{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T21:55:33Z","timestamp":1793224533527,"version":"4.5.0"},"reference-count":42,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,7,5]],"date-time":"2022-07-05T00:00:00Z","timestamp":1656979200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Osteoarthritis (OA) is a deteriorating disease of cartilage tissues mainly characterized as low-grade inflammation of the joint. Innate immune molecule surfactant protein D (SP-D) is a member of collectin family of collagenous Ca<jats:sup>2+<\/jats:sup>-dependent defense lectins and plays a vital role in the inflammatory and innate immune responses. The present study investigated the SP-D-mediated innate\/inflammatory bioregulation in OA and explored the underlying molecular mechanism. Transcriptome analysis revealed that SP-D regulated genes were strongly enriched in the inflammatory response, immune response, cellular response to lipopolysaccharide (LPS), PI3K-Akt signaling, Toll-like receptor (TLR) signaling, and extracellular matrix (ECM)-receptor interaction pathways. Knockdown of the SP-D gene by the recombinant adeno-associated virus promoted the macrophage specific markers of CD68, F4\/80 and TLR4 in the articular cartilage <jats:italic>in vivo<\/jats:italic>. SP-D alleviated the infiltration of synovial macrophages and neutrophils, and inhibited TLR4, TNF-\u03b1 and the phosphorylation of PI3K, Akt and NF-\u03baB p65 in cartilage. SP-D suppressed cartilage degeneration, inflammatory and immune responses in the rat OA model, whilst TAK-242 strengthened this improvement. In <jats:italic>in vitro<\/jats:italic> conditions, SP-D pre-treatment inhibited LPS-induced overproduction of inflammation-correlated cytokines such as IL-1\u03b2 and TNF-\u03b1, and suppressed the overexpression of TLR4, MD-2 and NLRP3. SP-D prevented the LPS-induced degradation of ECM by down-regulating MMP-13 and up-regulating collagen II. Blocking of TLR4 by TAK-242 further enhanced these manifestations. We also demonstrated that SP-D binds to the TLR4\/MD-2 complex to suppress TLR4-mediated PI3K\/Akt and NF-\u03baB signaling activation in chondrocytes. Taken together, these findings indicate that SP-D has chondroprotective properties dependent on TLR4-mediated PI3K\/Akt and NF-\u03baB signaling and that SP-D has an optimal bioregulatory effect on the inflammatory and innate responses in OA.<\/jats:p>","DOI":"10.3389\/fimmu.2022.913901","type":"journal-article","created":{"date-parts":[[2022,7,5]],"date-time":"2022-07-05T05:03:07Z","timestamp":1656997387000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":21,"title":["Innate\/Inflammatory Bioregulation of Surfactant Protein D Alleviates Rat Osteoarthritis by Inhibiting Toll-Like Receptor 4 Signaling"],"prefix":"10.3389","volume":"13","author":[{"given":"Huanyu","family":"Jiang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yubiao","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geliang","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaobin","family":"Shang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianghua","family":"Ming","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming","family":"Deng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaming","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yonggang","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiqing","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,7,5]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"iv10","DOI":"10.1093\/rheumatology\/kex399","article-title":"The Role of Fat and Inflammation in the Pathogenesis and Management of Osteoarthritis","volume":"57","author":"Urban","year":"2018","journal-title":"Rheumatol (Oxford England)"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1038\/nrrheum.2017.50","article-title":"The Role of Metabolism in the Pathogenesis of Osteoarthritis","volume":"13","author":"Mobasheri","year":"2017","journal-title":"Nat Rev Rheumatol"},{"key":"B3","first-page":"57","article-title":"Innate Inflammation and Synovial Macrophages in Osteoarthritis Pathophysiology","author":"Griffin","year":"2019","journal-title":"Clin Exp Rheumatol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.02264","article-title":"The Dual Role of Surfactant Protein-D in Vascular Inflammation and Development of Cardiovascular Disease","volume":"10","author":"Colmorten","year":"2019","journal-title":"Front Immunol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.01368","article-title":"The Role and Molecular Mechanism of Action of Surfactant Protein D in Innate Host Defense Against Influenza a Virus","volume":"9","author":"Hsieh","year":"2018","journal-title":"Front Immunol"},{"key":"B6","article-title":"Increased Expression of Surfactant Protein a and D in Rheumatoid Arthritic Synovial Fluid (RASF)","volume":"47","author":"Kankavi","year":"2006","journal-title":"Croat Med J"},{"key":"B7","doi-asserted-by":"publisher","first-page":"R39","DOI":"10.1186\/ar2948","article-title":"Circulating Surfactant Protein -D is Low and Correlates Negatively With Systemic Inflammation in Early, Untreated Rheumatoid Arthritis","volume":"12","author":"Christensen","year":"2010","journal-title":"Arthritis Res Ther"},{"key":"B8","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1111\/apm.12785","article-title":"Localization of Surfactant Protein-D in the Rheumatoid Synovial Membrane","volume":"126","author":"Christensen","year":"2018","journal-title":"APMIS"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2020.104690","article-title":"Berberine-Mediated Up-Regulation of Surfactant Protein D Facilitates Cartilage Repair by Modulating Immune Responses via the Inhibition of TLR4\/NF-\u0138b Signaling","volume":"155","author":"Zhou","year":"2020","journal-title":"Pharmacol Res"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2017.10.170","article-title":"Surfactant Protein D Attenuates Nitric Oxide-Stimulated Apoptosis in Rat Chondrocyte by Suppressing P38 MAPK Signaling","volume":"495","author":"Zhou","year":"2018","journal-title":"Biochem Biophys Res Commun"},{"key":"B11","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1007\/s00383-015-3812-y","article-title":"Surfactant Protein-D Attenuates the Lipopolysaccharide-Induced Inflammation in Human Intestinal Cells Overexpressing Toll-Like Receptor 4","volume":"32","author":"Saka","year":"2016","journal-title":"Pediatr Surg Int"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1021\/bi060176z","article-title":"Human Pulmonary Surfactant Protein D Binds the Extracellular Domains of Toll-Like Receptors 2 and 4 Through the Carbohydrate Recognition Domain by a Mechanism Different From its Binding to Phosphatidylinositol and Lipopolysaccharide","volume":"45","author":"Ohya","year":"2006","journal-title":"Biochemistry"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.01455","article-title":"Toll-Like Receptor 4 (TLR4)\/Opioid Receptor Pathway Crosstalk and Impact on Opioid Analgesia, Immune Function, and Gastrointestinal Motility","volume":"11","author":"Zhang","year":"2020","journal-title":"Front Immunol"},{"key":"B14","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1016\/j.bbi.2017.08.018","article-title":"Protraction of Neuropathic Pain by Morphine is Mediated by Spinal Damage Associated Molecular Patterns (Damps) in Male Rats","volume":"72","author":"Grace","year":"2018","journal-title":"Brain Behav Immun"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2222.2009.03367.x","article-title":"Surfactant Protein D Inhibits Mite-Induced Alveolar Macrophage and Dendritic Cell Activations Through TLR Signalling and DC-SIGN Expression","volume":"40","author":"Liu","year":"2010","journal-title":"Clin Exp Allergy"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1016\/j.joca.2020.03.002","article-title":"Activation of Innate Immunity by 14-3-3 \u0395, a New Potential Alarmin in Osteoarthritis","volume":"28","author":"Millerand","year":"2020","journal-title":"Osteoarthritis Cartilage"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.3390\/biology9040065","article-title":"Osteoarthritis and Toll-Like Receptors: When Innate Immunity Meets Chondrocyte Apoptosis","volume":"9","author":"Barreto","year":"2020","journal-title":"Biol (Basel)"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1038\/nrrheum.2014.209","article-title":"TLR4 Signalling in Osteoarthritis\u2013Finding Targets for Candidate Dmoads","volume":"11","author":"G\u00f3mez","year":"2015","journal-title":"Nat Rev Rheumatol"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.bone.2005.08.007","article-title":"Characterization of Articular Cartilage and Subchondral Bone Changes in the Rat Anterior Cruciate Ligament Transection and Meniscectomized Models of Osteoarthritis","volume":"38","author":"Hayami","year":"2006","journal-title":"Bone"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1007\/s00109-020-01972-1","article-title":"Chemically Modified Curcumin (CMC2.24) Alleviates Osteoarthritis Progression by Restoring Cartilage Homeostasis and Inhibiting Chondrocyte Apoptosis","volume":"98","author":"Zhou","year":"2020","journal-title":"via NF-\u03baB\/HIF-2\u03b1 Axis J Mol Med (Berl)"},{"key":"B21","doi-asserted-by":"publisher","first-page":"R139","DOI":"10.1186\/ar4601","article-title":"Extracorporeal Shockwave Therapy in Osteoporotic Osteoarthritis of the Knee in Rats: An Experiment in Animals","volume":"16","author":"Wang","year":"2014","journal-title":"Arthritis Res Ther"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-020-0285-6","article-title":"Defining Trained Immunity and its Role in Health and Disease","volume":"20","author":"Netea","year":"2020","journal-title":"Nat Rev Immunol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/j.joca.2020.01.011","article-title":"Role of TLR2 and TLR4 in Regulation of Articular Chondrocyte Homeostasis","volume":"28","author":"Wang","year":"2020","journal-title":"Osteoarthritis Cartilage"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/key187","article-title":"Surfactant Protein-D, a Potential Mediator of Inflammation in Axial Spondyloarthritis","volume":"57","author":"Munk","year":"2018","journal-title":"Rheumatol (Oxford)"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1097\/SHK.0000000000001244","article-title":"Surfactant Protein D Dampens Lung Injury by Suppressing NLRP3 Inflammasome Activation and NF-\u03bab Signaling in Acute Pancreatitis","volume":"51","author":"Yu","year":"2019","journal-title":"Shock"},{"key":"B26","doi-asserted-by":"publisher","first-page":"148","DOI":"10.1186\/s12974-019-1538-9","article-title":"Ciprofloxacin and Levofloxacin Attenuate Microglia Inflammatory Response via TLR4\/NF-Kb Pathway","volume":"16","author":"Zusso","year":"2019","journal-title":"J Neuroinflammation"},{"key":"B27","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1016\/j.molimm.2019.03.003","article-title":"Structural Variants of Salmonella Typhimurium Lipopolysaccharide Induce Less Dimerization of TLR4\/MD-2 and Reduced Pro-Inflammatory Cytokine Production in Human Monocytes","volume":"111","author":"Aldapa-Vega","year":"2019","journal-title":"Mol Immunol"},{"key":"B28","doi-asserted-by":"publisher","first-page":"e2715","DOI":"10.1038\/cddis.2017.129","article-title":"TNF-\u03b1-Induced LRG1 Promotes Angiogenesis and Mesenchymal Stem Cell Migration in the Subchondral Bone During Osteoarthritis","volume":"8","author":"Wang","year":"2017","journal-title":"Cell Death Dis"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1016\/j.joca.2020.01.013","article-title":"Anti-Inflammatory Effects of Naproxen Sodium on Human Osteoarthritis Synovial Fluid Immune Cells","volume":"28","author":"Hsueh","year":"2020","journal-title":"Osteoarthritis Cartilage"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22041742","article-title":"Overview of MMP-13 as a Promising Target for the Treatment of Osteoarthritis","volume":"22","author":"Hu","year":"2021","journal-title":"Int J Mol Sci"},{"key":"B31","doi-asserted-by":"publisher","first-page":"e0203502","DOI":"10.1371\/journal.pone.0203502","article-title":"Evaluation of Surfactant Proteins a, B, C, and D in Articular Cartilage, Synovial Membrane and Synovial Fluid of Healthy as Well as Patients With Osteoarthritis and Rheumatoid Arthritis","volume":"13","author":"Hartjen","year":"2018","journal-title":"PloS One"},{"key":"B32","doi-asserted-by":"publisher","first-page":"146","DOI":"10.1186\/s13075-019-1923-x","article-title":"Synovial Fluid Biomarkers Associated With Osteoarthritis Severity Reflect Macrophage and Neutrophil Related Inflammation","volume":"21","author":"Haraden","year":"2019","journal-title":"Arthritis Res Ther"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1038\/s41584-022-00749-9","article-title":"Synovial Inflammation in Osteoarthritis Progression","volume":"18","author":"Sanchez-Lopez","year":"2022","journal-title":"Nat Rev Rheumatol"},{"key":"B34","doi-asserted-by":"publisher","first-page":"464","DOI":"10.1038\/s41419-019-1696-9","article-title":"Fgf1(\u0394hbs) Ameliorates Chronic Kidney Disease via PI3K\/AKT Mediated Suppression of Oxidative Stress and Inflammation","volume":"10","author":"Wang","year":"2019","journal-title":"Cell Death Dis"},{"key":"B35","doi-asserted-by":"publisher","first-page":"1087","DOI":"10.1038\/s41419-018-1126-4","article-title":"Nimbolide, a Neem Limonoid Inhibits Cytoprotective Autophagy to Activate Apoptosis via Modulation of the PI3K\/Akt\/GSK-3\u03b2 Signalling Pathway in Oral Cancer","volume":"9","author":"Sophia","year":"2018","journal-title":"Cell Death Dis"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2019.105782","article-title":"Naringin Mitigates Myocardial Strain and the Inflammatory Response in Sepsis-Induced Myocardial Dysfunction Through Regulation of PI3K\/AKT\/NF-\u03bab Pathway","volume":"75","author":"Sun","year":"2019","journal-title":"Int Immunopharmacol"},{"key":"B37","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s10753-016-0447-7","article-title":"Indirubin Inhibits LPS-Induced Inflammation via TLR4 Abrogation Mediated by the NF-Kb and MAPK Signaling Pathways","volume":"40","author":"Lai","year":"2017","journal-title":"Inflammation"},{"key":"B38","doi-asserted-by":"publisher","first-page":"292","DOI":"10.1016\/j.jep.2017.07.009","article-title":"Pudilan Xiaoyan Oral Liquid Alleviates LPS-Induced Respiratory Injury Through Decreasing Nitroxidative Stress and Blocking TLR4 Activation Along With NF-\u03bab Phosphorylation in Mice","volume":"214","author":"Feng","year":"2018","journal-title":"J Ethnopharmacol"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.AC118.001720","article-title":"A Malaria Protein Factor Induces IL-4 Production by Dendritic Cells via PI3K-Akt-NF-\u03bab Signaling Independent of Myd88\/TRIF and Promotes Th2 Response","volume":"293","author":"Wu","year":"2018","journal-title":"J Biol Chem"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1016\/j.imbio.2016.08.013","article-title":"Pneumococcal Dnaj Modulates Dendritic Cell-Mediated Th1 and Th17 Immune Responses Through Toll-Like Receptor 4 Signaling Pathway","volume":"222","author":"Wu","year":"2017","journal-title":"Immunobiology"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.2147\/DDDT.S244059","article-title":"Resveratrol Exerts Anti-Osteoarthritic Effect by Inhibiting TLR4\/NF-\u03bab Signaling Pathway via the TLR4\/Akt\/Foxo1 Axis in IL-1\u03b2-Stimulated SW1353 Cells","volume":"14","author":"Xu","year":"2020","journal-title":"Drug Des Devel Ther"},{"key":"B42","doi-asserted-by":"publisher","first-page":"R111","DOI":"10.1186\/ar4291","article-title":"Bacterial Lipopolysaccharides Form Procollagen-Endotoxin Complexes That Trigger Cartilage Inflammation and Degeneration: Implications for the Development of Rheumatoid Arthritis","volume":"15","author":"Lorenz","year":"2013","journal-title":"Arthritis Res Ther"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.913901\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,7,5]],"date-time":"2022-07-05T05:03:15Z","timestamp":1656997395000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.913901\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7,5]]},"references-count":42,"alternative-id":["10.3389\/fimmu.2022.913901"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2022.913901","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,7,5]]},"article-number":"913901"}}