Studying Macrophage Receptor Evolution and Function using Bioinformatics

Abstract

During infection, macrophages are important for the uptake and clearance of mi- crobial products, and producing inflamamtory cytokines. Receptors on the surface of the macrophage bind to bacterial components, and initiate inflammatory pathways. Although it is known that this inflammatory response is mediated through surface re- ceptors, the regulation of this response and the evolution of these receptors remains un- clear. This work uses a bioinformatic approach to study the effect of age on lipopolysac- charide (LPS) tolerized macrophages, and the evolution of the class A Scavenger Recep- tors (cA-SRs). Previous work has shown that the cA-SRs are evolutionarily related to each other, however the exact nature of this relationship remains unclear because of differences in the functional domains of the proteins. Several of the cA-SRs possess a Scavenger Re- ceptor Cysteine Rich (SRCR) domain, however its exact function and origin remains un- known. Previous studies have shown the SRCR domain is involved in ligand binding in the MAcrophage Receptor with COllagenous structure (MARCO), a member of the cA-SR family. Using recently identified extant species, we show that the SRCR domain has a common origin within the cA-SRs and that several areas within the SRCR domain are under positive selection within MARCO. In addition, recent functional data sug- gests that MARCO may be co-evolving with the Toll-Like Receptor 2 and CD14 Using a model of 40 non co-evolving proteins, we show that MARCO has indeed co-evolved with TLR2 and CD14. We also identified a polymorphism within the collagenous do- main of MARCO that contains a human specific variant. Future experiments to confirm these bioinformatic predictions can further our understanding of macrophage biology and the innate immune system.