Macrophages are strategically located throughout the body tissues, where they ingest and process foreign materials, dead cells and debris and recruit additional macrophages in response to inflammatory signals They are highly heterogeneous cells that can rapidly change their function in response to local microenvironmental signals In this Review, we discuss the four stages of orderly inflammation mediated by macrophages: recruitment to tissues; differentiation and activation in situ; conversion to suppressive cells; and restoration of tissue homeostasis We also discuss the protective and pathogenic functions of the various macrophage subsets in antimicrobial defence, antitumour immune responses, metabolism and obesity, allergy and asthma, tumorigenesis, autoimmunity, atherosclerosis, fibrosis and wound healing Finally, we briefly discuss the characterization of macrophage heterogeneity in humans

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Protective and pathogenic functions of macrophage subsets

Macrophages, the most plastic cells of the haematopoietic system, are found in all tissues and show great functional diversity. They have roles in development, homeostasis, tissue repair and immunity. Although tissue macrophages are anatomically distinct from one another, and have different transcriptional profiles and functional capabilities, they are all required for the maintenance of homeostasis. However, these reparative and homeostatic functions can be subverted by chronic insults, resulting in a causal association of macrophages with disease states. In this Review, we discuss how macrophages regulate normal physiology and development, and provide several examples of their pathophysiological roles in disease. We define the 'hallmarks' of macrophages according to the states that they adopt during the performance of their various roles, taking into account new insights into the diversity of their lineages, identities and regulation. It is essential to understand this diversity because macrophages have emerged as important therapeutic targets in many human diseases.

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Macrophage biology in development, homeostasis and disease

Recent advances have provided substantial insight into the maintenance of mucosal immunity and the pathogenesis of inflammatory bowel disease. Cellular programs responsible for intestinal homeostasis use diverse intracellular and intercellular networks to promote immune tolerance, inflammation or epithelial restitution. Complex interfaces integrate local host and microbial signals to activate appropriate effector programs selectively and even drive plasticity between these programs. In addition, genetic studies and mouse models have emphasized the role of genetic predispositions and how they affect interactions with microbial and environmental factors, leading to pro-colitogenic perturbations of the host-commensal relationship.

Genetics and pathogenesis of inflammatory bowel disease

[Crohn's disease].

Intestinal homeostasis depends on complex interactions between the microbiota, the intestinal epithelium and the host immune system. Diverse regulatory mechanisms cooperate to maintain intestinal homeostasis, and a breakdown in these pathways may precipitate the chronic inflammatory pathology found in inflammatory bowel disease. It is now evident that immune effector modules that drive intestinal inflammation are conserved across innate and adaptive leukocytes and can be controlled by host regulatory cells. Recent evidence suggests that several factors may tip the balance between homeostasis and intestinal inflammation, presenting future challenges for the development of new therapies for inflammatory bowel disease.

Intestinal homeostasis and its breakdown in inflammatory bowel disease

http://www.cell.com/article/S1550413121006288/pdf

A purine metabolic checkpoint that prevents autoimmunity and autoinflammation

Summary 
Complex human diseases can show significant heterogeneity between patients with the same phenotypic disorder. An outlier detection strategy was developed to identify variants at the level of gene transcription that are of potential biological and phenotypic importance. Here we describe a graphical software package (z-score outlier detection (ZODET)) that enables identification and visualisation of gross abnormalities in gene expression (outliers) in individuals, using whole genome microarray data. Mean and standard deviation of expression in a healthy control cohort is used to detect both over and under-expressed probes in individual test subjects. We compared the potential of ZODET to detect outlier genes in gene expression datasets with a previously described statistical method, gene tissue index (GTI), using a simulated expression dataset and a publicly available monocyte-derived macrophage microarray dataset. Taken together, these results support ZODET as a novel approach to identify outlier genes of potential pathogenic relevance in complex human diseases. The algorithm is implemented using R packages and Java.
Availability 
The software is freely available from http://www.ucl.ac.uk/medicine/molecular-medicine/publications/microarray-outlier-analysis.

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ZODET: Software for the Identification, Analysis and Visualisation of Outlier Genes in Microarray Expression Data

Mounting evidence suggests the pathogenesis of Crohn’s disease (CD) involves an
impaired acute inflammatory response. Monocyte-derived macrophages from CD
patients release deficient levels of pro-inflammatory cytokines in response to
Escherichia coli, arising from post-translational trafficking abnormalities. In this thesis,
the macrophage responses to microbial stimuli were further characterised, and the
underlying molecular lesions investigated.
Macrophage TNF release was attenuated in response to Escherichia coli,
Candida albicans and Toll-like receptor (TLR) stimulation in CD. This deficit was
unrelated to use of medication, age, gender and smoking status. Patients with stricturing
and colonic disease demonstrated the most profound defects in response to TLR2 and
TLR4 stimulation respectively. Genotyping for 34 known CD susceptibility
polymorphisms revealed no detectable association between any individual variant and
impaired TNF release. However in CD, TNF secretion in response to Escherichia coli
was weakly correlated with overall genetic risk score.
Macrophage sphingolipid and phospholipid compositions were subsequently
investigated, given the prominent role of these molecules in vesicle trafficking. Mass
spectrometric analysis revealed no gross abnormalities in CD macrophages, although a
reduced percentage of phosphatidylinositol 16:0/18:1 was synthesised over 3 hours; the
same species was also present at reduced levels in ileal biopsies.
Given the heterogeneity of CD, a microarray outlier analysis strategy was
developed to identify specific gene expression abnormalities in individual patients. A
subset of patients had deficient expression of optineurin, a molecule implicated in
vesicle trafficking and autophagy. These individuals shared a number of allelic variants, which were associated with optineurin expression levels. Macrophages from these
patients had attenuated TNF secretion downstream of TLR2. Concordantly, depletion of
optineurin in THP-1 cells impaired TNF release after TLR2 activation.
This study supports a role for immune deficiency in the pathogenesis of CD and
identifies abnormal optineurin expression as a relevant molecular abnormality in a
subset of patients.

Gavin W. Sewell

Papers

A purine metabolic checkpoint that prevents autoimmunity and autoinflammation

ZODET: Software for the Identification, Analysis and Visualisation of Outlier Genes in Microarray Expression Data

An investigation of molecular defects underlying impaired acute inflammation in Crohn’s disease

Shotgun cholanomics of ileal fluid.

Endoscopy, but not as we know it.