Lipopolysaccharide and Curcumin Co-Stimulation Potentiates Olfactory Ensheathing Cell Phagocytosis Via Enhancing Their Activation

Abstract

The gradual deterioration following central nervous system (CNS) injuries or neurodegenerative disorders is usually accompanied by infiltration of degenerated and apoptotic neural tissue debris. A rapid and efficient clearance of these deteriorated cell products is of pivotal importance in creating a permissive environment for regeneration of those damaged neurons. Our recent report revealed that the phagocytic activity of olfactory ensheathing cells (OECs) can make a substantial contribution to neuronal growth in such a hostile environment. However, little is known about how to further increase the ability of OECs in phagocytosing deleterious products. Here, we used an in vitro model of primary cells to investigate the effects of lipopolysaccharide (LPS) and curcumin (CCM) co-stimulation on phagocytic activity of OECs and the possible underlying mechanisms. Our results showed that co-stimulation using LPS and CCM can significantly enhance the activation of OECs, displaying a remarkable up-regulation in chemokine (C-X-C motif) ligand 1, chemokine (C-X-C motif) ligand 2, tumor necrosis factor-α, and Toll-like receptor 4, increased OEC proliferative activity, and improved phagocytic capacity compared with normal and LPS- or CCM-treated OECs. More importantly, this potentiated phagocytosis activity greatly facilitated neuronal growth under hostile culture conditions. Moreover, the up-regulation of transglutaminase-2 and phosphatidylserine receptor in OECs activated by LPS and CCM co-stimulation are likely responsible for mechanisms underlying the observed cellular events, because cystamine (a specific inhibitor of transglutaminase-2) and neutrophil elastase (a cleavage enzyme of phosphatidylserine receptor) can effectively abrogate all the positive effects of OECs, including phagocytic capacity and promotive effects on neuronal growth. This study provides an alternative strategy for the repair of traumatic nerve injury and neurologic diseases with the application of OECs in combination with LPS and CCM.

Phagocytosis by Peripheral Glia: Importance for Nervous System Functions and Implications in Injury and Disease

“…Olfactory neurons undergo cell death via apoptosis upon reaching the end of their lifespan, displaying the "eat me" signal phosphatidylserine. In vitro studies have shown that OECs recognize phosphatidylserine on apoptotic neurons via phosphatidylserine receptors prior to engulfment (He et al, 2014;Hao et al, 2017). As discussed earlier, phagocytes usually possess a number of receptors that recognize phosphatidylserine on an apoptotic target; while some receptors directly recognize phosphatidylserine, others require bridging molecules to aid attachment.…”

“…In vitro phagocytic assays have also shown that OECs are capable of taking up debris derived from several types of axons (generated by destruction of axons, thus resembling an injury containing both apoptotic and necrotic bodies) as well as myelin debris (He et al, 2014;Nazareth et al, 2015aNazareth et al, , 2020Khankan et al, 2016;Hao et al, 2017). OECs can, like SCs, actively phagocytose and degrade necrotic cells in vitro (also via phosphatidylserine recognition).…”

“…Astrocyte phagocytosis of myelin, Aβ Upregulated after injury. Potential role in myelin phagocytosis CNS Glia: (Gaultier et al, 2009;Fricker et al, 2012;Liu et al, 2017) (Bowman et al, 2003;Olson and Miller, 2004;Jack et al, 2005;Farina et al, 2007;Lee and Landreth, 2010;Lee et al, 2013;Rajbhandari et al, 2014) SCs: (Oliveira et al, 2003;Boivin et al, 2007;Goethals et al, 2010;Mattos et al, 2011) OECs: (Vincent et al, 2007;Hao et al, 2017) NOD-like receptors (NLRs)…”

Key differences between olfactory ensheathing cells and Schwann cells regarding phagocytosis of necrotic cells: implications for transplantation therapies

“…The transplanted cells are thought to promote regeneration by secreting growth factors and guidance factors, by providing physical support, and by clearing debris arising from dead cells 13,15 . It has also been suggested that stimulation of the phagocytic activity to more rapidly clear the injury site of cell debris will further promote regeneration 13,[17][18][19][20][21] . To date, it remains unknown how peripheral glia recognize, internalize and process necrotic targets.…”

The plant natural product 2-methoxy-1,4-naphthoquinone stimulates therapeutic neural repair properties of olfactory ensheathing cells

“…As debris removal is critical for regeneration, stimulation of OEC phagocytosis may also be favourable. Low-dose curcumin has been shown to strongly stimulate the phagocytic activity of OECs 13,27 , in addition to stimulating both proliferation and migration 13 . Eremophila microtheca compounds have also been shown to enhance phagocytic activity, migration and cell viability of OECs 15 .…”