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Emerging role of IL-16 in cytokine-mediated regulation of multiple sclerosis

Significance statement


We summarize multifaceted molecular pathways of a lymphocyte chemotactic factor, interleukin-16 (IL-16), in the regulation of relapsing multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). MS is a chronic inflammatory and progressive demyelinating and neurodegenerative disease of the central nervous system (CNS). Autoimmune responses to myelin and other CNS antigens mediated by CD4+ T cells are critical for initiation and progression of the disease. Locally produced cytokines are pleiotropic factors, which accomplish their inflammatory, anti-inflammatory and immune modulatory properties through complex interactions within microenvironment-specific cytokines and cell networks. IL-16 has an intricate role in regulating the progression of CD4+Th1-mediated inflammation in relapsing-remitting EAE and relapsing MS. IL-16 is the only exclusive chemotactic factor for CD4+ T cells and critical regulator of CD4+Tbet+ Th1 cell homing into the CNS in relapsing EAE and RRMS. IL-16 also induces migration of CD4+CD25+FOXP3+Treg cells and de novo FOXP3 transcription. Because of receptor cross-desensitization, IL-16 binding to CD4 has the potential to modulate chemokine-regulated migration of CCR5+CD4+Th1 cells. Similarly, it modulates CXCR3- and CXCR4-induced migrations, which are all implicated in the pathogenesis of MS. Furthermore, CD4+ T cells are subjected to regulation by IL-16, including cell activation, CD25 (IL-2Rα) expression, MHC class II molecule expression, co-stimulatory and inhibitory molecule expression, production of Th1 and Th2 cytokines and cooperation with DC, B and T cells. All of these CD4+ T cell functions are contributory to development and regulation of Th1 autoimmune responses to myelin and other CNS auto-antigens, which are critical for initiation and/or progression of MS. An intricate unique property of IL-16 emerges from being a shared molecule between the immune and nervous systems. A spliced isoform of neuronal IL-16 (NIL-16), which is contained within cerebellar granule neurons (CGN) and hippocampal neurons, is involved in regulation of neuronal homeostasis and synaptic functions. The molecular structure of PDZ-containing domains makes IL-16 a scaffolding protein, thus allowing for protein-protein or protein-nucleic acid interactions. These types of interactions, supported by IL-16, are of particular importance in regulation of viral infection and malignant cell proliferation, all of which are relevant to mechanisms of pathogenesis and/or complications of immune suppressive therapy of RRMS. Low-dose anti-IL-16 therapy reversed signs of MOG35-55-induced relapsing-remitting EAE in (B6 x SJL)F1 mice. Cross-species reactivity and high efficacy of anti-IL-16 therapy further emphasize the advantages of IL-16- based therapy for MS and other progressive autoimmune, inflammatory, demyelinating and neurodegenerative disease.

Figure Legend: 

B cell derived IL-16 in infiltrating EAE lesion. IL-16 immunoreactivity (arrow – IL-16-PE) was observed in infiltrating B220+ B cells (arrow – B220-FITC), shown in lumbar spinal cord of a relapsing mouse (third relapse 84 days-post-immunization with severity score 3.5). Note IL-16 in the cytoplasm and likely cell membrane of a B cell. Note adjacent mononuclear cells in the close proximity of IL-16 expressing B cell (arrow – merge). Membrane-bound IL-16 suggests its role in a B cell – adjacent mononuclear cell communication (three-color immunofluorescence at 200X magnification). *This image was published in original manuscript by Skundric DS, Dai R, Zakarian VL, Bessert D, Skoff RP, Cruikshank WW, Kurjakovic Z. Anti-IL-16 therapy reduces CD4+ T-cell infiltration and improves paralysis and histopathology of relapsing EAE. J Neurosci Res, 2005, 79 (5): 680-693.

Emerging role of IL-16 in cytokine-mediated regulation of multiple sclerosis. Global Medical Discovery












Journal Reference

Skundric DS1, Cruikshank WW2, Montgomery PC1, Lisak RP3, Tse HY4. Cytokine. 2015 . pii: S1043-4666(15)00009-5.

1Department of Immunology and Microbiology, Wayne State University, Detroit, MI, USA.

2Pulmonary Center, Boston University, Boston, MA, USA.

3Department of Immunology and Microbiology, Wayne State University, Detroit, MI, USA; Department of Neurology, Wayne State University, Detroit, MI, USA.

4Department of Immunology and Microbiology, Wayne State University, Detroit, MI, USA; Department of Neurology, Wayne State University, Detroit, MI, USA. Electronic address: [email protected]


Cytokines are pleiotropic soluble mediators of cellular functions. Cytokines are critical in immune pathogenesis of human diseases, including autoimmune CD4+ T cell mediated chronic inflammatory, demyelinating and neurodegenerative diseases of the central nervous system (CNS), multiple  sclerosis (MS). In MS and its experimental model, experimental autoimmune encephalomyelitis (EAE), chronic persistence and/or reoccurrence of inflammation in the CNS causes chronic progressive or relapsing disease, accompanied with demyelination and damage to axons and oligodendrocytes, which ultimately leads to paralysis and disability. As opposed to other cytokines, whose effects are not limited to the CD4+ T cell subset, IL-16 exerts its biological properties by exclusive binding and signaling through CD4 receptor. IL-16 selectively regulates migration of all CD4 expressing T cells regardless of their activation state, which is of critical importance for immune modulation and potential therapy of MS. Other major biological properties of IL-16 essential for the function of CD4+ T cells include regulation of: T cell activation, CD25 expression, MHC class II expression, dendritic cell (DC)-T cell cooperation, B cell-T cell and T cell-T cell cooperation, inflammatory cytokine production and modulation of chemokine regulated T cell chemo-attraction. In this article we outline immune pathogenesis of the disease necessary to understand significance of cytokines and IL-16 in MS regulation. We revisit cytokine regulation with emphasis on involvement of IL-16 mechanisms, implicated in MS progression and important for development of new therapies. We emphasize the significance of similar IL-16 mechanisms for other chronic inflammatory CNS diseases.

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