Olfactory Ensheathing Cells Grafted Into the Retina of RCS Rats Suppress Inflammation by Down-Regulating the JAK/STAT Pathway

Abstract

The inflammatory microenvironment in the retina plays a vital role in the pathogenesis and progression of retinitis pigmentosa (RP). Microglial inflammatory cytokines production leads to gliosis and apoptosis of retinal neurons, and ultimately, visual loss. Cell-based therapies using grafted olfactory ensheathing cells (OECs) have demonstrated modulation of degenerative microenvironments in the central nervous system (CNS), in a number of animal models. However, mechanisms by which grafted OECs can reduce degeneration in the retina are not well understood. In the present study, we set up an in vitro OEC/BV2 microglia co-culture system, and an in vivo royal college of surgeons (RCS) rat model, used cell transplantation, immunohistochemistry, RT-PCR, western blot to explore the mechanisms by which OECs affect expression of pro- or anti-inflammatory cytokines and polarization of M(IL-6) and M(Arg1) type microglial activation in the retina. We found that compared with the LPS (Lipopolysaccharide) and olfactory nerve fibroblast (ONF), the OEC and BV2 co-culture group modulate microglial cytokines releasing toward the anti-inflammation, and away from the pro-inflammation, which was followed by higher IL-4 and IL-10 and lower TNF-a and IL-6 in their expression levels. In vivo , the transplantation group significantly reduced activated resident microglia/infiltrated macrophage, and expression of pro-inflammatory cytokines in RCS rats retina, increased anti-inflammatory cytokines in transplantation area. Additionally, we found that OECs expressed SOCS3 and down-regulated the JAK2/STAT3 (Janus Kinase 2/Signal Transducer and Activator of Transcription 3) pathway. Thirdly, OEC transplantation reduced Caspase-3 expression, protected inner retinal neurons and photoreceptors and therefore, delayed the visual function degeneration. In conclusion, our data suggest that OECs delay retinal degeneration in RP, at least in part through immunomodulation of microglia via the JAK/STAT pathway.

Hyperoxalemia Leads to Oxidative Stress in Endothelial Cells and Mice with Chronic Kidney Disease

“…In vitro, oxalate caused a dose-dependent increase in the secretion of inflammatory factors, including MDA, IL-6, TNF-α, and CRP, in HAECs but not in HASMCs, indicating that vascular endothelial cells might be the target cells of oxalateinduced vascular calcification. The JAK2/STAT3 signaling pathway plays an important role in regulating the secretion of inflammatory factors [34,35]. Our study indicated a potential role for JAK2/STAT3 signaling in increasing the inflammatory factors and activating oxidative stress by high oxalate concentrations as p-JAK2 and p-STAT3 levels were significantly upregulated in HAECs.…”

Intravenous transplantation of olfactory ensheathing cells reduces neuroinflammation after spinal cord injury via interleukin-1 receptor antagonist

“…In vitro microglial activation was induced by LPS (Figure 7 A). Highly aggressive proliferating immortalized (HAPI) microglial cells were treated with LPS (1 mg/mL) for 4 h 28 before co-culturing with OECs or IL-1Ra knockdown OECs in the transwell co-culture system for another 24 h. The results obtained from immunocytochemistry indicated that the LPS stimulation significantly activated HAPI microglial cells (Figure 7 B). The averaged fluorescent intensity of microglial markers Iba-1 and CD40 was significantly increased (64.52 ± 1.37 vs. 39.48 ± 0.82, p < 0.0001 and 60.67 ± 3.85 vs. 48.48 ± 0.71, p < 0.0001, respectively).…”

Activation of adenosine A3 receptor reduces early brain injury by alleviating neuroinflammation after subarachnoid hemorrhage in elderly rats

“…Neuroinflammation is considered as a predominant pathological hallmark of brain damage after SAH [ 32 , 33 ]. During neuroinflammation following SAH, activated microglia are a pivotal source for a plethora of various cytokines and chemokines in the central nervous system [ 34 ].…”