IL-12p35 Inhibits Neuroinflammation and Ameliorates Autoimmune Encephalomyelitis.

Jin Kyeong Choi,Cheng-Rong Yu,Chang He,Mary J Mattapallil,Charles E Egwuagu,Ivy M Dambuza,Anita N Uche,Rachel R Caspi

doi:10.3389/fimmu.2017.01258

Abstract

Multiple sclerosis (MS) is an inflammatory demyelinating disease in which cytokines produced by immune cells that infiltrate the brain and spinal cord play a central role. We show here that the IL-12p35, the alpha subunit of IL-12 or IL-35 cytokine, might be an effective biologic for suppressing neuroinflammatory responses and ameliorating the pathology of experimental autoimmune encephalomyelitis (EAE), the mouse model of human MS. We further show that IL-12p35 conferred protection from neuropathy by inhibiting the expansion of pathogenic Th17 and Th1 cells and inhibiting trafficking of inflammatory cells into the brain and spinal cord. In addition, in vitro exposure of encephalitogenic cells to IL-12p35 suppressed their capacity to induce EAE by adoptive transfer. Importantly, the IL-12p35-mediated expansion of Treg and Breg cells and its amelioration of EAE correlated with inhibition of cytokine-induced activation of STAT1/STAT3 pathways. Moreover, IL-12p35 inhibited lymphocyte proliferation by suppressing the expressions of cell-cycle regulatory proteins. Taken together, these results suggest that IL-12p35 can be exploited as a novel biologic for treating central nervous system autoimmune diseases and offers the promise of ex vivo production of large amounts of Tregs and Bregs for immunotherapy.

Highlights

Multiple sclerosis (MS) is a complex inflammatory demyelinating and degenerative disease thought to be triggered by blood-borne leukocytes that invade the central nervous system (CNS)
pathogen-associated molecular patterns (PAMPs) that act through TLRs on dendritic cells (DCs) lead to the production of pro-inflammatory IL-12 family cytokines as well as suppressive members of the family that guard against excessive immune responses that cause autoimmune pathology
While these heterodimeric cytokines are under intense investigation, less attention has been given to the physiological functions of the individual single chain proteins that are themselves differentially regulated by pathways downstream of distinct adaptor molecules that mediate transcriptional programs activated by TLRs

Summary

Introduction

Multiple sclerosis (MS) is a complex inflammatory demyelinating and degenerative disease thought to be triggered by blood-borne leukocytes that invade the central nervous system (CNS). These cells produce inflammatory cytokines such as IL-17 and IFN-γ that act on CNS-resident cells (microglia and astrocytes) to elicit production of additional cytokines (IL-1, IL-6, IL-12, IL-23, and TNF-α) and chemokines that promote further recruitment of leukocytes, which fuel the inflammatory cascade [1, 2]. The requirement of pathogen-associated molecular patterns (PAMPs) contained in CFA for induction of EAE has led to interest in pathways that regulate cytokines elicited in response to PAMPs [8]. Regarding potential biologics for MS, the IL-12/IL-6 family of cytokines are of significant interest as they regulate the initiation, intensity, and duration of immune responses and are direct targets of TLR agonists present in CFA [8]

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