An aggrecan fragment drives osteoarthritis pain through Toll-like receptor 2

AbstractPain is the predominant symptom of osteoarthritis, but the connection between joint damage and the genesis of pain is not well understood. Loss of articular cartilage is a hallmark of osteoarthritis, and it occurs through enzymatic degradation of aggrecan by ADAMTS-4/5-mediated cleavage in the interglobular domain (E373-374 A). Further cleavage by MMPs (N341-342 F) releases a 32-amino-acid aggrecan fragment (32-mer). We investigated the role of this 32-mer in driving joint pain. We demonstrated that the 32-mer excites dorsal root ganglion (DRG) nociceptive neurons, both in culture and in intact explants. Treatment of cultured sensory neurons with the 32-mer induced them to express the pro-algesic chemokine, MCP-1/CCL2. These effects were mediated through Toll-like receptor (TLR)2, which we demonstrated was expressed by nociceptive neurons. In addition, intra-articular injection of the 32-mer provoked knee hyperalgesia in wild-type but not Tlr2 null mice. Blocking the production or action of the 32-mer in transgenic mice prevented the development of knee hyperalgesia in a murine model of osteoarthritis. These findings suggest that the aggrecan 32-mer fragment directly activates TLR2 on joint nociceptors and is an important mediator of the development of osteoarthritis-associated joint pain.

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Toll-Like Receptor 2 is Involved in Abnormal Pregnancy in Mice Infected with Toxoplasma gondii During Late Pregnancy

Frontiers in Microbiology ◽

10.3389/fmicb.2021.741104 ◽

2021 ◽

Vol 12 ◽

Author(s):

Rina Ikeda ◽

Nanako Ushio ◽

Ahmed M. Abdou ◽

Hidefumi Furuoka ◽

Yoshifumi Nishikawa

Keyword(s):

Toxoplasma Gondii ◽

Premature Birth ◽

Disease Onset ◽

Congenital Toxoplasmosis ◽

Late Pregnancy ◽

Toll Like Receptor ◽

Wild Type ◽

Abnormal Pregnancy ◽

Toll Like Receptor 2

Infection with Toxoplasma gondii during pregnancy causes failure of pregnancy maintenance, resulting in fetal death, abortion, stillbirth, or premature birth, but the mechanism of disease onset remains unclear. Although Toll-like receptor 2 (TLR2) is expressed on antigen-presenting cells and trophoblasts, the role of TLR2 in T. gondii infection during pregnancy is unknown. In this study, we investigated the role of TLR2 in congenital toxoplasmosis using TLR2-deficient (TLR2−/−) mice. T. gondii infection on gestational day 12.5 (Gd12.5) induced more abnormal pregnancy, including premature birth and stillbirth, in wild-type mice than in TLR2−/− mice. Multiple calcifications were observed in the placentas of the infected wild-type mice. At Gd18.5 (6days postinfection), the parasite numbers in the placenta and uterus and the histological changes did not differ significantly between the wild-type and TLR2−/− mice. However, T. gondii infection reduced the mRNA expression of interleukin-12p40 (IL-12p40) and increased IL-4 and IL-10 mRNAs in the placentas of the wild-type mice. In contrast, the placentas of the TLR2−/− mice showed no changes in the expression of these cytokines, including IL-6 and tumor necrosis factor α, in response to T. gondii infection. Serum interferon-γ levels were significantly lower in the infected TLR2−/− mice than in the infected wild-type mice on Gd18.5. Thus, the TLR2−/− mice were less susceptible to the induction of immune responses by T. gondii infection during late pregnancy. Therefore, TLR2 signaling may play a role in the development of disease states during pregnancy, specifically placental hypofunction.

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Abstract 169: Activation of the Phosphoinositide 3-Kinase/Akt Pathway is Responsible for Cardioprotection Induced by Modulation of TLR2

Circulation ◽

10.1161/circ.116.suppl_16.ii_11-c ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Chuanfu Li ◽

Fang Hua ◽

Tuanzhu Ha ◽

Jing Ma ◽

Jim Kelley ◽

...

Keyword(s):

Ischemic Injury ◽

Akt Signaling ◽

Toll Like Receptor ◽

Akt Signaling Pathway ◽

Wild Type ◽

Tlr2 Ligand ◽

Toll Like Receptor 2 ◽

Phosphoinositide 3 Kinase ◽

Dependent Mechanism

Activation of the phosphoinositide-3 kinase/Akt (PI3K/Akt) signaling pathway protects cells from ischemic injury. We have reported that the immune modulator, glucan, rapidly induces cardioprotection. Dectin-1 is a specific receptor for glucan and Toll-like receptor 2 (TLR2) is required for transmitting the signal from Dectin-1 into cells. However, the role of modulation of TLR2 in cardioprotection has not been investigated. We hypothesized that modulation of TLR2 will induce cardioprotection through a PI3K/Akt-dependent mechanism. To evaluate our hypothesis, we examined the effect of modulation of TLR2 on myocardial ischemic injury. TLR2 knockout (KO) (n=8) and wild type mice (n=8) were treated with glucan (1 mg/25g) or peptidoglycan (PDG, 75 μg/25g), a specific TLR2 ligand, one hr before the hearts were subjected to ischemia (1 hr)/reperfusion (4 hrs). Untreated mice (n=8) were also subjected to I/R. Myocardial infarction was determined by TTC staining. Infarct size was significantly reduced in glucan (11.6 ± 2.38% vs 36.1 ± 3.48%, p<0.01) and PDG (10.5 ± 3.03% vs 30.1 ± 7.59%, p<0.01) treated mice vs untreated mice. The levels of phospho-Akt (0.80 ± 0.10 vs 0.45 ± 0.09) and phospho-GSK3β (0.66 ± 0.14 vs 0.33 ± 0.10) were significantly increased in the myocardium of glucan treated mice compared with untreated mice. However, both glucan and PDG-induced cardioprotection were completely abolished in TLR2 KO mice. To investigate whether PI3K/Akt signaling is involved in cardioprotection induced by modulation of TLR2, we administered glucan (1 mg/25g) or PDG (75 μg/25g) to kdAkt (kinase deficient Akt) transgenic mice (n=8) one hr before myocardial I/R. Both glucan and PDG-induced cardioprotection were completely abolished in kdAkt mice. The results suggest that modulation of TLR2, either directly or indirectly, will induce cardioprotection through a PI3K/Akt dependent mechanism and that there is a critical link between TLR2 and PI3K/Akt signaling during myocardial I/R.

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