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

/pdf/protective-and-pathogenic-functions-of-macrophage-subsets-5d5nlezyqd.pdf

Protective and pathogenic functions of macrophage subsets

Fibrosis is defined by the overgrowth, hardening, and/or scarring of various tissues and is attributed to excess deposition of extracellular matrix components including collagen. Fibrosis is the end result of chronic inflammatory reactions induced by a variety of stimuli including persistent infections, autoimmune reactions, allergic responses, chemical insults, radiation, and tissue injury. Although current treatments for fibrotic diseases such as idiopathic pulmonary fibrosis, liver cirrhosis, systemic sclerosis, progressive kidney disease, and cardiovascular fibrosis typically target the inflammatory response, there is accumulating evidence that the mechanisms driving fibrogenesis are distinct from those regulating inflammation. In fact, some studies have suggested that ongoing inflammation is needed to reverse established and progressive fibrosis. The key cellular mediator of fibrosis is the myofibroblast, which when activated serves as the primary collagen-producing cell. Myofibroblasts are generated from a variety of sources including resident mesenchymal cells, epithelial and endothelial cells in processes termed epithelial/endothelial-mesenchymal (EMT/EndMT) transition, as well as from circulating fibroblast-like cells called fibrocytes that are derived from bone-marrow stem cells. Myofibroblasts are activated by a variety of mechanisms, including paracrine signals derived from lymphocytes and macrophages, autocrine factors secreted by myofibroblasts, and pathogen-associated molecular patterns (PAMPS) produced by pathogenic organisms that interact with pattern recognition receptors (i.e. TLRs) on fibroblasts. Cytokines (IL-13, IL-21, TGF-beta1), chemokines (MCP-1, MIP-1beta), angiogenic factors (VEGF), growth factors (PDGF), peroxisome proliferator-activated receptors (PPARs), acute phase proteins (SAP), caspases, and components of the renin-angiotensin-aldosterone system (ANG II) have been identified as important regulators of fibrosis and are being investigated as potential targets of antifibrotic drugs. This review explores our current understanding of the cellular and molecular mechanisms of fibrogenesis.

/pdf/cellular-and-molecular-mechanisms-of-fibrosis-48v3c6itoz.pdf

Cellular and molecular mechanisms of fibrosis.

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.

/pdf/macrophage-biology-in-development-homeostasis-and-disease-2nq2u94n8n.pdf

Macrophage biology in development, homeostasis and disease

The integrin family of cell adhesion receptors regulates a diverse array of cellular functions crucial to the initiation, progression and metastasis of solid tumours. The importance of integrins in several cell types that affect tumour progression has made them an appealing target for cancer therapy. Integrin antagonists, including the alphavbeta3 and alphavbeta5 inhibitor cilengitide, have shown encouraging activity in Phase II clinical trials and cilengitide is currently being tested in a Phase III trial in patients with glioblastoma. These exciting clinical developments emphasize the need to identify how integrin antagonists influence the tumour and its microenvironment.

/pdf/integrins-in-cancer-biological-implications-and-therapeutic-2ejzg8fop4.pdf

Integrins in cancer: biological implications and therapeutic opportunities

The extracellular matrix (ECM) is a highly dynamic structure that is present in all tissues and continuously undergoes controlled remodelling. This process involves quantitative and qualitative changes in the ECM, mediated by specific enzymes that are responsible for ECM degradation, such as metalloproteinases. The ECM interacts with cells to regulate diverse functions, including proliferation, migration and differentiation. ECM remodelling is crucial for regulating the morphogenesis of the intestine and lungs, as well as of the mammary and submandibular glands. Dysregulation of ECM composition, structure, stiffness and abundance contributes to several pathological conditions, such as fibrosis and invasive cancer. A better understanding of how the ECM regulates organ structure and function and of how ECM remodelling affects disease progression will contribute to the development of new therapeutics.

/pdf/remodelling-the-extracellular-matrix-in-development-and-4thd3cxc2p.pdf

Remodelling the extracellular matrix in development and disease.

https://aasldpubs.onlinelibrary.wiley.com/doi/pdf/10.1002/hep.22832

Senescence of activated stellate cells: not just early retirement.

Kynurenine 3-monooxygenase (KMO) is a critical regulator of inflammation. The preferred KMO substrate, kynurenine, is converted to 3-hydroxykynurenine (3HK), and this product exhibits cytotoxicity through mechanisms that culminate in apoptosis. Here, we report that overexpression of human KMO with orthotopic localisation to mitochondria creates a metabolic environment during which the cell exhibits increased tolerance for exogenous 3HK-mediated cellular injury. Using the selective KMO inhibitor Ro61-8048, we show that KMO enzyme function is essential for cellular protection. Pan-caspase inhibition with Z-VAD-FMK confirmed apoptosis as the mode of cell death. By defining expression of pathway components upstream and downstream of KMO, we observed alterations in other key kynurenine pathway components, particularly tryptophan-2,3-dioxygenase upregulation, through bidirectional nonlinear feedback. KMO overexpression also increased expression of inducible nitric oxide synthase (iNOS). These changes in gene expression are functionally relevant, because siRNA knockdown of the pathway components kynureninase and quinolinate phosphoribosyl transferase caused cells to revert to a state of susceptibility to 3HK-mediated apoptosis. In summary, KMO overexpression, and importantly KMO activity, have metabolic repercussions that fundamentally affect resistance to cell stress.

/pdf/overexpression-of-human-kynurenine-3-monooxygenase-protects-hogw91gnrf.pdf

Overexpression of human kynurenine-3-monooxygenase protects against 3-hydroxykynurenine-mediated apoptosis through bidirectional nonlinear feedback.

Aims: To test the hypothesis that single nucleotide polymorphisms (SNPs) within genes (or their promoter regions) encoding cytokines, growth factors, and intercellular adhesion molecules modulate the risk of development of chronic pancreatitis (CP).

Methods: DNA was extracted from peripheral blood leucocytes or formalin fixed, paraffin wax embedded tissue from 53 patients with CP and 266 healthy controls. SNPs within the interleukin 1β (IL-1β), IL-6, IL-8, tumour necrosis factor α (TNFα) and vascular endothelial growth factor (VEGF) gene promoter regions and the transforming growth factor β1 (TGFβ1) and intercellular cell adhesion molecule 1 (ICAM-1) genes were genotyped by the amplification refractory mutation system polymerase chain reaction or 5′ nuclease (Taqman®) techniques. Patient–control comparisons were made using 2 × 2 contingency tables and χ2 analyses.

Results: A non-significant decrease in the frequency of the IL-8 −251 AA genotype and a non-significant increase in the frequency of the ICAM-1 +469 GA genotype was seen in patients compared with controls. No associations were identified between SNPs in the promoter regions of the IL-1β, IL-6, or TNFα proinflammatory cytokines genes or the TGFβ1 and VEGF genes and susceptibility to CP.

Conclusions: This preliminary study suggests that genetic polymorphism within several cytokine genes is unlikely to influence susceptibility to CP, but the possible role of IL-8 and ICAM-1 polymorphisms in the development of this disease requires further investigation.

https://jcp.bmj.com/content/jclinpath/58/6/595.full.pdf

Influence of cytokine and ICAM-1 gene polymorphisms on susceptibility to chronic pancreatitis

https://aasldpubs.onlinelibrary.wiley.com/doi/pdf/10.1053/jhep.2003.50224

Regulating hepatic inflammation: pathogen-associated molecular patterns take their toll.

See article on page 719 

It is widely accepted that TGF-β1 is a potent growth inhibitory and profibrotic cytokine which plays a pivotal role in the physiological process of wound healing as well as in the pathogenesis of organ fibrosis.1 TGF-β expression has been shown to be increased in a wide range of fibrotic diseases. In the liver, TGF-β1 mRNA expression has been demonstrated to correlate with ongoing fibrotic injury in both experimental animal models and in human liver diseases. TGF-β1 mediates its profibrotic actions by stimulating fibroblasts and related cell types, including in the liver the hepatic stellate cell (HSC), to secrete a wide range of extracellular matrix proteins. In pathological conditions this leads to accumulation of fibrotic matrix or in a more physiological context to the efficient healing of wounds.2-4 Furthermore, blocking TGF-β activity by a variety of strategies has been shown to inhibit fibrosis in a series of experimental models. However, TGF-β has other important actions, namely its immunomodulatory properties and its antiproliferative effects …

https://gut.bmj.com/content/gutjnl/46/5/593.full.pdf

John P. Iredale

Papers

Senescence of activated stellate cells: not just early retirement.

Overexpression of human kynurenine-3-monooxygenase protects against 3-hydroxykynurenine-mediated apoptosis through bidirectional nonlinear feedback.

Influence of cytokine and ICAM-1 gene polymorphisms on susceptibility to chronic pancreatitis

Regulating hepatic inflammation: pathogen-associated molecular patterns take their toll.

Hepatic regeneration and TGF-beta: growing to a prosperous perfection.