Tissue Microenvironments Define and Get Reinforced by Macrophage Phenotypes in Homeostasis or during Inflammation, Repair and Fibrosis

Current macrophage phenotype classifications are based on distinct in vitro culture conditions that do not adequately mirror complex tissue environments. In vivo monocyte progenitors populate all tissues for immune surveillance which supports the maintenance of homeostasis as well as regaining homeostasis after injury. Here we propose to classify macrophage phenotypes according to prototypical tissue environments, e.g. as they occur during homeostasis as well as during the different phases of (dermal) wound healing. In tissue necrosis and/or infection, damage- and/or pathogen-associated molecular patterns induce proinflammatory macrophages by Toll-like receptors or inflammasomes. Such classically activated macrophages contribute to further tissue inflammation and damage. Apoptotic cells and antiinflammatory cytokines dominate in postinflammatory tissues which induce macrophages to produce more antiinflammatory mediators. Similarly, tumor-associated macrophages also confer immunosuppression in tumor stroma. Insufficient parenchymal healing despite abundant growth factors pushes macrophages to gain a profibrotic phenotype and promote fibrocyte recruitment which both enforce tissue scarring. Ischemic scars are largely devoid of cytokines and growth factors so that fibrolytic macrophages that predominantly secrete proteases digest the excess extracellular matrix. Together, macrophages stabilize their surrounding tissue microenvironments by adapting different phenotypes as feed-forward mechanisms to maintain tissue homeostasis or regain it following injury. Furthermore, macrophage heterogeneity in healthy or injured tissues mirrors spatial and temporal differences in microenvironments during the various stages of tissue injury and repair. Copyright (C) 2012 S. Karger AG, Base

Controlling the Response: Predictive Modeling of a Highly Central, Pathogen-Targeted Core Response Module in Macrophage Activation

We have investigated macrophage activation using computational analyses of a compendium of transcriptomic data covering responses to agonists of the TLR pathway, Salmonella infection, and manufactured amorphous silica nanoparticle exposure. We inferred regulatory relationship networks using this compendium and discovered that genes with high betweenness centrality, so-called bottlenecks, code for proteins targeted by pathogens. Furthermore, combining a novel set of bioinformatics tools, topological analysis with analysis of differentially expressed genes under the different stimuli, we identified a conserved core response module that is differentially expressed in response to all studied conditions. This module occupies a highly central position in the inferred network and is also enriched in genes preferentially targeted by pathogens. The module includes cytokines, interferon induced genes such as Ifit1 and 2, effectors of inflammation, Cox1 and Oas1 and Oasl2, and transcription factors including AP1, Egr1 and 2 and Mafb. Predictive modeling using a reverse-engineering approach reveals dynamic differences between the responses to each stimulus and predicts the regulatory influences directing this module. We speculate that this module may be an early checkpoint for progression to apoptosis and/or inflammation during macrophage activation

Effect of host resistance on genetic structure of core and accessory chromosomes in Irish Zymoseptoria tritici populations

In agricultural pathosystems resistant cultivars are typically only temporarily effective, as widespread growth of said cultivars drives selection for pathogen genotypes capable of infecting them. A gene-for-gene interaction between Z. tritici and wheat has been demonstrated for one cultivar; however results of studies into the relevance of these interactions in the field remain inconsistent. Because genetic drift does not appear to occur between Z. tritici populations that are not widely geographically separated, according to neutral genetic theory if adaptation to different host cultivars is occurring, reduced genetic variation, and some differentiation between populations sourced from different cultivars should be observed. Selectively neutral microsatellite markers were used to genotype 260 isolates of Z. tritici taken from two naturally infected randomized block trials of four different cultivars, representing a spectrum of resistance to Z. tritici from susceptible to resistant. By calculating genetic parameters such as overall heterozygosity and FST from this genotypic data, the presented study aimed to determine if genetic drift or host selection is impacting on the genetic structure of the Irish Z. tritici population. Results indicated that diversity was distributed almost entirely within, rather than among populations, with little or no differentiation, and almost no clone isolates were present in the dataset. However this result was not reflected in the accessory chromosomes, where evidence of minor but significant genetic structure was found. This lack of structure in the core chromosomes and weak structure in the accessory chromosomes confirms that forces of genetic drift and selection are minor compared to sexual reproduction, in concurrence with multiple previous studies on other populations worldwide.</p