Jacareubin inhibits TLR4-induced lung inflammatory response caused by the RBD domain of SARS-CoV-2 Spike protein

Abstract

Background COVID-19, the disease caused by SARS-CoV-2 virus infection, has been a major public health problem worldwide in the last 2 years. SARS-CoV-2-dependent activation of innate immune receptors contributes to the strong local and systemic inflammatory reaction associated with rapid disease evolution. The receptor-binding domain (RBD) of Spike (S) viral protein (S-RBD) is essential for virus infection and its interacting molecules in target cells are still under identification. On the other hand, the search for accessible natural molecules with potential therapeutic use has been intense and remains an active field of investigation. Methods C57BL6/J (control) and Toll-like receptor (TLR) 4-deficient ( Lps del ) mice were nebulized with recombinant S-RBD. Tumor Necrosis Factor-alpha (TNF-α) and Interleukin (IL)-6 production in bronchoalveolar lavages (BALs) was determined by enzyme-linked immunosorbent assay (ELISA). Lung-infiltrating cells recovered in BALs were quantified by hematoxylin–eosin (H&E) stain. In selected groups of animals, the natural compound Jacareubin or dexamethasone were intraperitoneally (ip) administered 2 hours before nebulization. Results A rapid lung production of TNF-α and IL-6 and cell infiltration was induced by S-RBD nebulization in control but not in Lps del mice. Pre-treatment with Jacareubin or dexamethasone prevented S-RBD-induced TNF-α and IL-6 secretion in BALs from control animals. Conclusions S-RBD domain promotes lung TNF-α and IL-6 production in a TLR4-dependent fashion in C57BL6/J mice. Xanthone Jacareubin possesses potential anti-COVID-19 properties that, together with the previously tested anti-inflammatory activity, safety, and tolerance, make it a valuable drug to be further investigated for the treatment of cytokine production caused by SARS-CoV-2 infection. Supplementary Information The online version contains supplementary material available at 10.1007/s43440-022-00398-5.

SARS-CoV-2 spike receptor-binding domain is internalized and promotes protein ISGylation in human induced pluripotent stem cell-derived cardiomyocytes

“…It has been revealed that mRNA vaccines can result in spike protein expression in the muscle tissue, as well as in the lymphatic system and other cells including cardiomyocytes after entry into the circulation 20 . S-RBD is a key domain of spike protein which binds to ACE2 and has been implicated in inflammation 30 , 31 . In the human heart tissue, ACE2 is expressed in the cardiomyocytes and pericytes and human iPSC-CMs express ACE2 33 , suggesting that the human isogenic iPSC-CMs are a useful experimental tool.…”

“…S-RBD promoted the activation and maturation of human dendritic cells with the activation of NF-kβ pathway 29 . S-RBD also significantly aggravated lipopolysaccharide-induced acute lung injury in an in vivo mouse model through NF-kβ pathway 30 , 31 . However, the effects of S-RBD on the innate immune response of cardiomyocytes have not yet been elucidated.…”