Emerging role of IL-16 in cytokine-mediated regulation of multiple sclerosis
Introduction
Multiple sclerosis (MS) is a chronic inflammatory, demyelinating, neurodegenerative and progressive paralytic disease of the central nervous system (CNS), caused by axonal degeneration and damage or dysfunction of neurons and oligodendrocytes [1], [2]. The etiology of MS is not understood. Complex interactions between genetic, environmental and epigenetic factors are implicated in the regulation of the disease. The autoimmune nature of MS is strongly suggested by evidence of myelin-specific autoreactive T cells and antibodies and responsiveness of MS patients to immunomodulatory therapies.
Multiple sclerosis is the second most common neurological disorder leading to disability in young adults, surpassed only by trauma. MS affects working populations between 20 and 50 years of age. Accumulating clinical and epidemiologic data raises awareness of early and late onset disease in children and older adults, respectively. Incidence of childhood and late onset are lower compared to that in young adults. Nevertheless, MS poses a serious health concern. Differences in the clinical course of disease and in responses to therapy between age groups present additional challenges to understanding the complex pathophysiology of MS. MS affects about 2.5 million people world wide. Patients suffering from this progressive, debilitating disease require therapy, counseling, and rehabilitation. Most often, with the advancement of the disease, MS patients are unable to continue working and to maintain their basic daily activities [1]. The ratio of female to male MS patients is 2–3:1. Higher incidence of MS among women is suggestive of sex hormone regulation of the disease. Epidemiological studies and more recent studies of blood have also indicated a link between vitamin D insufficiency and MS [1], [2].
Genetic studies have made enormous progress in revealing risk alleles associated with MS. To date, many genome-wide-association studies (GWAS) supported the view of polygenic regulation of susceptibility to autoimmune diseases including MS. A large number of genes associated with immune functions show linkage to MS. The International Multiple Sclerosis Genetics Consortium (IMSGC) undertook an analysis of immune-related loci and reported on 48 new susceptibility variants for MS [3]. The strongest MS susceptibility locus is the major histocompatibility complex (MHC) in chromosome 6p21.3. In the MHC class II segment of the MHC locus, the HLA-DRB∗1501 gene exhibits the strongest signal, with hierarchical allelic and haplotypic effects in different populations of MS patients. A cytokine IL-16 contributes to the regulation of expression of MHC class II on CD4+ mononuclear cells. A protective linkage in the MHC Class I region has been identified. Association with MS has been suggested for many other genes including those encoding cytokines, their cognate receptors, cytokine receptor associated signaling molecules, some chemokines, chemokine receptors, co-stimulatory and inhibitory molecules expressed on the cell membrane of immune cells. These genes include tumor necrosis factor alpha (TNFα), IL-7R, IL-2Rα, tyrosine-protein kinase-2, macrophage chemoattractant protein-1 (MCP-1) and CC chemokine receptor-5 (CCR5). [4]. Functional studies are needed in order to evaluate and refine the genetic association with mechanisms of the disease in order to successfully translate accumulating knowledge into MS therapy. Recent data on epigenetic regulation of autoimmune diseases further add to the complexity of factors associated with MS. To our knowledge, data on MS linkage with IL-16 gene have not been reported.
Combination of genetic susceptibility and infectious environmental factors, such as bacteria, parasites, fungus and viruses, as triggers of autoimmune mediated CNS tissue damage has been proposed and reexamined [5]. It is outside the scope of this article to elaborate on all proposed environmental influences. We will discuss some data indicating association between viruses including MS-associated retrovirus (MSRV) with MS. A functional relationship between MSR, HERV-W, its endogenous family, has been reported [6]. Binding of viral proteins, including retroviruses, such as human delta-retrovirus T lymphotropic virus type 1 (HTLV-1) Tax oncoprotein, to PDZ (postsynaptic density/disc large/zona occludens-1) domain binding site of the precursor of IL-16 (pro-IL-16) in HTLV-1 infected T cells and subsequent deregulation of cell cycle, has been shown [7]. Pro-IL-16 contains three domains, which allow protein–protein interactions. After cleavage with active caspase-3, two PDZ domains remain in the N-terminal portion while one PDZ domain goes to C-terminal, bioactive IL-16. Bioactive IL-16 is the only PDZ domain containing secreted cytokine. This function of pro-IL-16 is important for similar mechanisms implicated in autoimmune diseases including MS and in cancer development.
Most immunomodulatory MS therapies work through non-specific immunosuppressive and anti-inflammatory effects [1], [2], [8]. Although these therapies provide reduction of relapse rate and in new lesions, as demonstrated by MRI along with showing of disability in some patients, there is a lack of noticeable effects in others. Better understanding of specific mechanisms of the disease progression is critical for development of new specifically targeted therapies. Development of therapies aimed at regulation of autoimmune and regulatory CD4+ T cell subsets is of critical importance because of their central role in the pathogenesis of MS.
Experimental autoimmune encephalomyelitis (EAE) serves as a model to study primarily autoimmune mechanisms of MS. EAE is induced in genetically susceptible species and strains by immunization with myelin proteins or their encephalitogenic peptides or by adoptive transfer of in vitro re-stimulated myelin antigen cognate T cells. Myelin oligodendrocyte protein (MOG) is important for immune pathology of MS. Sequence of events in immune pathogenesis of EAE, initiated by challenge with myelin specific antigen, starts by the increase in permeability of the blood–brain barrier (BBB) and transmigration of antigen-specific T cells from the peripheral blood into the CNS. These interactions are coordinated by T cell chemoattractant cytokines and chemokines. Infiltrating T cells produce and locally release cytokines. Likewise, glia and other resident cell types produce inflammatory and some immune cytokines. Cytokines regulate complex cellular interactions between local antigen presenting cells (APC) and infiltrating lymphocytes. Interactions between autoreactive and regulatory T cells are central in the regulation of local inflammation and tissue damage. Strong immune responses to myelin oligodendrocyte glycoprotein (MOG) p35–55 (MOG35–55) by CD4+ Th1 cells and B cells are found in patients with MS. The encephalitogenic epitope of MOG35–55 is highly conserved among species, including mouse and human, which makes data from mouse studies more relevant for human pathology. In response to MOG35–55, a hybrid (B6 × SJL)F1 strain of mice develops severe, relapsing-remitting disease. In these mice, CNS inflammation is predominated by CD4+ T cells, followed by B cells and demyelinating lesions and axonal damage are pronounced. A relationship between IL-16 and severity of CD4+ T cell infiltration, occurrence of relapsing disease, and degrees of demyelination and axonal damage are demonstrated in (B6 × SJL) F1 mice with MOG35–55 induced EAE [9]. We will mainly emphasize this particular EAE model because of similarities it shares with relapsing-remitting course of MS, histopathology of lesions that resemble the type III lesion of MS, and similarities in IL-16 mediated mechanisms of immune regulation.
Cytokines comprise large families of small molecular glycoproteins, indispensable for regulation of developmental and immune functions. Cytokines are essential for the regulation of both innate and adoptive immune responses. Pleiotropic effects of cytokines include immune cell activation, differentiation and migration. By nature of their regulatory effects, cytokines may support, suppress or modulate inflammation. We will discuss cytokines in relation to their role in regulation of Th1, Th2, Th17, antigen presenting cells (APC), glial and neuronal function in MS and EAE. The complexity of cytokine interactions and networks are outside the scope of this article. We will revisit major mechanisms implicated in the regulation of progression of MS and CNS tissue damage.
The lymphocyte chemotactic factor, interleukin-16 (IL-16), is a cytokine constitutive to T lymphocytes [10]. Other cell types including monocytes/macrophages, dendritic cells, mast cells, fibroblasts and microglia can produce IL-16. IL-16 is a key regulator of the biological properties of CD4+ T cells including, migration, T cell activation, CD25 (IL-2Rα) expression, MHC class II expression, cytokine synthesis, DC-T cell cooperation, B cell–T cell cooperation, T cell–T cell cooperation, inflammatory cytokine production and modulation of chemokine regulated T cell migration by heterologous receptor cross-desensitization of chemokine G-protein-coupled receptor-signaling of CCR5, CXCR4 and CXCR3 [11]. Each of these pleiotropic functions of IL-16 will be discussed in the following sections, alongside mechanisms pertinent for MS immune pathology. Thus, IL-16 is postulated to be a proinflammatory and immunoregulatory molecule with an important role in recruitment and activation of CD4+ T cells at the site of inflammation [12]. In subsequent sections, we will discuss relevant IL-16-mediated mechanisms in relation to aspects of MS pathogenesis.
The precursor molecule, pro-IL-16 (80 kDa), is generated in T lymphocytes. In quiescent CD4+ T cells, only pro-IL-16 (80 kDa) can be detected. Following CD4+ T cell activation, an intermediate product of cleavage (50–60 kDa) and bioactive IL-16 (17 kDa) are readily observed. Cleavage and release of bioactive IL-16 are distinctly regulated among T-cell subsets. In CD4+ T cells, T-cell receptor (TCR) mediated or cytokine induced T-cell activation leads to serine phosphorylation and enzymatic cleavage of pro-IL-16 at an STDS site between the Asp510 and the Ser511 by activated caspase-3 and release of active C-terminal portion of IL-16 (17 kDa) from the remaining N-terminal fragment, which translocates to the nucleus [13]. Cleavage of the C-terminal portion of pro-IL-16 is regulated by serine phosphorylation of pro-IL-16 on Ser144, which engages Erk1/2 kinase activity, while the secretion of bioactive IL-16 is regulated by MAP kinase [14]. Bioactive IL-16 is then secreted from activated T cells. Following secretion from the T cell, IL-16 “multimerizes” into homotetramers composed of 14–17 kDa chains, necessary for the binding to CD4 receptor and subsequent signaling. Bioactive IL-16 induces chemoattraction of CD4+ T cells by binding to the CD4 co-receptor. Signaling that involves p56lck and rearrangement of actin cytoskeleton with the requirement for SH2/SH3 recruitment domains suggests involvement of other intracellular signaling proteins. The minimal C-terminal peptide RRKS (corresponding to Arg106 to Ser109) was shown to be critical for mediating chemoattracting activity of bioactive IL-16 [15]. While the secreted C-terminal domain of IL-16 achieves its pleiotropic effects on CD4+ cells through CD4 receptor-initiated signaling pathways, the residual N-terminal domain translocates to the nucleus, where it induces G0/G1 cell cycle arrest by the inhibition of Skp2 transcription in a p27(KIP1)-dependent manner [16]. Nuclear translocation of the N-terminal portion of IL-16 is enabled by the CcN motif, which contains a nuclear localization sequence (NLS), a protein kinase CK2 substrate site and a cdc2 kinase substrate site [17].
Structurally and functionally, IL-16 is highly conserved across species including human and mouse, which makes studies of its regulation in a mouse model relevant to human pathology. In humans, the gene encoding IL-16 is located on chromosome 15q26.3. In the promoter region of IL-16, a -295T-to-C polymorphism was found to underlie different levels of IL-16 gene expression, which has been associated with some autoimmune diseases including systemic lupus erythematosus (SLE), Crohn’s and Graves’ disease [18]. Association between IL-16 promoter polymorphism and immune mediated diseases such as, asthma and allergic contact dermatitis [19] has been suggested. Similar genetic links between IL-16 and cerebrovascular disease, ischemic stroke [20] have been reported.
Of great interest for the pathophysiology of inflammation-mediated neurological diseases is the fact that IL-16 is a molecule expressed in both the immune and nervous systems. A larger splice variant (141 kD) of lymphocyte IL-16, which is contained within CD4+ post-mitotic granule neurons in the cerebellum and hippocampus, is termed neuronal IL-16 (NIL-16) [21]. Similarly to pro-IL-16, proN-IL-16 is subjected to posttranslational enzymatic cleavage by caspase-3. Compared to lymphocyte pro-IL-16, NIL-16 contains two additional PDZ domains in its N-terminal portion, which interact with neuronal ion channels. The C-terminal portion is identical to the lymphocyte bioactive IL-16 including the CD4 binding site at the C-terminal portion of the secreted cytokine. The role of NIL-16 in maintenance of neuronal homeostasis is not completely understood. It was demonstrated that IL-16 supports survival of cerebellar granule neurons and induces c-Fos expression through CD4-dependent and p56(lck)-dependent signaling pathway [22]. Specific contribution of NIL-16 to the regulation of autoimmune-mediated neuroinflammation remains unknown. Studies from relapsing-remitting MS (RRMS) tissue and corresponding MOG35–55 induced relapsing EAE in (B6 × SJL) F1 (H-2b/s) mice suggest a role for NIL-16 in neuro-immune communications in lesions of gray matter including the cerebellum and hippocampus and in adjacent normal appearing gray matter (NAGM) [Skundric, unpublished]. Future studies in this direction are required for the development of specifically targeted therapies aimed at preventing or ameliorating neuronal damage.
Section snippets
Clinical course
The onset and clinical course of MS are unpredictable. Clinical symptoms of MS are heterogeneous and primarily include loss of motor and sensory functions in the extremities and visual impairments. Blurred or decreased vision in one eye along with distorted color vision for red and green optic neuritis are common first symptoms of MS. Patients experience muscular weakness in their extremities, which poses problems with walking or even standing. Sensory symptoms include paresthesias,
IL-16 regulation of antigen presenting cell (APC)–T cell communication
Compromise of the BBB, accumulation of inflammatory cytokines and chemokines, co-ordinate expression of cell adhesion molecules and glial cell activation are complex interconnected processes that precede CNS infiltration by activated antigen presenting cells (APC), including dendritic cells (DC), macrophages and lymphocytes. Resident non-neuronal cells including microglia and astrocytes, and innate immune cells, DC and macrophages, actively participate in regulation of neuroinflammation.
IL-16 regulation of CD4+ T cells
Once infiltrating mononuclear cells gain entry into brain and spinal cord parenchyma, they produce cytokines including IL-16, IFN-γ, IL-17, IL-9, IL-2, IL-4, IL-10, IL-6, IL-7, IL-12, IL-23 and TGF-β among others. Some of these locally produced cytokines, which have chemoattractant properties, including IL-16, provide additional chemotactic signals and/or regulate functional properties of infiltrating CD4+ autoreactive helper T cells (Th), which express TCR specificities for encephalitogenic
Conclusions
Cytokines have an important role in initiation and perpetuation of inflammation in relapsing MS and relapsing-remitting EAE. Locally produced cytokines accomplish their inflammatory, anti-inflammatory and immune modulatory properties through complex interactions within microenvironment-specific cytokine and cell networks. IL-16 has an important role in cytokine- mediated regulation of progression of Th1-mediated inflammation in relapsing-remitting EAE and relapsing MS. IL-16 is an important
Acknowledgements
Data cited and discussed in this article were in part supported by a Pilot Project Grant from the National Multiple Sclerosis Society (NMSS) PP0701 and PP0958 and Development Award from the American Diabetes Association (No. 255FR) to DSS.
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2023, Developmental and Comparative ImmunologyCitation Excerpt :The binding of IL-16 to CD4 results in the activation of PI3K, ERK, p38, and PKC kinase cascades, while the N-terminal peptide forms a complex with HSC70 and initiates p27-mediated cell cycle signaling (Richmond et al., 2014). IL-16 is constitutively expressed by a spectrum of non-immune cells including neuronal cells, epithelial cells, fibroblasts and immune cells including eosinophils, DCs, monocytes, macrophages and T cells (Skundric et al., 2015). IL-16 transcripts are exclusively detected in lymphoid tissues in the normal state, whereas IL-16 mRNA could be synthesized in non-lymphoid tissues during inflammation (Skundric et al., 2015).
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