Cathelicidins and the regulation of the innate immune system

Summary

Cathelicidins are part of the innate host defence system and play an important role in the protection against invading pathogens. While initially identified as antimicrobial peptides, cathelicidins have been shown to exert various immunomodulatory functions as well. In this thesis, we aimed to identify the underlying mechanisms behind the regulatory effect of cathelicidins during immune activation, with an emphasis on the regulation of TLR activation. This includes an initial comparison of 12 cathelicidins from 6 different species on known cathelicidin functions, such as antimicrobial activity, regulation of TLR activation and induction of chemokine expression. Furthermore, the mechanisms behind enhancement of DNA-induced TLR9/21 activation by the chicken cathelicidin-2 (CATH-2) were analyzed in detail, showing the importance of endosomal cathelicidin degradation to increase TLR9/21 activation. To better understand the role of cathelicidins during infections, the effect of cathelicidins on E. coli-induced macrophage activation was analyzed as well. This led to the observation that cathelicidins only inhibit E. coli-induced immune activation when bacteria have lost their viability. This inhibition is the result of direct interaction between cathelicidins and bacterial outer membrane components (LPS and lipoproteins), which prevents TLR4 and TLR2 activation. In addition, the inhibitory effect of cathelicidins on immune activation by Gram-negative bacteria was tested in a murine model, which showed that killing of P. aeruginosa by CATH-2 limits in vivo lung inflammation.

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