Interleukin-4 Protects Dopaminergic Neurons In vitro but Is Dispensable for MPTP-Induced Neurodegeneration In vivo

Abstract

Microglia are involved in physiological as well as neuropathological processes in the central nervous system (CNS). Their functional states are often referred to as M1-like and M2-like activation, and are believed to contribute to neuroinflammation-mediated neurodegeneration or neuroprotection, respectively. Parkinson’s disease (PD) is one the most common neurodegenerative disease and is characterized by the progressive loss of midbrain dopaminergic (mDA) neurons in the substantia nigra resulting in bradykinesia, tremor, and rigidity. Interleukin 4 (IL4)-mediated M2-like activation of microglia, which is characterized by upregulation of alternative markers Arginase 1 (Arg1) and Chitinase 3 like 3 (Ym1) has been well studied in vitro but the role of endogenous IL4 during CNS pathologies in vivo is not well understood. Interestingly, microglia activation by IL4 has been described to promote neuroprotective and neurorestorative effects, which might be important to slow the progression of neurodegenerative diseases. In the present study, we addressed the role of endogenous and exogenous IL4 during MPP+-induced degeneration of mDA neurons in vitro and further addressed the impact of IL4-deficiency on neurodegeneration in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD in vivo. Our results clearly demonstrate that exogenous IL4 is important to protect mDA neurons in vitro, but endogenous IL4 seems to be dispensable for development and maintenance of the nigrostriatal system as well as MPTP-induced loss of TH+ neurons in vivo. These results underline the importance of IL4 in promoting a neuroprotective microglia activation state and strengthen the therapeutic potential of exogenous IL4 for protection of mDA neurons in PD models.

A systematic review and meta-analysis of inflammatory biomarkers in Parkinson’s disease

“…Our results revealed controversial findings for the anti-inflammatory marker IL-4 in peripheral blood and CSF, possibly suggesting dual functions in the CNS. IL-4 shapes microglial functions to promotes the survival of dopaminergic neurons in animal models 32 , which underlines the therapeutic potential of IL-4 administration in PD. In addition, IL-4 promotes neurodegeneration in proinflammatory rat models by contributing to microglial activation, IL-1β production, and BBB disruption 33 .…”

Interleukin-4 Contributes to Degeneration of Dopamine Neurons in the Lipopolysaccharide-treated Substantia Nigrain vivo

“…The current results are incompatible to our previous report that IL-4 enhances neuronal survival after traumatic spinal cord injury and in LPS-treated cortex in vivo by regulating neuroinflammation [ 12 47 ]. Hühner and colleagues have recently reported that exogenous IL-4 protects MPP + -induced degeneration of midbrain DA neurons in vitro , but endogenous IL-4 has no effect on MPTP-induced degeneration of nigrostriatal dopamine neurons in IL-4 knock-out mice in vivo [ 48 ]. On the other hand in the present study, IL-4 contributes to microglial activation, production of IL-1β, and disruption of BBB and astrocytes which subsequently led to the degeneration of DA neurons in the LPS-treated SN in vivo .…”

Microglia Phenotypes in Aging and Neurodegenerative Diseases

“…The anti-inflammatory cytokine IL-4 is also involved in PD pathology. In mixed neuron-glia culture, inhibition of endogenous microglia-derived IL-4 enhanced MPTPinduced neurotoxicity, and exogenous administration of IL-4 in the mouse MPTP model protects against neurotoxicity, indicating a potential protective role of IL-4 in PD [348]. In addition to IL-4 and IL-10, the pleiotropic M2 cytokine TGF-β mediates neuroprotective functions in inflammation and neurotoxin PD models; it limits M1 microglial activation and dopaminergic neurodegeneration [349,350].…”