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

Kamalakannan, V.; Shiny, A.; Babu, S.; Narayanan, R.B.

PLoS Neglected Tropical Diseases; 2015; 9; e0003675.       

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-a 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.

Author Summary: Despite knowing the significance of Wolbachia in helminth infections, our understanding of immunity and pathogenesis remains incomplete. Therefore, considering the gravity of the problem, the present study provides evidence that Wolbachia heat shock protein 60 induces apoptosis and senescence through TLR-4. Also, binding of rWmhsp60 to TLR-4 triggered caspase cascade activation following, ROS-mediated mitochondrial potential loss. Moreover, we found that nuclear translocation of NF-?B p65 was predominantly related to TLR-4 expression and resulted in apoptosis- and senescence-mediated inflammation via TNF-a and IL-6. Hence, we hypothesized that modifying TLR-4 expression may provide a plausible target for designing antiparasitic drugs. Here we have shown that induction of autophagy by rapamycin destabilizes TLR-4 expression and protects monocytes from rWmhsp60-induced apoptosis and senescence. In addition, rapamycin-induced monocytes were unresponsive to rWmhsp60 and triggered lymphocyte activation after PHA stimulation. Thus, synergistic usage of rapamycin with existing anti-filarial drugs might reduce the TLR-mediated inflammatory reactions following microfilaricidal treatment.

Back to List of publications / Home