Proteoglycan 4 Reduces Neuroinflammation and Protects the Blood–Brain Barrier after Traumatic Brain Injury

Abstract

Neuroinflammation and dysfunction of the blood-brain barrier (BBB) are two prominent mechanisms of secondary injury in neurotrauma. It has been suggested that Toll-like receptors (TLRs) play important roles in initiating and propagating neuroinflammation resulting from traumatic brain injury (TBI), but potential beneficial effects of targeting these receptors in TBI have not been broadly studied. Here, we investigated the effect of targeting TLRs with proteoglycan 4 (PRG4) on post-traumatic neuroinflammation and BBB function. PRG4 is a mucinous glycoprotein with strong anti-inflammatory properties, exerting its biological effects by interfering with TLR2/4 signaling. In addition, PRG4 has the ability to inhibit activation of cluster of differentiation 44 (CD44), a cell-surface glycoprotein playing an important role in inflammation. Using the controlled cortical impact model of TBI in rats, we showed a rapid and prolonged upregulation of message for TLR2/4 and CD44 in the injured cortex. In the in vitro model of the BBB, recombinant human PRG4 (rhPRG4) crossed the endothelial monolayers through a high-capacity, saturable transport system. In rats sustaining TBI, PRG4 delivery to the brain was enhanced by post-traumatic increase in BBB permeability. rhPRG4 injected intravenously at 1 h post-TBI potently inhibited post-traumatic activation of nuclear factor kappa B and extracellular signal-regulated kinases 1/2, the two major signal transduction pathways associated with TLR2/4 and CD44, and curtailed the post-traumatic influx of monocytes. In addition, PRG4 restored normal BBB function after TBI by preventing the post-traumatic loss of tight junction protein claudin 5 and reduced neuronal death. Our observations provide support for therapeutic strategies targeting TLRs in TBI.

Recombinant Human Proteoglycan 4 Regulates Phagocytic Activation of Monocytes and Reduces IL-1β Secretion by Urate Crystal Stimulated Gout PBMCs

“…rhPRG4 was also shown to reduce cytokine and chemokine secretions from immortalized corneal epithelial cells at 300μg/mL in vitro and inflammation in an experimental dry eye disease model ( 61 ). rhPRG4 reduced neuroinflammation and influx of monocytes in a rat model of traumatic brain injury, mediated by its regulation of the ERK1/2 pathway, downstream of CD44 and TLR2/4 engagements ( 62 ). Our current study extends the anti-inflammatory activity of rhPRG4 to controlling IL-1β secretion by PBMCs from patients with acute gout flares, where the efficacious rhPRG4 concentration was in the range of what was reported as efficacious in in vitro models of human synoviocytes, macrophages, endothelial and corneal epithelial cells.…”

Microenvironmental Variations After Blood-Brain Barrier Breakdown in Traumatic Brain Injury

“…To exert the anti-inflammatory effect, the agents or molecule may target certain type of immune cells to enhance their function, change the phenotypes, inhibit the secretion of pro-inflammatory factors, or enhance the secretion of anti-inflammatory factors (Table 2). There are several agents attenuate inflammation by inhibiting the accumulation and activation of immune cells, such as microglia, T cells, astrocytes, and monocytes (Prabhakara et al, 2018;Hummel et al, 2020;Bennett et al, 2021). More studies have focused on the process of shifting from M1 microglial phenotype to the M2.…”

“…A study has demonstrated that P7C3-A20, a compound that stabilizes the cellular energy levels, could increase the expression of TJ proteins in different region of the brain, e.g., claudin-5 in the cortex and hippocampus, and zona occludens-1 in the cortex (Vázquez-Rosa et al, 2020). Other agents or drugs, such as proteoglycan 4, rhFGF21 (Bennett et al, 2021), sesamin (Liu et al, 2017), capsazepine (TRPV1 inhibitor) (Yang D. X. et al, 2019), glibenclamide (Xu et al, 2017), TIMP1 (Tang et al, 2020), and TIMP3 (Menge et al, 2012) also have the effect on the expression of TJ and AJ proteins, such as claudin 5, occludens-1, and ZO-1.…”

2-Methoxyestradiol Alleviates Neuroinflammation and Brain Edema in Early Brain Injury After Subarachnoid Hemorrhage in Rats

“…It is well known that maintaining BBB integrity is crucial for homeostasis of the CNS. It is worth noting that the excessive neuroinflammatory responses may also damage the junctional complex of the BBB, leading to BBB dysfunction in a variety of inflammatory CNS diseases ( Chen et al, 2014a ; Bennett et al, 2021 ). Chen et al (2014a) showed that the overexpression of matrix metallopeptidase (MMP)-9 and vascular endothelial growth factor (VEGF) after SAH promoted the increase in BBB permeability, which was closely associated with both neuroinflammation and brain edema.…”