TYK2 activation and rapid antinociception via inhibition of Na⁺ and Ca²⁺ channels and suppression of action potential firing in nociceptors. In addition, IFN-β may also produce antinociception via interaction with mu-opioid receptors. A–F are reproduced “Reprinted/adapted with permission from Ref. [66]. 2016, Tan PH”. “G is reproduced from Reprinted/adapted with permission from Ref. [65]. 2012, Tan PH”.

Figure 4

Single-cell RNAseq showing the expression of Ifnar1 (A) and Ifnar21 (B) in different populations of mouse DRG neurons. Search engine of scatter plots of expression, reads-per-million (RPM), for any gene in 622 neurons assigned to individual populations. Values are grouped along the horizontal axis according to identified populations. Solid vertical lines separate major sensory neuron types in the order: NF (neurofilament), NP (non-peptidergic), PEP (peptidergic), TH (tyrosine hydroxylase) populations. Dashed vertical lines separate major populations into further subtypes, for example, NF1 to NF5 for NF major type. Vertical axis shows normalized expression level in RPM (reads per million) for individual cells. Each dot represents one neuron. Plotted from the database of Usoskin et al., 2015 [99].

Figure 5

Innate Recognition and Interferon Signaling by Coronaviruses. Upon binding to angiotensin-converting enzyme 2 (ACE2) and subsequent sensing of coronaviruses by various pathogen recognition receptors, including toll-like receptors (TLRs) (TLR3, TLR4, TLR7, TLR8) and RIG-I-like receptors (RLRs) (RIG-I, MDA5), activation of transcription factors nuclear factor-kB (NF-kB) and interferon regulatory factor 3 and 7 (IRF3, IRF7) stimulates the production of pro-inflammatory cytokines and type I and III interferons (IFNs), respectively. The JAK/STAT signaling pathway is activated by IFNs through autocrine and paracrine secretion to induce the expression of IFN-stimulated genes (ISGs). Type I IFNs and IFN III IFNs are both capable of inducing ISGs, but type I IFN signaling produces a stronger and faster response as well as inducing pro-inflammatory cytokines and chemokines. However, delayed IFN-I responses not only fail to control SARS-CoV-2 virus but can also cause chronic inflammation and tissue damage.

Figure 6

Modulation of neuroinflammation by type I IFNs in acute (blue) and chronic (red) neurological disease conditions. Note that IFN-α and IFN-β produce both beneficial and detrimental actions and may contribute to cognitive deficits (brain fog) in long-haul COVID.