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  • Pattern recognition receptors key elements in the innate

    2021-09-18

    Pattern recognition receptors - key elements in the innate immune response Every day, human beings are exposed to a broad range of microbes and foreign substances. Most of them are entirely harmless, however, some are pathogenic and have the potential to cause severe harm. The distinction between “harmful” and “harmless” is essential to ensure the rapid and thorough elimination of the (potential) microbial threats while leaving the host organism (mostly) uncompromised. Our adaptive immune system has the impressive ability to learn and memorize perceived microbial dangers/threats, and in turn to provide long-lasting protection against a particular pathogen that is capable of eliciting adaptive immune responses. This sophisticated and highly specific defense mechanism, however, takes days or sometimes even weeks to become established [1]. Therefore, early recognition of the pathogen and the immediate initiation of effective counter-attacks by the host organism are mediated via the innate immune system, which acts as the first line of defense against any kind of pathogenic threat [2]. Expressed primarily on the surface of innate immune cells, germline-encoded PRRs detect molecular structures present in proteins, nucleic acids, lipids, and Phenacetin that are characteristic not for a single pathogen, but instead represent conserved structural features defining entire classes of related pathogens: the pathogen-associated molecular patterns (PAMPs). Interactions of PAMP-containing molecules with their corresponding PRRs activate complex intracellular signal transduction pathways that elicit early (fast) response(s) to host infections [2,3]. Unlike the adaptive immune response, the recognition of potentially harmful compounds through PRRs is an ancient and hard-wired system, yet it is highly efficient at detecting a broad range of highly diverse viruses, bacteria, fungi, and protozoa via a limited number of constantly expressed PRRs [[2], [3], [4]]. Under pathophysiological conditions, for instance, during cellular stress and/or necrosis, human cells release biomolecules that harbor distinct molecular motifs, which act as so-called “danger-associated molecular patterns” (DAMPs), are also recognized by PRRs, and consequently trigger innate immune response(s) [[5], [6], [7]]. At first glance, it is somewhat counterintuitive that even endogenous molecules, which usually are perceived as “self” and hence harmless, activate a class of receptors of the innate immune system, which deals with pathogenic challenges/treats. However, tissues can be destroyed or ruptured even under non-infectious conditions, such as, e.g., trauma caused by burns or injury, and the detection of such endogenous molecules in order to elicit similar cellular programs as in the case of PAMPs is highly advantageous; this is because the cellular responses/programs required for, in example wound healing are very similar to those that counteract the pathogen's violation of barriers, prevent the entry of pathogens, and ultimately lead to tissue restoration [5,7]. We review research progress on formyl peptide receptors (FPRs), a family of PRRs (Pattern Recognition Receptors) that recognize a huge variety of pathogen-derived and endogenous ligands. There are first indications that these GPCRs (G-protein coupled receptors) are also subject to agonistic activation via so-called “functional selectivity” or “biased agonism”. This recent concept describes the ability of ligands to evoke different outcomes while acting on the same GPCR. This concept can be applied to the development of novel FPR-based therapies. In the light of biased agonism, we envision that formyl peptide receptors are extremely promising and relevant targets for future drug development, for instance, to combat chronically progressing diseases. For instance, the two compounds Cmpd17b and Cmpd43 are both dual agonists for FPR1 and FPR2 [[8], [9], [10], [11]], however, only Cmpd17b is cardioprotective in vivo and in vitro [10].