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TLR4 and TNFR1 blockade dampen M1 macrophage activation and shifts them towards an M2 phenotype

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Abstract

The Gram-negative bacterial lipopolysaccharide (LPS)-induced sepsis has emerged as major concern worldwide due to the pressing need to develop its effective treatment strategies which is not available yet. LPS is the major causative agent in the pathogenesis of septic shock. In macrophages, LPS interacts with cell surface TLR4 leading to reactive oxygen species (ROS), TNF-α, IL-1β production, oxidative stress and markedly activated the MAPKs and NF-kB pathway. Post cell isolation, the macrophages were subjected to administration with neutralizing antibodies to TLR4 and TNFR1 either alone or in combination prior to LPS challenge. Subsequently, we performed flow cytometric analysis along with Western blots, reactive oxygen species production, and TNF-α, IL-1β release. Outcomes suggested that the dual blockade of TLR4 and TNFR1 was indeed beneficial in shifting the LPS-induced M1 polarization towards M2. Both TLR4 and TNFR1 exhibited dependency during LPS stimulation. Furthermore, the switch towards the M2 phenotype might be responsible for the decreased levels of TNF-α, IL-1β, NO, and superoxide anion and the simultaneous elevation in the activity level of anti-oxidant enzymes like SOD, CAT (catalase), and GSH content in the isolated peritoneal macrophages. Simultaneous blocking of both TLR4 and TNFR1 also showed reduced expression of NF-kB, JNK, and COX-2 by promoting TNFR2-mediated TNF-α signaling. The increased arginase activity further confirmed the polarization towards M2. Thus it may be inferred that dual blockade of TLR4 and TNFR1 might be an alternative therapeutic approach for regulating of sepsis in future.

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Acknowledgements

The authors are 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. The author is indebted to CRNN (BD Bioscience Room), Kolkata, for allowing us to use the FACS facilities.

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    Ritasha Sawoo, Rajen Dey, Rituparna Ghosh & Biswadev Bishayi

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Sawoo, R., Dey, R., Ghosh, R. et al. TLR4 and TNFR1 blockade dampen M1 macrophage activation and shifts them towards an M2 phenotype. Immunol Res 69, 334–351 (2021). https://doi.org/10.1007/s12026-021-09209-0

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