Abstract
Inter-species variations in structure and function of molecules and receptors important in innate immunity have been investigated quite well in the past years. A prominent example is the species-specific activation of the TLR4/MD-2 receptor complex by structurally different lipid A or its precursor lipid IVA, which represents an important intermediate in lipid A biosynthesis. Lipid IVA acts antagonistic in humans but agonistic in mouse. This difference in action is due to structural differences between human and mouse TLR4/MD-2.
One highly important branch of the innate immune system is the complement system that ensures a strong host defense after having recognized pathogens. Complement comprises a higher number of serum proteins that, after activation, act in a reaction cascade. This system can be activated by three different pathways, leading to the production of several active components. Recently, it could be shown that, in certain infectious and chronic inflammatory disorders, particular complement products are able to interact directly with other innate immune signaling molecules, like TLR.
In this article, authors clearly prove important functional differences between rodent and human complement that are thought to contribute to the different immune responses of rats and humans. They show that human and rat complement differed in the modulation of the inflammatory response to Neisseria gonorrhoeae, and to certain PAMPs. Contrary to human serum, which had no or sometimes an up-regulating effect, rat serum down-regulated MyD88-dependent pro-inflammatory cytokine responses in macrophages. This inhibitory effect of rat serum was due to complement C3a–C3a receptor interactions which reduced NF-κB and NLRP3 inflammasome-mediated caspase-1 activation.