The reciprocal interactions between microglia and T cells in Parkinson’s disease: a double-edged sword

Abstract

In Parkinson's disease (PD), neurotoxic microglia, Th1 cells, and Th17 cells are overactivated. Overactivation of these immune cells exacerbates the disease process and leads to the pathological development of pro-inflammatory cytokines, chemokines, and contact-killing compounds, causing the loss of dopaminergic neurons. So far, we have mainly focused on the role of the specific class of immune cells in PD while neglecting the impact of interactions among immune cells on the disease. Therefore, this review demonstrates the reciprocal interplays between microglia and T cells and the associated subpopulations through cytokine and chemokine production that impair and/or protect the pathological process of PD. Furthermore, potential targets and models of PD neuroinflammation are highlighted to provide the new ideas/directions for future research.

Age-dependent Powassan Virus Lethality is Directed by Glial Cell Activation and Divergent Neuroinflammatory Cytokine Responses in a Murine Model

“…The CD8 positive T cells observed were sparse and dispersed sporadically in the pons and cerebellum of 10 and 50 week old mice 15 dpi, with maximal CD8 positive areas of the CNS presented, and no quantifiable differences in 10 or 50 week old POWV infected brains (Figure S4A,B). These CD4 and CD8 T cell findings differ dramatically from the ubiquitous staining of microglia/macrophage and astrocytes within the CNS of 10 and 50 week old mice 15 dpi, and foster roles for phagocytic glial cells and their responses in lethal POWV encephalitis( 43, 44, 47, 58, 59, 73–78 ).…”

“…Activated glia cell responses promote T helper (Th) cell effector functions by directing pro-inflammatory Th1-type cytokines or anti-inflammatory Th2 cytokine responses that in the CNS opposingly contribute to neuropathology or neuroprotection( 1, 44, 46, 52, 57, 59, 62, 63, 78 ). We assayed the CNS of POWV LI9 infected 10 and 50 week old mice (n=3) for induced cytokine and chemokine responses 15 dpi by qRT-PCR and compared responses 5, 10 and 15 dpi to age-matched controls (Figure 7A).…”

“…In contrast, the induction of IL-10, TGF, IL-4 and chemokines in the CNS of 10 week old mice reflects a neuroprotective, antiinflammatory M2 microglial, Th2 response (57,(59)(60)(61)63) , supporting POWV clearance from the CNS. Thus ubiquitous glial cell activation results in age specific M1/Th1 or M2/Th2 type cytokine responses as neuroinflammatory determinants (78,81) of age-dependent POWV lethality. The high level induction of Th1 cytokines in POWV infected 50 week old mice suggests roles for activated glial responses in failed viral clearance from the CNS, age-dependent POWV lethality and persistent neuroinflammation.…”

“…Astrocytes similarly maintain CNS homeostasis, but on activation induce GFAP, glial scar formation, S100B activation of microglial RAGE receptors and IL-12 directed inflammatory responses that augment microglial inflammation in the CNS( 46–48, 56, 69, 77, 81, 96 ). As a result, altering the balance of neurotoxic and neuroprotective glial cells in the CNS may direct damaging inflammatory CNS hyperactivation during POWV infection of the CNS( 44, 47, 59, 62, 63, 69, 74, 76–78, 85, 97 ).…”

Immune Regulatory Functions of Macrophages and Microglia in Central Nervous System Diseases

“…These oligomers can lead to neurotoxic effects by inducing mitochondrial dysfunction, endoplasmic reticulum stress, proteostasis disruption, synaptic impairment, cell apoptosis, and inflammation [ 289 ]. Microglia, in concert with T cells, play a central role in mediating the aforementioned neurotoxic effects in the CNS [ 291 ]. Individuals affected by PD exhibit motor symptoms such as bradykinesia, muscle tone rigidity, resting tremor, and postural instability as well as non-motor symptoms such as sleep disorders, sensory abnormalities, and autonomic dysfunctions [ 292 , 293 ].…”