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Autophagy protects monocytes from Wolbachia heat shock protein 60-induced apoptosis and senescence.

ABSTRACT: Monocyte dysfunction by filarial antigens has been a major mechanism underlying immune evasion following hyporesponsiveness during patent lymphatic filariasis. Recent studies have initiated a paradigm shift to comprehend the immunological interactions of Wolbachia and its antigens in inflammation, apoptosis, lymphocyte anergy, etc. Here we showed that recombinant Wolbachia heat shock protein 60 (rWmhsp60) interacts with TLR-4 and induces apoptosis in monocytes of endemic normal but not in chronic patients. Higher levels of reactive oxygen species (ROS) induced after TLR-4 stimulation resulted in loss of mitochondrial membrane potential and caspase cascade activation, which are the plausible reason for apoptosis. Furthermore, release in ROS owing to TLR-4 signaling resulted in the activation of NF-?B p65 nuclear translocation which leads to inflammation and apoptosis via TNF receptor pathway following the increase in IL-6 and TNF-? level. Here for the first time, we report that in addition to apoptosis, rWmhsp60 antigen in filarial pathogenesis also induces molecular senescence in monocytes. Targeting TLR-4, therefore, presents a promising candidate for treating rWmhsp60-induced apoptosis and senescence. Strikingly, induction of autophagy by rapamycin detains TLR-4 in late endosomes and subverts TLR-4-rWmhsp60 interaction, thus protecting TLR-4-mediated apoptosis and senescence. Furthermore, rapamycin-induced monocytes were unresponsive to rWmhsp60, and activated lymphocytes following PHA stimulation. This study demonstrates that autophagy mediates the degradation of TLR-4 signaling and protects monocytes from rWmhsp60 induced apoptosis and senescence.

SUBMITTER: Kamalakannan V

PROVIDER: S-EPMC4388636 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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Autophagy protects monocytes from Wolbachia heat shock protein 60-induced apoptosis and senescence.

Kamalakannan Vijayan V Shiny Abijit A Babu Subash S Narayanan Rangarajan Badri RB

PLoS neglected tropical diseases 20150407 4

Monocyte dysfunction by filarial antigens has been a major mechanism underlying immune evasion following hyporesponsiveness during patent lymphatic filariasis. Recent studies have initiated a paradigm shift to comprehend the immunological interactions of Wolbachia and its antigens in inflammation, apoptosis, lymphocyte anergy, etc. Here we showed that recombinant Wolbachia heat shock protein 60 (rWmhsp60) interacts with TLR-4 and induces apoptosis in monocytes of endemic normal but not in chroni ...[more]

PMID: 25849993

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Project description:BACKGROUND:Bone marrow mesenchymal stem cells (BMSCs) can partially repair chemotherapy-induced ovarian damage. However, low survival rate after transplantation hampers the therapeutic efficiency of BMSCs. Heat shock pretreatment (HSP) effectively improves the cell survival. This study attempted to investigate the mechanisms of HSP on BMSCs survival and the effects of heat shock-pretreated BMSCs (HS-MSCs) on cisplatin-induced granulosa cell (GC) apoptosis. METHODS:BMSCs were isolated, cultured, and identified. After receiving HSP for different duration times in a 42 °C water bath, the apoptotic rates of BMSCs were detected by Annexin V-FITC/PI to determine the optimal condition of HSP. Cisplatin was added to the medium of HS-MSCs to simulate chemotherapy environment. The proliferative curve, apoptotic rate, and viability of HS-MSCs were determined by CCK-8, Annexin V-FITC/PI, and Hoechst33342/PI respectively to explore the alteration of biological characteristics. The levels of heat shock protein 70 and 90 (HSP70 and HSP90) and the expressions of autophagy-related markers (Beclin1 and LC3B) were detected by Western blot. In addition, the autophagosomes were observed by transmission electronic microscopy to discuss the possible mechanisms. The GCs were isolated, cultured, and identified. The HS-MSCs were co-cultured with GCs before and after the addition of cisplatin. Then, the apoptotic rate and viability of GCs were detected to investigate the therapeutic and preventive effects of HS-MSCs on GC apoptosis. RESULTS:After receiving HSP at 42 °C for 1?h, BMSCs represented the lowest apoptotic rate. After the addition of cisplatin, the apoptotic rate of HS-MSCs (11.94%?±?0.63%) was lower than that of BMSCs (14.30%?±?0.80%) and the percentage of HS-MSCs expressing bright blue/dull red fluorescence was lower than that of BMSCs. The expression of HSP70 and HSP90 increased, while the number of autophagosomes, the expression of Beclin1, and the LC3BII/LC3BI ratio decreased in HS-MSCs. The apoptotic rates of GCs co-cultured with HS-MSCs before and after the addition of cisplatin were 39.88%?±?1.65% and 36.72%?±?0.96%, both lower than those of cisplatin-induced GCs (53.81%?±?1.89%). CONCLUSION:HSP can alleviate the apoptosis and improve the survival of BMSCs under chemotherapy environment. The mechanism may be associated with the elevated expression of HSP70 and HSP90 and the attenuation of autophagy. Moreover, HS-MSCs have both therapeutic and preventive effects on cisplatin-induced GC apoptosis.

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Autophagy protects monocytes from Wolbachia heat shock protein 60-induced apoptosis and senescence.

Publications

Autophagy protects monocytes from Wolbachia heat shock protein 60-induced apoptosis and senescence.

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