The role of TLR9 in stress-dependent autophagy formation

Lim, Jae Sung; Kim, Hyeon Sik; Nguyen, Kim Cuc Thi; Cho, Kyung A

doi:10.1016/j.bbrc.2016.10.105

Cited by 13 publications

(7 citation statements)

References 27 publications

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“…Our previous study showed that CtsK is closely related to TLR9 in the development of arthritis and periodontitis-aggravating arthritis (19). At the same time, a relationship between TLR9 and autophagy has also been demonstrated (21,33,34). Sanjuan et al revealed that stimulating RAW264.7 cells with a TLR9 ligand promotes the maturation of phagosomes, which then participate in autophagy (35).…”

Section: Discussionmentioning

confidence: 97%

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Inhibition of Cathepsin K Alleviates Autophagy-Related Inflammation in Periodontitis-Aggravating Arthritis

et al. 2020

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Objective: Rheumatoid arthritis (RA) and periodontitis share many common epidemiological and pathological features with emerging studies reporting a relationship between the two diseases. Recently, RA and periodontitis have been associated with autophagy. In the current study, we investigated the effects of cathepsin K (CtsK) inhibition on RA with periodontitis in a mouse model and its immunological function affecting autophagy. Methods: To topically inhibit CtsK periodontitis with arthritis in the animal model, adeno-associated virus (AAV) transfection was performed in periodontal and knee joint regions. Transfection of small interfering RNA (siRNA) was performed to inhibit CtsK in RAW264.7 cells. The effects of CtsK inhibition on the autophagy pathway were then evaluated in both the in vivo and in vitro experiments. Results: RA and periodontitis aggravated destruction and inflammation in their respective lesion areas. Inhibition of CtsK had multiple effects: 1) reduced destruction of alveolar bone and articular tissue; 2) decreased macrophage numbers and inflammatory cytokine expression in the synovium; and 3) alleviated expression of autophagy related transcription factor EB (TFEB) and microtubule-associated protein 1A/1B-light chain 3 (LC3) at the protein level in knee joints. Inhibition of CtsK in vitro reduced the expression of autophagy-related proteins and related inflammatory factors. Conclusion: Our data revealed that the inhibition of CtsK resisted the destruction of articular tissues and relieved inflammation of RA with periodontitis. Furthermore, CtsK was implicated as an imperative regulator of the autophagy pathway in RA and macrophages.

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Section: Discussionmentioning

confidence: 97%

“…Our previous study revealed that the osteoimmunological function of CtsK regulates both periodontitis and RA through the Toll-like receptor 9 (TLR9) signaling pathway (19). Whereas TLR9 is closely related to autophagy (20,21), it is likely that CtsK also affects the autophagy response in RA.…”

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confidence: 99%

Inhibition of Cathepsin K Alleviates Autophagy-Related Inflammation in Periodontitis-Aggravating Arthritis

et al. 2020

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“…Second, the depression-like behavior-preventing effects associated with intra-VH 3-MA administration could be due to the quick toll-like receptor 9 (TLR9) recruitment-inhibiting and/or oxidative stress-relieving character of 3-MA. After all, a previous report has indicated LC3II may reciprocally activate the TLR9 in a fast mode at the early stage of mitochondrial autophagy [ 43 ]. And TLR9 activation has been lately revealed to significantly induce cellular oxidative stress [ 44 ].…”

Section: Discussionmentioning

confidence: 99%

Stress while lacking of control induces ventral hippocampal autophagic flux hyperactivity and a depression-like behavior

et al. 2022

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“…The mechanisms involved could include effects on tumor immunity, tumor invasion, or autophagy. [ 3 , 10 , 15 , 51 ] There may however be, SNP-based modifications of the effect of TLR9 on these cellular processes among AA TNBC patients. This could explain the lack of protection that tumor TLR9 provides in other ethnic groups.…”

Section: Discussionmentioning

confidence: 99%

Lower frequency of TLR9 variant associated with protection from breast cancer among African Americans

et al. 2017

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IntroductionToll-like receptor 9 (TLR9) is an innate immune system DNA-receptor that regulates tumor invasion and immunity in vitro. Low tumor TLR9 expression has been associated with poor survival in Caucasian patients with triple negative breast cancer (TNBC). African American (AA) patients with TNBC have worse prognosis than Caucasians but whether this is due to differences in tumor biology remains controversial. We studied the prognostic significance of tumor Toll like receptor-9 (TLR9) protein expression among African American (AA) triple negative breast cancer (TNBC) patients. Germline TLR9 variants in European Americans (EAs) and AAs were investigated, to determine their contribution to AA breast cancer risk.MethodsTLR9 expression was studied with immunohistochemistry in archival tumors. Exome Variant Server and The Cancer Genome Atlas were used to determine the genetic variation in the general EA and AA populations, and AA breast cancer cases. Minor allele frequencies (MAFs) were compared between EAs (n = 4300), AAs (n = 2203), and/or AA breast cancer cases (n = 131).ResultsThirty-two TLR9 variants had a statistically significant MAF difference between general EAs and AAs. Twenty-one of them affect a CpG site. Rs352140, a variant previously associated with protection from breast cancer, is more common in EAs than AAs (p = 2.20E-16). EAs had more synonymous alleles, while AAs had more rare coding alleles. Similar analyses comparing AA breast cancer cases with AA controls did not reveal any variant class differences; however, three previously unreported TLR9 variants were associated with late onset breast cancer. Although not statistically significant, rs352140 was observed less frequently in AA cases compared to controls. Tumor TLR9 protein expression was not associated with prognosis.ConclusionsTumor TLR9 expression is not associated with prognosis in AA TNBC. Significant differences were detected in TLR9 variant MAFs between EAs and AAs. They may affect TLR9 expression and function. Rs352140, which may protect from breast cancer, is 1.6 X more common among EAs. These findings call for a detailed analysis of the contribution of TLR9 to breast cancer pathophysiology and health disparities.

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The role of TLR9 in stress-dependent autophagy formation

Cited by 13 publications

References 27 publications

Inhibition of Cathepsin K Alleviates Autophagy-Related Inflammation in Periodontitis-Aggravating Arthritis

Inhibition of Cathepsin K Alleviates Autophagy-Related Inflammation in Periodontitis-Aggravating Arthritis

Stress while lacking of control induces ventral hippocampal autophagic flux hyperactivity and a depression-like behavior

Lower frequency of TLR9 variant associated with protection from breast cancer among African Americans

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