GM-CSF induces neuroprotective and anti-inflammatory responses in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine intoxicated mice

Abstract

Innate and adaptive immune responses can speed nigrostriatal neurodegeneration in Parkinson’s disease (PD). We posit that GM-CSF can attenuate such responses. In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxicated mice, GM-CSF given prior to MPTP protected nigral dopaminergic neurons coincident with altered microglial morphologies and regulatory T cell (Treg) induction. Adoptive transfer of GM-CSF-induced Treg to MPTP mice protected nigral neurons and their striatal termini. Gene expression analyses revealed novel immune-based neuronal protection pathways. The results provide evidence that GM-CSF modulation of immunity could be of clinical benefit for PD.

Manganese-Enhanced Magnetic Resonance Imaging for Detection of Vasoactive Intestinal Peptide Receptor 2 Agonist Therapy in a Model of Parkinson's Disease

“…Such aberrations serve to change the brain's microenvironment, where a proinflammatory dominance ensues. These notions are further supported by preclinical studies performed in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD where intervention by immune modulation serves to protect dopaminergic neurons within the nigrostriatal pathway [13,19].…”

“…Frozen midbrain sections (30 μm) were immunostained for either tyrosine hydroxylase (TH) (anti-TH, 1:2000; EMD Millipore, Billerica, MA, USA), Mac-1 (anti-CD11b, 1:1000; AbD Serotech, Raleigh, NC, USA), or glial fibrillary acidic protein (anti-GFAP, 1:1000; Dako, Carpinteria, CA, USA). Within the SN, numbers of GFAP + cells/mm 2 , Mac-1 + cells/mm 2 , total numbers of TH + Nissl + (dopaminergic neurons), and total numbers of TH -Nissl + (nondopaminergic neurons) were estimated using stereological analysis via Stereo Investigator software with the optical fractionator module (MBF Bioscience, Williston, VT, USA), as previously described [13].…”

“…Indeed, neuronal loss is accompanied by robust microgliosis, astrocytosis, and release of proinflammatory neurotoxic mediators [8][9][10][11]. Recent works from our own laboratories have served to highlight the role of effector T cells (Teffs) and regulatory T cells (Tregs) in attenuating such neuroinflammatory response cascades [12,13]. The balance between effector T cells and Treg activities leads to respective degenerative or protective effects in the brain, depending on defined T-cell polarity and cell phenotype [2,12,[14][15][16][17].…”

“…Mobilizing specific regulatory T-cell adaptive immune responses affects microglial reactivity and protect against nigrostriatal degeneration [12,13,19]. The use of immunomodulatory compounds, such as granulocyte macrophage colony-stimulating factor (GM-CSF) and vasoactive intestinal peptide (VIP), shifts immune phenotypes and functions from neurotoxic to neuroprotective regulatory responses [13,[19][20][21][22].…”

“…The use of immunomodulatory compounds, such as granulocyte macrophage colony-stimulating factor (GM-CSF) and vasoactive intestinal peptide (VIP), shifts immune phenotypes and functions from neurotoxic to neuroprotective regulatory responses [13,[19][20][21][22]. Specifically targeting VIP receptor 2 (VIPR2) with a modified VIP analog (referred to as LBT-3627) has shown robust neuroprotective activities in MPTP-intoxicated mice [19].…”