Macrophage Comparative Express Gateway
MacGate is a publicly available resource focused on divergent gene regulation in human and mouse macrophages. The website displays expression data generated from a custom microarray, which we specifically collected and analysed to investigate divergent gene regulation in response to lipopolysaccharide (LPS), a component of Gram-negative bacterial cell walls that stimulates inflammatory responses via Toll-like receptor 4. These and other analyses are published in Schroder et al.,2012, PNAS USA. The expression of 3041 human and 2945 mouse genes was interrogated over a timecourse of LPS stimulation in human macrophages and two mouse macrophage populations respectively. The expression data pages for each gene interrogated on the array are arranged according to orthology clusters, and can be retrieved by searching for gene names or identifiers, or by simply browsing the database.
Immune response genes are among the most rapidly evolving genes, since successful hosts are obliged to ‘keep up’ with rapidly evolving pathogens. Species differences in immune responses can result from evolution in protein coding sequences, but spatial and temporal differences in expression and regulation of orthologous genes are also likely to contribute to phenotypic differences in immune responses between species. Macrophages are cells of the innate immune system that perform critical functions with respect to pathogen surveillance and elimination. They recognize and respond to a range of invariant pathogen components (pathogen associated molecular patterns, or PAMPs) in order to alert the host and limit infection. Insufficient or inappropriate responses to PAMPs can lead to systemic inflammation and disease. Lipopolysaccharide (LPS), a component of the outer membrane of gram-negative bacteria, is one of the most toxic PAMPs; and is responsible for the life-threatening condition, septic shock, in the context of gram-negative infection. LPS signals through Toll-Like Receptor 4 (TLR4) in both humans and mice. Although the basic biology and signaling from TLR4 is conserved between humans and mice, many therapeutics with demonstrated efficacy in reducing inflammation and mortality in mouse septic shock models show no benefit clinically, or even increase mortality. Since transcriptional regulation is a key mechanism of control in the innate immune response to LPS and other PAMPs, we hypothesized that the identification of divergently regulated genes in humans and mice will lead to novel insights into the inflammatory response and potential targets for human inflammatory diseases.
We are grateful to David Wood and Cas Simons from QFAB for building the database.