title: 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-κB p65 nuclear translocation which leads to inflammation and apoptosis via TNF receptor pathway following the increase in IL-6 and TNF-α 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.
authors: Centre for Biotechnology, Anna University, Chennai, Tamil Nadu, India.
authors: Vijayan
authors: V
authors: Kamalakannan
authors: Madras Diabetes Research Foundation and Dr. Mohan's Diabetes Specialties Centre, Chennai, Tamil Nadu, India.
authors: Abijit
authors: A
authors: Shiny
authors: National Institutes of Health-National Institute for Research in Tuberculosis-International Center for Excellence in Research, National Institute for Research in Tuberculosis, Chetpet, Chennai, Tamil Nadu, India.
authors: Subash
authors: S
authors: Babu
authors: Centre for Biotechnology, Anna University, Chennai, Tamil Nadu, India.
authors: Rangarajan Badri
authors: RB
authors: Narayanan
mesh_terms: D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001343:Autophagy; D018834:Chaperonin 60 / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D007249:Inflammation; D015850:Interleukin-6; D008214:Lymphocytes; D008297:Male; D053078:Membrane Potential, Mitochondrial; D009000:Monocytes / Q000187:drug effects* / Q000502:physiology; D016328:NF-kappa B / Q000378:metabolism; D020011:Protective Agents; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha; D020577:Wolbachia / Q000378:metabolism*
chemical_list: D018834:Chaperonin 60; D015850:Interleukin-6; D016328:NF-kappa B; D020011:Protective Agents; D017382:Reactive Oxygen Species; C439524:TNF protein, human; D014409:Tumor Necrosis Factor-alpha