Schwann cell-specific regulation of IL-1 and IL-1Ra during EAN: possible relevance for immune regulation at paranodal regions

Abstract

We reported Schwann cell (SC)-specific autoregulation of IL-1 in vitro [J. Neuroimmunol. 74 (1997a)]. Whether SC resume this autoregulatory potential in vivo and what significance it may have for processes leading to inflammation and demyelination of the peripheral nerve remain obscure. Therefore, we examine SC-specific autoregulation of IL-1α, IL-1β and their natural antagonist IL-1 receptor antagonist (IL-1Ra) during experimental autoimmune neuritis (EAN), a model for the human Guillain–Barre syndrome.

Autoregulation of IL-1 by SC was analyzed in both, actively induced and adoptively transferred, EAN. Sciatic nerves were sampled before the onset of clinical signs, 2 to 11 days post immunization (dpi), with P2 peptide, and during clinically manifest disease, 11 to15 dpi. In adoptively transferred EAN, sciatic nerves were analyzed at preclinical stage, 2 to 4 days post P2 peptide-specific cell transfer (dpt) and during clinical manifested phase, 5 to 10 dpt.

In both models, IL-1α and IL-1β were expressed by SC, during preclinical EAN. IL-1Ra was not detectable in SC at preclinical stage. Further development and progression to clinically manifest disease was accompanied by SC-specific expression of IL-1Ra. Although present in other cells in the nerve, IL-1α and IL-1β were hardly detectable in SC during clinical EAN. IL-1Ra immunoreactivity highly co-localized with myelin associated glycoprotein (MAG), one of the markers for paranodal regions, sites essential for proper impulse transmission. Paranodes are also primary sites where activated macrophages make contact with SC, prior to infiltration.

SC-specific autoregulation of IL-1 and IL-1Ra is suggestive of its relevance for immune regulation at paranodes during EAN.

Introduction

Schwann cells (SC) are glia of the peripheral nervous system (PNS). Besides their roles in myelination, trophic support and regeneration of axons, SC exhibit potential for some immune functions, similarly to non-myelinating glia of the central nervous system (CNS) Armati and Pollard, 1996, Lisak et al., 1997. SC can be induced to produce cytokines Bolin et al., 1995, Gillen et al., 1998, Rutkowski et al., 1999 and chemokines, express MHC class II molecules, adhesion molecules and serve as antigen presenting cells Gold et al., 1995, Toews et al., 1998.

Peripheral nerve myelin is specifically organized by SC membrane extensions wrapped around axons, forming multilayered myelin sheets, periodically interrupted by nodes of Ranvier. Paranodal regions of SC membranes are especially important for impulse transmission and conductivity of the nerve. Proper function of the paranode is maintained by molecules that are selectively localized at these sites, such as myelin-associated glycoprotein (MAG), connexin32, potassium channel KV1.5, E-cadherin and actin (Scherer, 1996).

During inflammatory neuropathies including Guillain–Barre syndrome, the earliest structural changes are located at the nodal and paranodal regions Rosen et al., 1990, Griffin et al., 1996. During the inflammation to the peripheral nerve, by elaboration of cytokines and chemokines, SC have an active role by providing chemoattractant signal to extraneurial mononuclear cells (Fujioka et al., 1999). The initial macrophage–SC contact occurs at paranodal membranes where macrophages make direct contact with basal lamina, extend their processes beneath the myelin terminal loops and enter periaxonal spaces. While the significance of SC-derived production of certain cytokines to endoneurium already infiltrated with activated mononuclear cells may be minimal, their specific accumulation at paranodal regions may lead to important immunomodulation of SC–macrophage interactions.

IL-1 is an inflammatory cytokine and can be produced by cultured SC Bergsteinsdottir et al., 1991, Skundric et al., 1997a. IL-1 has a significant regulatory role in the production of nerve growth factor (NGF) (Lindholm et al., 1987) and leukemia inhibitory factor (LIF) in the peripheral nervous system (PNS) (Carlson and Hart, 1996). Biologic activities of IL-1α and IL-1β in glia and neurons include regulation of immune functions, such as cytokine and chemokine production, expression of adhesion and co-stimulatory molecules and antigen presentation Chao et al., 1995, Dalakas, 1999, Vitkovic et al., 2000. IL-1 was shown to be important in experimental allergic encephalomyelitis (EAE). EAE is an autoimmune, inflammatory, demyelinating disease of the CNS equivalent to EAN in the PNS. Treatment with IL-1Ra led to significant alteration of local inflammation and disease progression Jacobs et al., 1991, Martin and Near, 1995. Inflammatory cytokines including IL-1 play an important role in the pathogenesis of EAN Bai et al., 1997, Zhu et al., 1997. IL-1 activates macrophages and provides co-stimulatory signals for infiltrating myelin-specific T cells (O'Neill and Greene, 1998). IL-1Ra is a specific antagonist of IL-1 biologic activities which exists in two alternatively spliced forms, as an intracellular (icIL-1Ra) or secreted (sIL-1Ra) protein Arend et al., 1991, Eisenberg et al., 1991, Evans et al., 1995, Dinarello, 1998. Identification of the SC-specific form of IL-1Ra still needs to be determined. IL-1Ra has been shown to protect from EAE Jacobs et al., 1991, Badovinac et al., 1998, ischemic damage and exitoxic shock in the CNS (Toulmond and Rothwell, 1995). Therefore, we examined SC-specific autoregulation of IL-1 in vivo during the development and progression of inflammation in order to understand its role in local immune regulation.

Our results show that SC regulate IL-1 in a specific autocrine manner by a downregulation of IL-1α and IL-1β and upregulation of IL-1Ra transcription throughout the course of preclinical and clinical EAN.