Connecting Metainflammation and Neuroinflammation Through the PTN-MK-RPTPβ/ζ Axis: Relevance in Therapeutic Development

Abstract

Inflammation is a common factor of pathologies such as obesity, type 2 diabetes or neurodegenerative diseases. Chronic inflammation is considered part of the pathogenic mechanisms of different disorders associated with aging. Interestingly, peripheral inflammation and the associated metabolic alterations not only facilitate insulin resistance and diabetes but also neurodegenerative disorders. Therefore, the identification of novel pathways, common to the development of these diseases, which modulate the immune response and signaling is key. It will provide highly relevant information to advance our knowledge of the multifactorial process of aging, and to establish new biomarkers and/or therapeutic targets to counteract the underlying chronic inflammatory processes. One novel pathway that regulates peripheral and central immune responses is triggered by the cytokines pleiotrophin (PTN) and midkine (MK), which bind its receptor, Receptor Protein Tyrosine Phosphatase (RPTP) β/ζ, and inactivate its phosphatase activity. In this review, we compile a growing body of knowledge suggesting that PTN and MK modulate the immune response and/or inflammation in different pathologies characterized by peripheral inflammation associated with insulin resistance, such as aging, and in central disorders characterized by overt neuroinflammation, such as neurodegenerative diseases and endotoxemia. Evidence strongly suggests that regulation of the PTN and MK signaling pathways may provide new therapeutic opportunities particularly in those neurological disorders characterized by increased PTN and/or MK cerebral levels and neuroinflammation. Importantly, we discuss existing therapeutics, and others being developed, that modulate these signaling pathways, and their potential use in pathologies characterized by overt neuroinflammation.

Disruption of Midkine gene reduces traumatic brain injury through the modulation of neuroinflammation

“…MK may act as a modulator of CNS neuroinflammation depending on the inflammatory stimulus [29,44]. Although our results showed MK-deficiency to regulate microglia-mediated neuroinflammation, the same was not valid for astrocytosis in the perilesional cortex after TBI.…”

“…Although our results showed MK-deficiency to regulate microglia-mediated neuroinflammation, the same was not valid for astrocytosis in the perilesional cortex after TBI. While MK reduces the microglia responses and astrocytosis induced by amphetamine in the striatum, LPS-induced neuroinflammation seems to be potentiated by MK [44]. Therefore, TBI-induced glial response may be different from the drug-induced one.…”

“…Both cytokines are novel modulators of neuroinflammation and play different roles based on the inflammatory stimulus and the duration of the neuroinflammatory processes. Therefore, the MK/PTN signaling pathways are novel therapeutic strategies to modulate neuroinflammation in acute and chronic pathological states [44]. Inhibiting MK as well as PTN may be beneficial in neuroinflammatory states that promote exacerbation of neurodegeneration.…”

The Role of Macrophage Migration Inhibitory Factor in Alzheimer′s Disease: Conventionally Pathogenetic or Unconventionally Protective?

“…There are also other well promoting factors in the pathogenesis of AD including hyperinsulinemia and diabetes, as well as the occurrence of accompanying neuroinflammation [2]. It has also recently been proposed that a common pathogenetic pathway connecting diabetes, subchronic inflammation, and AD may rely on the activation of the common pathogenetic pathway consisting of PTN-MK-RPTPβ/ζ Axis [9]. Strengthening the causal link between deregulated glycaemic homeostasis, including insulin secretion and resistance and AD, is the recent identification of a newly indicated form of diabetes named "type 3" diabetes that is characterized as a brain-insulin resistant state linked to AD [10].…”

Midkine-a is required for cell cycle progression of Müller glia during neuronal regeneration

“…In several forms of cancers, Midkine promotes both proliferation and metastasis (Muramatsu, 2011). Midkine is also involved in inflammatory diseases by modulating immune cell activities (Herradon et al, 2019;Muramatsu, 2011;Weckbach et al, 2011). The diverse functions of Midkine are transduced through cell surface receptors, which may function as an individual trans-membrane protein or as members of a multi-protein complex (Muramatsu, 2011;Weckbach et al, 2011;Xu et al, 2014).…”