Nrf2-mediated anti-inflammatory polarization of macrophages as therapeutic targets for osteoarthritis

Abstract

Macrophages are the most abundant immune cells within the synovial joints, and also the main innate immune effector cells triggering the initial inflammatory responses in the pathological process of osteoarthritis (OA). The transition of synovial macrophages between pro-inflammatory and anti-inflammatory phenotypes can play a key role in building the intra-articular microenvironment. The pro-inflammatory cascade induced by TNF-α, IL-1β, and IL-6 is closely related to M1 macrophages, resulting in the production of pro-chondrolytic mediators. However, IL-10, IL1RA, CCL-18, IGF, and TGF are closely related to M2 macrophages, leading to the protection of cartilage and the promoted regeneration. The inhibition of NF-κB signaling pathway is central in OA treatment via controlling inflammatory responses in macrophages, while the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway appears not to attract widespread attention in the field. Nrf2 is a transcription factor encoding a large number of antioxidant enzymes. The activation of Nrf2 can have antioxidant and anti-inflammatory effects, which can also have complex crosstalk with NF-κB signaling pathway. The activation of Nrf2 can inhibit the M1 polarization and promote the M2 polarization through potential signaling transductions including TGF-β/SMAD, TLR/NF-κB, and JAK/STAT signaling pathways, with the regulation or cooperation of Notch, NLRP3, PI3K/Akt, and MAPK signaling. And the expression of heme oxygenase-1 (HO-1) and the negative regulation of Nrf2 for NF-κB can be the main mechanisms for promotion. Furthermore, the candidates of OA treatment by activating Nrf2 to promote M2 phenotype macrophages in OA are also reviewed in this work, such as itaconate and fumarate derivatives, curcumin, quercetin, melatonin, mesenchymal stem cells, and low-intensity pulsed ultrasound.

Ginsenoside Rg1 Reduces Oxidative Stress Via Nrf2 Activation to Regulate Age-Related Mesenchymal Stem Cells Fate Switch Between Osteoblasts and Adipocytes

“…Nrf2 is an important pathway for regulating oxidative stress levels [ 25 ]. Activated Nrf2 forms bind to an antioxidant response element (ARE), which regulates the expression of various antioxidative stress and chemical damage-related enzymes, such as NQO1, and HO-1 subunit [ 26 , 27 ], and regulates the expression of these genes in various organs, including bone [ 28 , 29 ]. Researches have shown that the activation of Nrf2 can shift the switch between osteogenic lineage and adipogenic lineage in MSCs [ 25 , 28 ].…”

IRG1/itaconate increases IL-10 release to alleviate mechanical and thermal hypersensitivity in mice after nerve injury

“…Itaconate activates the Nrf2 pathway and plays the anti-inflammatory function ( 18 ). Meanwhile, the Nrf2 pathway could regulate the transcription of Heme oxygenase-1 (HO-1) and contribute to the production of IL-10 ( 51 , 52 ). We found that the level of Nrf2 in ipsilateral spinal cord of CCI mice was increased after 4-OI treatment.…”

Pterostilbene Attenuates Subarachnoid Hemorrhage-Induced Brain Injury through the SIRT1-Dependent Nrf2 Signaling Pathway

“…Xiao et al showed that Nrf2 could inhibit nod-like receptor pyrin domain-containing 3 inflammasome-mediated neuroinflammation and pyroptosis after cerebral ischemia-reperfusion injury [ 34 ]. In addition, Nrf2 has been demonstrated to regulate transforming growth factor- β , toll-like receptor 4/NF-кB, and Notch to affect microglial/macrophage polarization in different diseases models [ 35 , 36 ]. However, whether PTE modulates these molecular targets after SAH remains obscure.…”