Innate/Inflammatory Bioregulation of Surfactant Protein D Alleviates Rat Osteoarthritis by Inhibiting Toll-Like Receptor 4 Signaling

Abstract

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 Ca2+-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 in vivo. SP-D alleviated the infiltration of synovial macrophages and neutrophils, and inhibited TLR4, TNF-α and the phosphorylation of PI3K, Akt and NF-κB p65 in cartilage. SP-D suppressed cartilage degeneration, inflammatory and immune responses in the rat OA model, whilst TAK-242 strengthened this improvement. In in vitro conditions, SP-D pre-treatment inhibited LPS-induced overproduction of inflammation-correlated cytokines such as IL-1β and TNF-α, 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-κB signaling activation in chondrocytes. Taken together, these findings indicate that SP-D has chondroprotective properties dependent on TLR4-mediated PI3K/Akt and NF-κB signaling and that SP-D has an optimal bioregulatory effect on the inflammatory and innate responses in OA.

Injectable Ozone‐Rich Nanocomposite Hydrogel Loaded with D‐Mannose for Anti‐Inflammatory and Cartilage Protection in Osteoarthritis Treatment

“…Macrophages proliferate excessively and are abnormally recruited locally to joints during OA development. [ 34 ] In this study, a CCK‐8 assay and Edu staining were used to measure the proliferation of RAW 264.7 treated with different hydrogel groups. The results showed no significant differences in cell proliferation among the LPS, blank NPs@HPCH, O 2 NPs@HPCH, O 3 NPs@HPCH, and control groups.…”

Resatorvid alleviates experimental inflammatory TMJOA by restraining chondrocyte pyroptosis and synovial inflammation

“…The findings of this study regarding the protective effect of Resatorvid in an experimental inflammatory TMJOA model have not been documented but have been reported in knee OA and rheumatoid arthritis (RA) pathogenesis. Jiang’s study verified that administration of Resatorvid suppressed cartilage degeneration and inflammatory and immune responses in a rat OA model [ 30 ]. Samarpita et al confirmed that Resatorvid significantly reversed the body weight and paw thickness of adjuvant-induced arthritis (AIA) rats to the normal state, reduced the increased serum inflammatory factor levels, and ameliorated joint inflammatory symptoms [ 31 ].…”

Emerging Roles of Macrophage Polarization in Osteoarthritis: Mechanisms and Therapeutic Strategies

“…Emerging evidence has shown the critical role of the NF‐κB pathway in M1 polarization and subsequently inflammatory cytokine release, such as IL‐1β, IL‐6 and TNF‐α 70,71 . In OA, when PAMPs from microorganisms or DAMPs from damaged tissue are released, the activation of Toll‐like receptors (TLRs) leads to the M1 polarization, which is regulated via the TLR/NF‐κB signaling pathway 72 . This implies that the block of TLRs might be a potential target for not only M1 polarization but also a promising OA therapy.…”

“… 70 , 71 In OA, when PAMPs from microorganisms or DAMPs from damaged tissue are released, the activation of Toll‐like receptors (TLRs) leads to the M1 polarization, which is regulated via the TLR/NF‐κB signaling pathway. 72 This implies that the block of TLRs might be a potential target for not only M1 polarization but also a promising OA therapy. Berberine was found to inhibit M1 polarization through a block of the TLR4/MyD88/NF‐κB signaling pathway and attenuate inflammation in the early phase.…”