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Regulation of Staphylococcus aureus-induced CXCR1 expression via inhibition of receptor mobilization and receptor shedding during dual receptor (TNFR1 and IL-1R) neutralization

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Abstract

Our earlier studies proposed a radically new idea suggesting interdependency between TNF-α/TNFR1 and IL-1β/IL-1R pathways in modulation of Staphylococcus aureus-induced CXCL8/CXCR1 axis. However, the effects of inhibition of cytokine receptor mobilization at intracellular level and surface TNFR1 and IL-1R shedding on S. aureus-induced CXCR1 expression have not been studied so far in peritoneal macrophages. This study aimed to investigate the role of inhibition of receptor mobilization from the intracellular pool (using brefeldin A) and surface receptor shedding (using TAPI-1) on CXCR1 expression during dual receptor (TNFR1 plus IL-1R) neutralization in peritoneal macrophages isolated from wild-type Swiss Albino mice. Release of superoxide anion, nitric oxide, and hydrogen peroxide was measured and cytokine production was done by ELISA. Expression of surface receptors (TNFR1, IL-1R, and CXCR1) and inflammatory mediators was studied by Western blot. It was observed that S. aureus-infected macrophages showed elevated ROS production, secretion of TNF-α, IL-1β, and CXCL8, along with increased expression of surface receptors (TNFR1, IL-1R, and CXCR1), and inflammatory markers (iNOS and COX-2) compared with control or treated groups (p < 0.05). However, prior treatment of macrophages with BFA or TAPI-1 in the presence of anti-TNFR1 antibody and IRAP during S. aureus infection showed significant reduction of all these parameters (p < 0.05). We can conclude that targeting of TNFR1 and IL-1R (with major focus on surface expression study) either through blockage of intracellular receptor trafficking pathway or via surface receptor shedding diminishes TNFR1/IL-1R interaction and consequently downregulates CXCR1 expression along with inflammatory signalling pathways during bacterial infections.

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Acknowledgments

The author thanks the University Grants Commission (UGC), Government of India, New Delhi, India for funding this project under the University for potential of excellence (UPE) scheme in the UGC UPE II grant: Focus area: Modern Biology Group C2: Mechanistic and therapeutic aspects of infectious diseases (Sanctioned No. UGC/856/UPE-2/MOD BIO/2nd Inst dated 18 Sept 2017). The author is indebted to, Department of Science and Technology, Government of India for providing us with the instruments procured under the DST-PURSE programme to the Department of Physiology, University of Calcutta.

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  1. Department of Physiology, Immunology Laboratory, University of Calcutta, University Colleges of Science and Technology, 92 APC Road, Calcutta, West Bengal, 700009, India

    Puja Dutta, Sahin Sultana, Rajen Dey & Biswadev Bishayi

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  1. Puja Dutta
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Dutta, P., Sultana, S., Dey, R. et al. Regulation of Staphylococcus aureus-induced CXCR1 expression via inhibition of receptor mobilization and receptor shedding during dual receptor (TNFR1 and IL-1R) neutralization. Immunol Res 67, 241–260 (2019). https://doi.org/10.1007/s12026-019-09083-x

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