The therapeutic potential of interleukin-10 in neuroimmune diseases

doi:10.1016/j.neuropharm.2014.10.020

Neuropharmacology

Volume 96, Part A, September 2015, Pages 55-69

https://doi.org/10.1016/j.neuropharm.2014.10.020 Get rights and content

Highlights

•
Many neuroimmune diseases involve insufficient IL-10 signaling/bioavailability.
•
IL-10 is a potent anti-inflammatory cytokine released by immune cells and glia.
•
A variety of methods to increase IL-10 have been developed.
•
IL-10 therapy has been effective to treat 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’.

Introduction

Neuroimmune diseases are debilitating conditions, which involve substantial loss of quality of life. The key features of these diseases include ongoing inflammation, pain, fatigue, anxiety, and cognitive-impairments, although the etiologies and full range of symptoms of these diseases are quite diverse. Here, we will focus on four neuroimmune diseases as examples of the common etiologies of such pathologies [i.e. neuropathic pain (NP) (nerve trauma), osteoarthritis (OA) (peripheral inflammation), Parkinson's disease (PD) (neurodegeneration), and multiple sclerosis (MS) (autoimmune)]. Treatments for neuroimmune diseases have been developed, but notably, most patients remain either partially or fully refractory to treatment (Ali et al., 2013, Gutierrez et al., 2014, Tarazi et al., 2014b, Taruc-Uy and Lynch, 2013).

The purpose of this review is to explore the potential of interleukin-10 (IL-10)-based therapeutic strategies for the treatment of neuroimmune disease. IL-10 is a potent anti-inflammatory cytokine that is endogenously released by immune cells and glia as a process of negative feedback during inflammation (Kettenmann et al., 2011, Ledeboer et al., 2002, Moore et al., 2001). Importantly, insufficiencies in IL-10 signaling/bioavailability have been implicated in these disease states, and in animal studies, strategies aimed at increasing IL-10 have been effective in treating symptoms and pathology associated with neuroimmune diseases. The signaling pathways and function of IL-10, potential therapeutic benefits of IL-10 in neuroimmune disease, and various strategies aimed at increasing physiological levels of IL-10 will be discussed.

Section snippets

Cellular sources of IL-10

IL-10 was first described by Fiorentino et al. (1989) as a novel immune mediator secreted by T helper 2 (T_H2) cells that could inhibit the synthesis of interleukin 2 (IL-2) and interferon-γ (IFN-γ) in T_H1 cells. In the periphery, IL-10 is secreted by innate immune cells, including dendritic cells, macrophages, mast cells, natural killer cells, eosinophils and neutrophils, and by adaptive immune cells, including T_H1, T_H2, T_H17 and regulatory T cells (T_regs), as well as B cell subsets (Moore

IL-10 receptor and consequences of IL-10 receptor signaling

As described above, IL-10 is produced in inflammatory cascades, together with classical proinflammatory cytokines, such as TNF and IL-1β. However, regulation of such proinflammatory processes is achieved as a consequence of subsequent IL-10 activity at its cognate receptor (summarized in Fig. 2).

IL-10 exerts its innate and adaptive immune effects through its cognate cell surface receptor complex, a heterotetramer consisting of two IL-10 receptor 1 (IL-10R1) chains and two IL-10 receptor 2

Neuropathic pain

Neuropathic pain (NP) is a debilitating disorder originating from mechanical/chemical tissue damage, infection, or disease to the peripheral and/or central nervous system (CNS), which affects approximately four million people in the United States alone (Taylor, 2006). The common features of NP involve sensory disturbances including spontaneous pain, increased sensitivity to painful stimuli (hyperalgesia), and painful sensitivity to innocuous stimuli (allodynia) (Jensen et al., 2007, Macleod

IL-10 protein

Systemic administration of IL-10 protein is generally not feasible due to the rapid breakdown of the protein and its large size, which renders it incapable of crossing the blood brain barrier (Kastin et al., 2003, Li et al., 1994). In contrast, studies involving direct IT or intranasal administration of IL-10 protein have been mostly successful. However, this route of administration still produces only transient effects due to the rapid clearance of IL-10 protein from intrathecal space

Conclusion

In conclusion, IL-10 is implicated in neuroimmune diseases of varying etiologies such as NP (nerve trauma), OA (peripheral inflammation), PD (neurodegeneration), and MS (autoimmune). A common feature of these disorders is an insufficiency in IL-10 signaling/bioavailability and ongoing inflammation. In animal studies, increasing physiological levels of IL-10 in the context of these diseases has generally been a successful strategy to reduce disease symptoms and associated inflammation. Various

References (220)

T. Arimoto et al.
Interleukin-10 protects against inflammation-mediated degeneration of dopaminergic neurons in substantia nigra
Neurobiol. Aging
(2007)
M.M. Backonja et al.
Altered cytokine levels in the blood and cerebrospinal fluid of chronic pain patients
J. Neuroimmunol.
(2008)
M. Bialecka et al.
Interleukin-10 (IL10) and tumor necrosis factor alpha (TNF) gene polymorphisms in Parkinson's disease patients
Park. Relat. Disord.
(2008)
M. Bialecka et al.
Interleukin-10 gene polymorphism in Parkinson's disease patients
Arch. Med. Res.
(2007)
B. Brodacki et al.
Serum interleukin (IL-2, IL-10, IL-6, IL-4), TNFalpha, and INFgamma concentrations are elevated in patients with atypical and idiopathic parkinsonism
Neurosci. Lett.
(2008)
S. Cao et al.
NF-kappaB1 (p50) homodimers differentially regulate pro- and anti-inflammatory cytokines in macrophages
J. Biol. Chem.
(2006)
K.R. Chaudhuri et al.
Non-motor symptoms of Parkinson's disease: diagnosis and management
Lancet Neurol.
(2006)
A. Compston et al.
Multiple sclerosis
Lancet
(2008)
A.L. Croxford et al.
Mouse models for multiple sclerosis: historical facts and future implications
Biochim. Biophys. Acta
(2011)
S. Franchi et al.
Intravenous neural stem cells abolish nociceptive hypersensitivity and trigger nerve regeneration in experimental neuropathy
Pain
(2012)

A. George et al.

Wallerian degeneration after crush or chronic constriction injury of rodent sciatic nerve is associated with a depletion of endoneurial interleukin-10 protein

Exp. Neurol.

(2004)

P.M. Grace et al.

Peripheral immune contributions to the maintenance of central glial activation underlying neuropathic pain

Brain Behav. Immun.

(2011)

S. Grinberg et al.

Suppression of PLCbeta2 by endotoxin plays a role in the adenosine A(2A) receptor-mediated switch of macrophages from an inflammatory to an angiogenic phenotype

Am. J. Pathol.

(2009)

S.I. Gringhuis et al.

C-type lectin DC-SIGN modulates Toll-like receptor signaling via Raf-1 kinase-dependent acetylation of transcription factor NF-kappaB

Immunity

(2007)

J. Gutierrez et al.

Introduction to neuropathic pain Syndromes

Neurosurg. Clin. N. Am.

(2014)

S. Gyoneva et al.

Differential regulation of microglial motility by ATP/ADP and adenosine

Park. Relat. Disord.

(2009)

X. Hu et al.

IFN-gamma suppresses IL-10 production and synergizes with TLR2 by regulating GSK3 and CREB/AP-1 proteins

Immunity

(2006)

J. Imitola et al.

Cytokines in multiple sclerosis: from bench to bedside

Pharmacol. Ther.

(2005)

S. Issazadeh et al.

Cytokines in relapsing experimental autoimmune encephalomyelitis in DA rats: persistent mRNA expression of proinflammatory cytokines and absent expression of interleukin-10 and transforming growth factor-beta

J. Neuroimmunol.

(1996)

R. Jancalek et al.

Bilateral changes of IL-10 protein in lumbar and cervical dorsal root ganglia following proximal and distal chronic constriction injury of peripheral nerve

Neurosci. Lett.

(2011)

M.P. Jensen et al.

Symptom burden in persons with spinal cord injury

Arch. Phys. Med. Rehabilitation

(2007)

A.J. Kastin et al.

Interleukin-10 as a CNS therapeutic: the obstacle of the blood-brain/blood-spinal cord barrier

Brain Res. Mol. brain Res.

(2003)

T. Kawai et al.

TLR signaling

Semin. Immunol.

(2007)

S.J. Kenealy et al.

The genetic epidemiology of multiple sclerosis

J. Neuroimmunol.

(2003)

B. Koppelman et al.

Interleukin-10 down-regulates MHC class II alphabeta peptide complexes at the plasma membrane of monocytes by affecting arrival and recycling

Immunity

(1997)

P. Lacy et al.

Cytokine release from innate immune cells: association with diverse membrane trafficking pathways

Blood

(2011)

F. Lagarce et al.

Baclofen-loaded microspheres in gel suspensions for intrathecal drug delivery: in vitro and in vivo evaluation

Eur. J. Pharm. Biopharm. Off. J. Arbeitsgemeinschaft Pharm. Verfahr. e.V

(2005)

F. Lagarce et al.

Baclofen-loaded microspheres: preparation and efficacy testing in a new rabbit model

Eur. J. Pharm. Biopharm. Off. J. Arbeitsgemeinschaft Pharm. Verfahr. e.V

(2005)

A. Ledeboer et al.

Intrathecal interleukin-10 gene therapy attenuates paclitaxel-induced mechanical allodynia and proinflammatory cytokine expression in dorsal root ganglia in rats

Brain Behav. Immun.

(2007)

D. Li et al.

Interleukin-10 promoter polymorphisms in Chinese patients with Parkinson's disease

Neurosci. Lett.

(2012)

M. Locati et al.

Macrophage activation and polarization as an adaptive component of innate immunity

Adv. Immunol.

(2013)

N. Alaaeddine et al.

Inhibition of tumor necrosis factor alpha-induced prostaglandin E2 production by the antiinflammatory cytokines interleukin-4, interleukin-10, and interleukin-13 in osteoarthritic synovial fibroblasts: distinct targeting in the signaling pathways

Arthritis Rheum.

(1999)

R. Ali et al.

Drugs in development for relapsing multiple sclerosis

Drugs

(2013)

O. Ananieva et al.

The kinases MSK1 and MSK2 act as negative regulators of Toll-like receptor signaling

Nat. Immunol.

(2008)

A.C. Anderson et al.

IL-10 plays an important role in the homeostatic regulation of the autoreactive repertoire in naive mice

J. Immunol.

(2004)

P. Anderson

Post-transcriptional control of cytokine production

Nat. Immunol.

(2008)

F. Apparailly et al.

Adenovirus-mediated transfer of viral IL-10 gene inhibits murine collagen-induced arthritis

J. Immunol.

(1998)

S. Ayhan et al.

Effect of bioabsorbable osseous fixation materials on dura mater and brain tissue

Plastic Reconstr. Surg.

(2002)

A. Bachis et al.

Interleukin-10 prevents glutamate-mediated cerebellar granule cell death by blocking caspase-3-like activity

J. Neurosci.

(2001)

V. Balasingam et al.

Attenuation of astroglial reactivity by interleukin-10

J. Neurosci.

(1996)

C. Ball et al.

Rat interleukin-10: production and characterisation of biologically active protein in a recombinant bacterial expression system

Eur. Cytokine Netw.

(2001)

F.J. Barrat et al.

In vitro generation of interleukin 10-producing regulatory CD4(+) T cells is induced by immunosuppressive drugs and inhibited by T helper type 1 (Th1)- and Th2-inducing cytokines

J. Exp. Med.

(2002)

H. Batoulis et al.

Experimental autoimmune encephalomyelitis – achievements and prospective advances

APMIS Acta Pathol. Microbiol. Immunol. Scand.

(2011)

E. Bettelli et al.

IL-10 is critical in the regulation of autoimmune encephalomyelitis as demonstrated by studies of IL-10- and IL-4-deficient and transgenic mice

J. Immunol.

(1998)

A.S. Beutler et al.

AAV for pain: steps towards clinical translation

Gene Ther.

(2009)

A. Boonstra et al.

Macrophages and myeloid dendritic cells, but not plasmacytoid dendritic cells, produce IL-10 in response to MyD88- and TRIF-dependent TLR signals, and TLR-independent signals

J. Immunol.

(2006)

S. Botha-Scheepers et al.

Innate production of tumour necrosis factor alpha and interleukin 10 is associated with radiological progression of knee osteoarthritis

Ann. Rheum. Dis.

(2008)

Z.S. Boyd et al.

Interleukin-10 receptor signaling through STAT-3 regulates the apoptosis of retinal ganglion cells in response to stress

Invest. Ophthalmol. Vis. Sci.

(2003)

B. Cannella et al.

IL-10 fails to abrogate experimental autoimmune encephalomyelitis

J. Neurosci. Res.

(1996)

H. Chi et al.

Dynamic regulation of pro- and anti-inflammatory cytokines by MAPK phosphatase 1 (MKP-1) in innate immune responses

Proc. Natl. Acad. Sci. U. S. A.

(2006)

Cited by (172)

Interleukin-10 enhances activity of ventral tegmental area dopamine neurons resulting in increased dopamine release
2023, Brain, Behavior, and Immunity
Dopamine transmission from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) regulates important aspects of motivation and is influenced by the neuroimmune system. The neuroimmune system is a complex network of leukocytes, microglia and astrocytes that detect and remove foreign threats like bacteria or viruses and communicate with each other to regulate non-immune (e.g neuronal) cell activity through cytokine signaling. Inflammation is a key regulator of motivational states, though the effects of specific cytokines on VTA circuitry and motivation are largely unknown. Therefore, electrophysiology, neurochemical, immunohistochemical and behavioral studies were performed to determine the effects of the anti-inflammatory cytokine interleukin-10 (IL-10) on mesolimbic activity, dopamine transmission and conditioned behavior. IL-10 enhanced VTA dopamine firing and NAc dopamine levels via decreased VTA GABA currents in dopamine neurons. The IL-10 receptor was localized on VTA dopamine and non-dopamine cells. The IL-10 effects on dopamine neurons required post-synaptic phosphoinositide 3-kinase activity, and IL-10 appeared to have little-to-no efficacy on presynaptic GABA terminals. Intracranial IL-10 enhanced NAc dopamine levels in vivo and produced conditioned place aversion. Together, these studies identify the IL-10R on VTA dopamine neurons as a potential regulator of motivational states.
Intrathecal non-viral interleukin-10 gene therapy ameliorates neuropathic pain as measured by both classical static allodynia and a novel supra-spinally mediated pain assay, the Two-Arm Rodent Somatosensory (TARS) task
2023, Brain, Behavior, and Immunity
Intrathecal delivery of interleukin-10 (IL-10) gene therapy has been reported to be effective in suppressing pain enhancement in a variety of rodent models. However, all publications that have tested this treatment have relied upon measures of static allodynia (von Frey test) and thermal hyperalgesia (Hargreaves test). As this plasmid DNA IL-10 (pDNA-IL10) therapeutic approach is now in human clinical trials for multiple pain indications, including intrathecal delivery for human neuropathic pain, it is important to consider the recent concerns raised in the pain field that such tests reflect spinal rather than supraspinal processing of, and responsivity to, noxious stimuli. Consequently, this raises the question of whether intrathecal pDNA-IL10 can reverse established neuropathic pain when assessed by a test requiring supraspinal, rather than solely spinal, mediation of the behavioral response. The present study utilizes the rat sciatic chronic constriction injury (CCI) model of neuropathic pain to compare the expression of static allodynia with that of cognitively controlled choice behavior in a two-arm maze, adapted from Hayashida et al. (2019). This modification, termed the Two-Arm Rodent Somatosensory (TARS) task, provides rats free choice to reach a desired goal box via a short “arm” of the maze with tactile probes as flooring versus a longer “arm” of the maze with a smooth surface. Here we demonstrate that static allodynia and avoidance of the nociceptive flooring in TARS develop in parallel over time, and that both behaviors also resolve in parallel following intrathecal pDNA-IL10 gene therapy. Details for the construction and use of this new maze design are also provided. Together, this study documents both: (a) the important finding that intrathecal IL-10 gene therapy does indeed resolve neuropathic pain as measured by a supraspinally-mediated behavioral task, and (b) a new, supraspinally-mediated task that allows behavioral assessments across weeks and allows the analysis of both development and resolution of neuropathic pain by therapeutic interventions. As such, the TARS operant behavior task is an improvement over other approaches such as the mechanical conflict-avoidance system which have difficulties demonstrating development and reversal of pain behavior in a within-subject design.
Importance of NFκβ, IL-10 serum levels and DC-SIGN polymorphic haplotypes in determining dengue disease severity among eastern Indian patients
2022, Microbial Pathogenesis
Dengue viral (DENV) infection is most prevalent arboviral infection in India resulting in wide-range of symptomatic manifestation from simple (DF) to severe dengue (SD). DENV is internalized by dendritic cell receptor, DC-SIGN, which in turn activates inflammatory cytokines: NFκβ, IL-10 as adaptive immune response. Present study focused on role of DC-SIGN polymorphisms and these cytokines in SD development among eastern Indian patients.
DC-SIGN polymorphisms (rs735239, rs4804803, rs2287886) and NFκβ, IL-10 concentrations were analysed among 179 dengue patients and 123 healthy individuals by PCR-RFLP and sandwich ELISA, respectively. DENV copies/ml and serotype in patient-sera were measured by quantitative and qualitative real time PCR, respectively. Statistical and haplotype analysis were performed by GraphPad-Prism and SNPStat, respectively.
Prevalence of DENV serotypes among infected patients: DENV2>DENV4>DENV3>DENV1; those with DENV3 infection reported significantly increased IL-10 level. NFκβ and IL-10 concentrations were significantly elevated among SD patients. ROC curve analysis predicted cut-off values of NFκβ>13.46 ng/ml and IL-10 > 490.5 pg/ml to detect SD among infected patients with a good sensitivity and specificity. Patients with rs735239-GG, rs2287886-GG genotypes and GGG, GAG haplotypes were significantly associated with SD development, whereas, those with rs4804803-AG exhibited high DENVcopies/ml. Patients with these haplotypes also demonstrated increased NFκβ and IL-10.
This study emphasised importance of DC-SIGN GGG and GAG haplotypes, NFκβ and IL-10 concentrations in WHO-defined severe dengue development among infected patients.
Chronic Expression of Interleukin-10 Transgene Modulates Cardiac Sympathetic Ganglion Resulting in Reduced Ventricular Arrhythmia
2024, Human Gene Therapy
Low-contrast visual acuity test is associated with central inflammation and predicts disability development in newly diagnosed multiple sclerosis patients
2024, Frontiers in Neurology
Inflammatory Response Modulation by Low-dose Anti-inflammatory Drugs Treatment in an In vitro Osteoarthritis Cellular Model
2024, Current Medicinal Chemistry

View all citing articles on Scopus

View full text

Invited reviewThe therapeutic potential of interleukin-10 in neuroimmune diseases

Highlights

Abstract

Introduction

Section snippets

Cellular sources of IL-10

IL-10 receptor and consequences of IL-10 receptor signaling

Neuropathic pain

IL-10 protein

Conclusion

Neurobiol. Aging

J. Neuroimmunol.

Park. Relat. Disord.

Arch. Med. Res.

Neurosci. Lett.

J. Biol. Chem.

Lancet Neurol.

Lancet

Biochim. Biophys. Acta

Pain

Exp. Neurol.

Brain Behav. Immun.

Am. J. Pathol.

Immunity

Neurosurg. Clin. N. Am.

Park. Relat. Disord.

Immunity

Pharmacol. Ther.

J. Neuroimmunol.

Neurosci. Lett.

Arch. Phys. Med. Rehabilitation

Brain Res. Mol. brain Res.

Semin. Immunol.

J. Neuroimmunol.

Immunity

Blood

Eur. J. Pharm. Biopharm. Off. J. Arbeitsgemeinschaft Pharm. Verfahr. e.V

Eur. J. Pharm. Biopharm. Off. J. Arbeitsgemeinschaft Pharm. Verfahr. e.V

Brain Behav. Immun.

Neurosci. Lett.

Adv. Immunol.

Inhibition of tumor necrosis factor alpha-induced prostaglandin E2 production by the antiinflammatory cytokines interleukin-4, interleukin-10, and interleukin-13 in osteoarthritic synovial fibroblasts: distinct targeting in the signaling pathways

Arthritis Rheum.

Drugs in development for relapsing multiple sclerosis

Drugs

The kinases MSK1 and MSK2 act as negative regulators of Toll-like receptor signaling

Nat. Immunol.

IL-10 plays an important role in the homeostatic regulation of the autoreactive repertoire in naive mice

J. Immunol.

Post-transcriptional control of cytokine production

Nat. Immunol.

Adenovirus-mediated transfer of viral IL-10 gene inhibits murine collagen-induced arthritis

J. Immunol.

Effect of bioabsorbable osseous fixation materials on dura mater and brain tissue

Plastic Reconstr. Surg.

Interleukin-10 prevents glutamate-mediated cerebellar granule cell death by blocking caspase-3-like activity

J. Neurosci.

Attenuation of astroglial reactivity by interleukin-10

J. Neurosci.

Rat interleukin-10: production and characterisation of biologically active protein in a recombinant bacterial expression system

Eur. Cytokine Netw.

In vitro generation of interleukin 10-producing regulatory CD4(+) T cells is induced by immunosuppressive drugs and inhibited by T helper type 1 (Th1)- and Th2-inducing cytokines

J. Exp. Med.

Experimental autoimmune encephalomyelitis – achievements and prospective advances

APMIS Acta Pathol. Microbiol. Immunol. Scand.

IL-10 is critical in the regulation of autoimmune encephalomyelitis as demonstrated by studies of IL-10- and IL-4-deficient and transgenic mice

J. Immunol.

AAV for pain: steps towards clinical translation

Gene Ther.

Macrophages and myeloid dendritic cells, but not plasmacytoid dendritic cells, produce IL-10 in response to MyD88- and TRIF-dependent TLR signals, and TLR-independent signals

J. Immunol.

Innate production of tumour necrosis factor alpha and interleukin 10 is associated with radiological progression of knee osteoarthritis

Ann. Rheum. Dis.

Interleukin-10 receptor signaling through STAT-3 regulates the apoptosis of retinal ganglion cells in response to stress

Invest. Ophthalmol. Vis. Sci.

IL-10 fails to abrogate experimental autoimmune encephalomyelitis

J. Neurosci. Res.

Dynamic regulation of pro- and anti-inflammatory cytokines by MAPK phosphatase 1 (MKP-1) in innate immune responses

Proc. Natl. Acad. Sci. U. S. A.

Invited review
The therapeutic potential of interleukin-10 in neuroimmune diseases