Sulforaphene targets NLRP3 inflammasome to suppress M1 polarization of macrophages and inflammatory response in rheumatoid arthritis

This work aimed to explore the therapeutic effect and target of sulforaphene (LF) in mice with rheumatoid arthritis (RA). Lipopolysaccharide (LPS) and IFN‐γ were added to induce the M1 polarization of SMG cells, and later cells were pretreated with 5 μM and 15 μM LF. M1 cell proportion was detected by flow cytometry (FCM), inflammatory factors were measured by enzyme‐linked immunosorbent assay, and protein levels were analyzed by western blotting (WB) assay. Besides, small molecule‐protein docking and pull‐down assays were carried out to detect the binding of LF to NLRP3. After the knockdown of NLRP3 in SMG cells, the effect of LF was further detected. The RA mouse model was induced with collagen antibody and LPS, after LF intervention, H&E staining was performed to detect the pathological changes in mouse synovial membrane, whereas safranin O‐fast green staining was performed to detect cartilage injury, NLRP3 inflammasome and inflammatory factor levels in tissues. LF suppressed M1 polarization of macrophages, reduced M1 cell proportion and inflammatory factor levels, and suppressed the activation of NLRP3 inflammasome. After NLRP3 knockdown, LF did not further suppress the M1 polarization of macrophages. Pull‐down assay suggested that LF bound to NLRP3. As revealed by mouse experimental results, LF inhibited bone injury in mice, decreased M1 cell infiltration and inflammatory response in tissues, and inhibited NLRP3 inflammasome expression in tissues. LF targets NLRP3 to suppress the M1 polarization of macrophages and decrease tissue inflammation in RA.

[1]  L. Qian,et al.  NLRP3 gene polymorphisms and expression in rheumatoid arthritis , 2021, Experimental and therapeutic medicine.

[2]  E. af Klint,et al.  Tocilizumab decreases T cells but not macrophages in the synovium of patients with rheumatoid arthritis while it increases the levels of serum interleukin-6 and RANKL , 2021, RMD Open.

[3]  O. Mazda,et al.  Sustained Hypoxia Suppresses Joint Destruction in a Rat Model of Rheumatoid Arthritis via Negative Feedback of Hypoxia Inducible Factor-1α , 2021, International journal of molecular sciences.

[4]  Jianbo Xiao,et al.  Ginsenoside Rg1 ameliorates blood–brain barrier disruption and traumatic brain injury via attenuating macrophages derived exosomes miR-21 release , 2021, Acta pharmaceutica Sinica. B.

[5]  S. Eyre,et al.  Persistent inflammatory and non-inflammatory mechanisms in refractory rheumatoid arthritis , 2020, Nature Reviews Rheumatology.

[6]  S. Schülke,et al.  Update on the Pathomechanism, Diagnosis, and Treatment Options for Rheumatoid Arthritis , 2020, Cells.

[7]  Chunyan Wan,et al.  NLRP3 inflammasome mediates M1 macrophage polarization and IL-1β production in inflammatory root resorption. , 2020, Journal of clinical periodontology.

[8]  Qiong Xu,et al.  TET1 Knockdown Inhibits Porphyromonas gingivalis LPS/IFN-γ-Induced M1 Macrophage Polarization through the NF-κB Pathway in THP-1 Cells , 2019, International journal of molecular sciences.

[9]  Zhao‐Jun Wei,et al.  Liquiritin from Glycyrrhiza uralensis Attenuating Rheumatoid Arthritis via Reducing Inflammation, Suppressing Angiogenesis, and Inhibiting MAPK Signaling Pathway. , 2019, Journal of agricultural and food chemistry.

[10]  S. Wang,et al.  NLRP3 inflammasome activation contributes to the pathogenesis of rheumatoid arthritis , 2018, Clinical and experimental immunology.

[11]  Zhao‐Jun Wei,et al.  Salicin from Alangium chinense Ameliorates Rheumatoid Arthritis by Modulating the Nrf2-HO-1-ROS Pathways. , 2018, Journal of agricultural and food chemistry.

[12]  Xinwei Han,et al.  Sulforaphene enhances radiosensitivity of hepatocellular carcinoma through suppression of the NF‐κB pathway , 2017, Journal of biochemical and molecular toxicology.

[13]  Q. Lin,et al.  Genomics, transcriptomics and proteomics to elucidate the pathogenesis of rheumatoid arthritis , 2017, Rheumatology International.

[14]  I. Bruce,et al.  Atherosclerosis in rheumatoid arthritis: is it all about inflammation? , 2015, Nature Reviews Rheumatology.

[15]  Xin Zhang,et al.  Activation in M1 but not M2 Macrophages Contributes to Cardiac Remodeling after Myocardial Infarction in Rats: a Critical Role of the Calcium Sensing Receptor/NRLP3 Inflammasome , 2015, Cellular Physiology and Biochemistry.

[16]  J. Alexander,et al.  CD11b is protective in complement-mediated immune complex glomerulonephritis , 2015, Kidney international.

[17]  J. Barrett,et al.  Evidence of NLRP3-inflammasome activation in rheumatoid arthritis (RA); genetic variants within the NLRP3-inflammasome complex in relation to susceptibility to RA and response to anti-TNF treatment , 2013, Annals of the rheumatic diseases.

[18]  P. Söderkvist,et al.  Genetic variation in proteins of the cryopyrin inflammasome influences susceptibility and severity of rheumatoid arthritis (the Swedish TIRA project). , 2007, Rheumatology.

[19]  J. English,et al.  Rheumatoid arthritis: a review of the cutaneous manifestations. , 2005, Journal of the American Academy of Dermatology.

[20]  J. Smith,et al.  Rheumatoid ArthritisA Molecular Understanding , 2002, Annals of Internal Medicine.

[21]  A. Koch,et al.  Stimulation of neovascularization by human rheumatoid synovial tissue macrophages. , 1986, Arthritis and rheumatism.

[22]  D. Ring,et al.  Factors associated with pain intensity and magnitude of limitations among people with hip and knee arthritis. , 2021, Journal of orthopaedics.