Updates on immunity and inflammation in Parkinson disease pathology
Parkinson disease (PD) is a progressive, age‐related, neurodegenerative disease that is clinically characterized by tremor, slowness of movement, postural instability, and rigidity. The cause of PD is unknown, but it is believed that both environmental and genetic factors are implicated in the disease pathology. The primary disease‐related pathological hallmark involves the progressive loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) (Schneider & Obeso, 2015; Goswami et al., 2017). Deposition of protein aggregates containing α‐synuclein, termed Lewy bodies, is evident in multiple brain regions of patients with PD (Lotharius & Brundin, 2002; Olanow & Brundin, 2013). The pathology of parkinsonism involves the intense release of oxygen free radicals during enzymatic breakdown of dopamine and also during mitochondrial impairment (Herrera, Muñoz, Steinbusch, & Segura‐Aguilar, 2017; Lotharius & Brundin, 2002), loss of trophic factors, altered kinase activity, disrupted calcium homeostasis, blemished protein degradation, and neuroinflammation (Brady & Morfini, 2017; Cieri, Brini, & Calì, 2017; Domise & Vingtdeux, 2016; Jiang, Sun, & Chen, 2016; Lindholm et al., 2016; Tansey & Goldberg, 2010). The involvement of innate and adaptive immunity has also been suggested in PD pathology (Stone, Reynolds, Mosley, & Gendelman, 2009). Innate immunity involves nonspecific defense mechanisms that come into play immediately after the appearance of any foreign particle/object or any microbial infection in the body. This mechanism embraces the removal of foreign substances by phagocytosis, recruitment of subsequent immune cells to the site of infection, cytokine production, activation of complement cascade, and antigen presentation for activation of adaptive immunity. Innate immunity acts through the generic recognition of common cell signaling pathways called pathogen‐associated molecular patterns. Such events could be recognized by toll‐like receptors (TLRs), expressed by microglial cells, astrocytes, oligodendrocytes, and neurons (van Noort & Bsibsi, 2009). Activation of TLRs contributes to neuroinflammation by activating signaling cascades that result in proinflammatory cytokine and chemokine production as well as affecting the permeability of the blood‐brain barrier (Aravalli, Peterson, & Lokensgard, 2007). Adaptive immunity largely involves the infiltration of lymphocytes in the brain (Kurkowska‐Jastrzebska et al., 1999a). Evidence supports sustained inflammatory responses, T cell infiltration, and glial cell activation in patients with PD as well as in animal models of PD, which play vital roles in the degeneration of DA neurons (Kurkowska‐Jastrzebska et al., 1999b; Singh, Swarnkar, Goswami, & Nath, 2011). Findings suggest the possibility of developing potential therapies targeting the inflammatory responses and immune responses. Such immune responses engross the production of cytokines from glial cells as well as from neurons (Doty, Guillot‐Sestier, & Town, 2015; Letiembre et al., 2009). Cytokines production may sequentially initiate immune responses as well as this event could also be immunomodulator / immunoregulator of neural functions and neuronal survival. Synaptic or nonsynaptic release of neurotransmitters could also modulate the cytokine balance in the brain (Vizi et al., 1995). The peripheral dysregulated cytokine network has also been suggested in patients with PD (Reale et al., 2009a,b). Therefore, the neuroimmune reactions are bidirectional. Cytokines, chemokines, and other products of the immune system could modulate the action, differentiation, and survival of neuronal cells, while the release of neurotransmitters and neuropeptides plays a crucial role in influencing the immune reactions.