The coordinated outcome of STIM1-Orai1 and superoxide signalling is crucial for headkidney macrophage apoptosis and clearance of Mycobacterium fortuitum.

Dev Comp Immunol

Immunobiology Laboratory, Department of Zoology, University of Delhi, Delhi, 110 007, India; Faculty of Life Sciences and Biotechnology, South Asian University, New Delhi, 110 021, India. Electronic address:

Published: January 2021

AI Article Synopsis

  • The study focuses on how M. fortuitum bacteria affect headkidney macrophages (HKM) in the fish Clarias gariepinus by highlighting the importance of TLR-2-mediated processes in the pathogenic response.
  • Disruption of TLR-2 signaling helped reduce HKM cell death, allowing bacteria to survive longer.
  • The research identifies a connection between TLR-2 activation, ER-stress, and specific calcium signaling pathways (STIM1 and Orai1) that further lead to oxidative stress and apoptosis in HKM, critical for managing bacterial infection.

Article Abstract

The mechanisms underlying M. fortuitum-induced pathogenesis remains elusive. Using headkidney macrophages (HKM) from Clarias gariepinus, we report that TLR-2-mediated internalization of M. fortuitum is imperative to the induction of pathogenic effects. Inhibiting TLR-2 signalling alleviated HKM apoptosis, thereby favouring bacterial survival. Additionally, TLR-2-mediated cytosolic calcium (Ca) elevation was instrumental for eliciting ER-stress in infected HKM. ER-stress triggered the activation of membrane-proximal calcium entry channels comprising stromal interaction molecule 1 (STIM1) and calcium-release activated calcium channel 1 (Orai1). RNAi studies suggested STIM1-Orai1 signalling initiate calpain-mediated cleavage of nitric oxide synthase interacting protein, prompting the release of pro-apoptotic nitric oxide. Inhibiting STIM1-Orai1 signalling attenuated superoxide production (O) and vice versa. We conclude, TLR-2-induced ER-stress triggers STIM1/Orai1 expression and that the reciprocal association between STIM1-Orai1 signalling and oxidative stress is critical for sustaining (Ca) level, thereby prolonging ER-stress and maintenance of pro-oxidant rich environment to induce HKM apoptosis and bacterial clearance.

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Source
http://dx.doi.org/10.1016/j.dci.2020.103800DOI Listing

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