Estradiol Promotes M1-like Macrophage Activation through Cadherin-11 To Aggravate Temporomandibular Joint Inflammation in Rats

Abstract

Macrophages play a major role in joint inflammation. Estrogen is involved in rheumatoid arthritis and temporomandibular disorders. However, the underlying mechanism is still unclear. This study was done to verify and test how estrogen affects M1/M2-like macrophage polarization and then contributes to joint inflammation. Female rats were ovariectomized and treated with increasing doses of 17β-estradiol for 10 d and then intra-articularly injected with CFA to induce temporomandibular joint (TMJ) inflammation. The polarization of macrophages and expression of cadherin-11 was evaluated at 24 h after the induction of TMJ inflammation and after blocking cadherin-11 or estrogen receptors. NR8383 macrophages were treated with estradiol and TNF-α, with or without blocking cadherin-11 or estrogen receptors, to evaluate the expression of the M1/M2-like macrophage-associated genes. We found that estradiol increased the infiltration of macrophages with a proinflammatory M1-like predominant profile in the synovium of inflamed TMJ. In addition, estradiol dose-dependently upregulated the expressions of the M1-associated proinflammatory factor inducible NO synthase (iNOS) but repressed the expressions of the M2-associated genes IL-10 and arginase in NR8383 macrophages. Furthermore, estradiol mainly promoted cadherin-11 expression in M1-like macrophages of inflamed TMJ. By contrast, blockage of cadherin-11 concurrently reversed estradiol-potentiated M1-like macrophage activation and TMJ inflammation, as well as reversed TNF-α–induced induction of inducible NO synthase and NO in NR8383 macrophages. The blocking of estrogen receptors reversed estradiol-potentiated M1-like macrophage activation and cadherin-11 expression. These results suggested that estradiol could promote M1-like macrophage activation through cadherin-11 to aggravate the acute inflammation of TMJs.

Sexual dimorphism of estrogen‐sensitized synoviocytes contributes to gender difference in temporomandibular joint osteoarthritis

“…Female rats have higher levels of plasma estrogen than male rats, and previous studies showed that estrogen aggravates TMJ inflammation and TMJOA (Kou et al., , ; Wang, Kou, He et al., ). We hypothesized that estrogen might contribute to the enhanced sensitivity of female FLSs to response to inflammatory stimulus.…”

“…TMJOA is approximately twice as prevalent (and more severe) in women than in men (Carlsson, ; Israel et al., ; Stegenga et al., ; Zhao, & Ma, ). It is not surprising that previous studies have tried to explain the sex difference in TMJOA prevalence by focusing on sex hormones, such as estrogen, which has been considered to play an important role in the symptomatology of female‐predominant TMDs, synovitis, chondrocyte apoptosis, and inflammatory pain (Flake, Hermanstyne, & Gold, ; Guan, Kerins, Bellinger, & Kramer, ; Kou et al., , , ; Wang et al., ; Wu et al., ). The TMJ synovial membrane consists of a condensed one‐ to three‐cell‐thick lining layer of synoviocytes that overlies the loose connective tissue of the synovial sublining (Nozawa‐Inoue et al., ).…”

Genes expression profiling of alveolar macrophages exposed to non-functionalized, anionic and cationic multi-walled carbon nanotubes shows three different mechanisms of toxicity

“…Cell culture NR8383 rat alveolar macrophages were purchased from American Type Culture Collection (ATCC ® CRL2192 ™ ; Manassas; USA). Cells were cultured in Dulbecco's Modified Eagle Medium DMEM, high glucose [27,28] (Sigma-Aldrish; St. Louis; USA), supplemented with 15% Fetal Bovine Serum, FBS (Sigma-Aldrish; St. Louis; USA), 100 U/mL penicillin and 100 g/mL streptomycin, 4 mM l-glutamine and 0.25 μg/mL of amphotericin B (Sigma-Aldrish; St. Louis; USA). Cells were cultured at 37 °C in humidified chamber with 5% CO 2 .…”

Estrogen induces multiple regulatory B cell subtypes and promotes M2 microglia and neuroprotection during experimental autoimmune encephalomyelitis

“…During the later phase of disease, alternatively activated macrophages (M2) release anti-inflammatory cytokines and promote tissue repair (Gordon, 2003, Jiang et al, 2014, Mikita et al, 2011, Miron et al, 2013, Miron and Franklin, 2014). However, estrogen effects on the M1:M2 ratio is controversial; while some reported that estrogen induces M1 phenotype in macrophages; others have shown that estrogen treatment promotes M2 phenotype in microglia (Drew et al, 2003, Habib and Beyer, 2015, Kou et al, 2015, Toniolo et al, 2015). Furthermore, the effect of estrogen treatment on microglia during EAE has not been demonstrated.…”