Macrophages.com: An on-line community resource for innate immunity research

Abstract

Macrophages play a major role in tissue remodelling during development, wound healing and tissue homeostasis, and are central to innate immunity and to the pathology of tissue injury and inflammation. Given this fundamental role in many aspects of biological function, an enormous wealth of information has accumulated on these fascinating cells in the literature and other public repositories. With the escalation of genome-scale data derived from macrophages and related haematopoietic cell types, there is a growing need for an integrated resource that seeks to compile, organise and analyse our collective knowledge of macrophage biology. Here we describe a community-driven web-based resource, macrophages.com that aims to provide a portal onto various types of Omics data to facilitate comparative genomic studies, promoter and transcriptional network analyses, models of macrophage pathways together with other information on these cells. To this end, the website combines public and in-house analyses of expression data with pre-analysed views of co-expressed genes as supported by the network analysis tool BioLayout Express^3D, as well as providing access to maps of pathways active in macrophages. Macrophages.com also provides access to an extensive image library of macrophages in adult/embryonic tissue sections prepared from normal and transgenic mice. In addition, the site links to the Human Protein Atlas database so as to provide direct access to protein expression patterns in human macrophages. Finally, an integrated gene-centric portal provides the tools for rapid promoter analysis studies based on a comprehensive set of CAGE-derived transcription start site (TSS) sequences in human and mouse genomes as generated by the Functional Annotation of Mammalian genomes (FANTOM) projects initiated by the RIKEN Omics Science Center. Our aim is to continue to grow the macrophages.com resource using publicly available data, as well as in-house generated knowledge. In so doing we aim to provide a user-friendly community website and a community portal for access to comprehensive sets of macrophage-related data.

Introduction

Macrophages are a family of cells, comprising progenitors, blood monocytes and tissue macrophages that constitute 5–15% of the total cell number of most organs. Their numbers are increased still further in response to inflammatory stimuli. They are essential in many aspects of homeostasis and wound repair, and act as a first line of defence against pathogenic organisms (Hume, 2006). Furthermore, they coordinate both the innate and acquired immune response to infection (Hume, 2006). Correspondingly, a large proportion of the functional genetic polymorphism controlling resistance or susceptibility to such diseases occur in genes expressed in macrophages (Wells et al., 2005). Indeed in large-scale transcriptomics studies, macrophages were by far the richest source of novel mRNAs (Wells et al., 2003). Understanding the complexity of transcriptional regulation in macrophages is a pre-requisite to better decipher macrophage functions in both immunity and infection. The ability of isolate, culture and manipulate these cells has also made them a favourite subject for systems level modelling and analyses (Aderem, 2003, Zak and Aderem, 2009, Ramsey et al., 2008, Raza et al., 2010, Raza et al., 2008, Oda et al., 2004, Polouliakh et al., 2009).

Large-scale genomic analyses related to the innate immune responses of mammalian species have generated large sets of heterogeneous genomic data (Heng and Painter, 2008, Liu et al., 2006, Wells et al., 2003, Kawaji et al., 2011, Carninci, 2007, Carninci et al., 2005, Carninci et al., 2006, Novershtern et al., 2011, Hume et al., 2010, Mabbott et al., 2010). A growing need to store, retrieve and analyse these datasets has led to the emergence of various on-line data repositories. The InnateDB database (Lynn et al., 2008), provides manually curated protein–protein interaction data to help systems-levels analysis of immune responses in humans and mice. InnateDB also provides access to the visualisation of interactome-based pathways relevant to innate immunity. Some species-specific databases have also been developed for the investigation of immune systems in specific model organisms. The Immunome database (Ortutay and Vihinen, 2006) is an example of such species-specific resources which gathers human genes and proteins relevant to immunity. This resource was extended to provide phylogenetic tree visualisation with ImmTree (Ortutay et al., 2007) to facilitate the study of the evolution of the human immune system with ortholog gene groups of over 1800 metazoan immunity genes stored within ImmunomeBase, a multi-species database of immunity. The Immunome, ImmTree and ImmunomeBase resources were integrated into a single resource, namely the Immunome Knowledge Base (IKB) (Ortutay and Vihinen, 2009). The Immunology Database and Analysis Portal resource (www.immport.org) provides human data with a comprehensive list of immune-related genes and differential gene expression information. This resource includes single nucleotide polymorphisms (SNPs) data and a specialised section to analyse polymorphism in the human major histocompatibility complex. The Immunological Genome Project resource (Heng and Painter, 2008), also known as ImmGen, focuses on the mouse immune system with microarray-based expression studies and provides several browser views of gene expression profiling of a large number of distinct cell types of the myeloid and lymphoid lineages under specific experimental conditions. The IIDB repository (Korb et al., 2008) focuses on toll-like receptor (TLR) genes and TLR signalling pathways in the mouse genome. IIDB includes over 2000 genes associated with immune responses in mice and integrates annotations for over 100 microarray experiments. Despite the large amount of data accessible through these and other on-line portals with immunity-driven database backends, the current available innate immunity-based resources do not specifically focus on macrophage systems and do not provide access to detailed transcriptomic resources such as those deriving from the use of genome-scale 5′RACE or CAGE (Shiraki et al., 2003). In order to better comprehend the transcriptional regulation and gene expression activity occurring within macrophages, immunobiologists need access to macrophage-related datasets together with appropriate bioinformatics tools to visualise and analyse data in a user-friendly environment.

As reflected in the databases listed above there is a rapidly growing body of data derived from high-throughput analyses of macrophages in health and disease, as well as a wealth of information in the literature on their functional activity and signalling pathways. With a large scientific community interested in fundamental and applied aspects of macrophage biology, the need for an integrated research community website dedicated to analysis of these cells is obvious. Here we describe macrophages.com, a centralised portal on macrophage biology with the following objectives:

• Support the analysis and display of the growing body of data from the Riken Genome Network Project (RIKEN GNP), analysing mouse and human macrophage differentiation and other immune cell types.

• Provide access to microarray gene expression data sets derived from macrophage systems in multiple species.

• Provide user-friendly interfaces to mine these data.

• Provide access to models of signalling pathways pertinent to macrophage function.

• Provide bioinformatics tools to facilitate data analysis and allow comparative analysis of functional motifs and evolution in macrophage-active promoters.

• Centralise links to other research and teaching materials relevant to the study of these cells.

This resource integrates macrophage-related data and bioinformatics tools to facilitate comparative genomic analysis of gene expression and extend our understanding of transcriptional regulation in macrophages. The resource′s development is supported by major international groups interested in fundamental macrophage biology and provides them with a community portal to share macrophage-related data and discoveries on the role of these cells in innate and acquired immunity.