The therapeutic potential of interleukin-10 in neuroimmune diseases

Abstract

Neuroimmune diseases have diverse symptoms and etiologies but all involve pathological inflammation that affects normal central nervous system signaling. Critically, many neuroimmune diseases also involve insufficient signaling/bioavailability of interleukin-10 (IL-10). IL-10 is a potent anti-inflammatory cytokine released by immune cells and glia, which drives the regulation of a variety of anti-inflammatory processes. This review will focus on the signaling pathways and function of IL-10, the current evidence for insufficiencies in IL-10 signaling/bioavailability in neuroimmune diseases, as well as the implications for IL-10-based therapies to treating such problems. We will review in detail four pathologies as examples of the common etiologies of such disease states, namely neuropathic pain (nerve trauma), osteoarthritis (peripheral inflammation), Parkinson's disease (neurodegeneration), and multiple sclerosis (autoimmune). A number of methods to increase IL-10 have been developed (e.g. protein administration, viral vectors, naked plasmid DNA, plasmid DNA packaged in polymers to enhance their uptake into target cells, and adenosine 2A agonists), which will also be discussed. In general, IL-10-based therapies have been effective at treating both the symptoms and pathology associated with various neuroimmune diseases, with more sophisticated gene therapy-based methods producing sustained therapeutic effects lasting for several months following a single injection. These exciting results have resulted in IL-10-targeted therapeutics being positioned for upcoming clinical trials for treating neuroimmune diseases, including neuropathic pain. Although further research is necessary to determine the full range of effects associated with IL-10-based therapy, evidence suggests IL-10 may be an invaluable target for the treatment of neuroimmune disease. This article is part of a Special Issue entitled 'Neuroimmunology and Synaptic Function'.

Keywords: Interleukin-10; Interleukin-10 receptor; Multiple sclerosis; Neuropathic pain; Osteoarthritis; Parkinson's disease.

Fig. 1

Interleukin-10 (IL-10) gene transcription regulation. IL-10 transcription is initiated after a) CD209 signaling mediated via rapidly-accelerated fibrosarcoma (Raf)-1, which activates nuclear factor kappa-light-chain-enhancer of activated B cells (NFkB); b) Toll-like receptor 4 (TLR4) signaling mediated via TIR-domain-containing adaptor protein inducing IFNβ (TRIF) and Myeloid differentiation primary response gene 88 (MyD88). MyD88 activates nuclear factor kappa-light-chain-enhancer of activated B cells (NFkB). MyD88 also activates the mitogen activated protein kinases (MAPKs) p38 and extracellular related kinase (ERK), further activating mitogen- and stress-activated protein kinase (MSK) 1 and 2; c) Dectin-1 signaling mediated via the ERK pathway and upstream spleen tyrosine kinase (SYK) activation. IL-10 mRNA is post-transcriptionally regulated by a range of micro-RNAs and by tristetraprolin (TTP).

Fig. 2

Interleukin-10 (IL-10) receptor signaling. IL-10 exerts effects through a heterotetramer consisting of two IL-10 receptor 1 (IL-10R1) chains and two IL-10 receptor 2 (IL-10R2) chains. IL-10R1 activates Janus kinase 1 (Jak1), while IL-10R2 activates tyrosine kinase 2 (Tyk2), leading to phosphorylation of IL-10R1 followed by phosphorylation of STAT3 (other STAT proteins have also been implicated including STAT4 in T_H1 cells; STAT6 and GATA3 in T_H2 cells; and, STAT1 and STAT3 in T_H17 cells). Such signaling results in diverse consequences, such as a) cytokine modulation by the induction of A20-binding inhibitor of nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) (Abin-3) and dual specificity phosphatase-1 (DUSP-1) that inhibit mitogen activated protein kinase (MAPK) phosphorylation as well as NFkB. Suppressor of cytokine signaling (SOCS) 1 and 3 are also produced which target the p65 NFκB subunit for degradation and mark activated JAK-STAT complexes for degradation. Mitogen activated protein kinase (MAPK) phosphatase (MKP) expression, including MKP1, is elevated to inhibit MAPK signaling; b) decreased antigen presentation by reducing expression of major histocompatibility complex class II (MHC II) molecules by inducing membrane-associated RING-CH (MARCH) 1 and by inhibiting expression of adhesion (e.g. CD54) and co-stimulatory (e.g. CD86) molecules c) cell polarization via induction of transcription factors such as c-MAF, and d) neuroprotection by normalizing expression of excitatory amino acid transporter-2 (EAAT2), by releasing intracellular calcium stores via PI3K-AKT, by preventing apoptosis through restoration of suppressed anti-apoptotic factors Bcl-2 and Bcl-xl, and by attenuating caspase-3 expression.