*4.7. Mechanism of Action of Tacrolimus*

Tacrolimus (FK506) is another important calcineurin inhibitor, known from transplant medicine. In contrast to CsA, which binds to the immunophilin Cyp, tacrolimus binds to the immunophilin called FK-506 binding protein (FKBP12) (Figure 1). Due to tacrolimus, the FKBP forms a complex with the calcium-dependent phosphatase named calcineurin and inhibits the activity of calcineurin. Similar to CsA, tacrolimus has also been shown to have a favorable activity as antifibrotic agent, for example in patients with idiopathic inflammatory myopathy or antisynthetase syndrome- interstitial lung disease (ILD) [53,58]. Interestingly, in animal experiments, upregulated FK506-binding protein 10 (FKBP10) in bleomycin-induced lung fibrosis and IPF improved with knockdown of FKBP10, attenuating collagen secretion [59]. Although no firm conclusions can be drawn yet, tacrolimus also might have an anti-fibrotic activity in COVID-19.

Although clinical trials are still awaited, preliminary clinical experience reports suggest that tacrolimus is protective for liver transplant recipients, but so far not for other organs, for example kidneys. Concerning this observation in tacrolimus, an intriguing question is, if tacrolimus has a different degree of protection against CSS effects in various organs. In other words, is there possibly a specific organ effect, beyond the pharmacokinetics? The various cytokines may play different roles in solid organs. The most important cytokines resulting in CSS in the liver, may be different from the cytokines that are the most important ones in the kidney or lung. This is however still speculative. Nevertheless, in other (non-coronaviral) diseases, the different CNIs (CsA and tacrolimus), when compared to each other, were shown to be discordant in respect to the antiviral effects. This could be the result of the different cytokine profiles addressed by the different CNIs, leading to protection of different organs. Moreover, ACE2 is abundantly present in the lung epithelial cells, and CNIs only have antiviral effects after infection of the target cells, when the virus replication starts in the

cytoplasm. Different ACE2 density could contribute to differences in organ protection by CNIs, called the immunolocalization of ACE2. Another study suggested a different receptor repertoire potentially involved in the SARS-CoV-2 infection at the epithelial barriers and in the immune cells [60]. As mentioned before, the understanding of the pathogenesis is still incomplete.
