Monocyte en macrofaag dysfunctie bij Alcoholische en Non-Alcoholische leververvetting (NAFLD)

The human immune system is composed of two components; the innate and adaptive immune systems. Innate immunity usually refers non-specific defence system that is immediate in effect, while adaptive immunity is a more specific and complex form of host defence. Monocytes and macrophages are very versatile cells of the innate immune system. They don’t only sense and immediately respond to invading pathogens, but also are extremely important in maintaining tissue homeostasis. Monocytes are derived from a common myeloid precursor in the bone marrow and are then released in the circulation. They are rapidly recruited to sites of infection or tissue damage and can give rise to tissue macrophages under certain conditions. Three monocyte subsets exist, classical, non-classical and intermediate. These subsets differ in their surface expression of cluster of differentiation 14 (CD14) and 16 (CD16) and have different gene expression profiles and functional capabilities. Most adult macrophages are derived from embryonic precursors that seed developing tissue before birth and are maintained independently of monocytes. Intestinal and skin macrophages are exceptions and need to be constantly replenished by circulating monocytes. Macrophages are very dynamic cells; they are present in almost all tissues and display very site specific phenotypes and functions. Classification of macrophages has proofed to be difficult as these cells are very plastic and can change according to environmental cues. Currently macrophages are very simplistically classified as either M1-like/classically activated macrophages, these cells are usually involved in inflammation and can produce proinflammatory cytokines and chemokines and release nitric oxide or M2-like/alternatively activated macrophages, which play a role in homeostasis and release anti-inflammatory molecules including IL10 and TGFβ, but it is becoming more obvious the more we learn about these cells that more unique classes of macrophages exist. In our laboratory a central theme has been the role of macrophages and monocytes in the propagation of liver disease. To better understand the versatility of these cells and how changes in their phenotype and function can lead to diseased conditions, we investigated the role of intestinal macrophages, adipose tissue macrophages and circulating monocytes in the pathogenesis of alcoholic and fatty liver disease. Intestinal macrophages in steady state are very unique cells as they have the ability to maintain tolerance towards food antigens and intestinal microbiota, but also at the same time have the ability to effectively clear microbes breaching the epithelial barrier, which is composed of only a single layer of columnar epithelial cells. To do this these cells have a specific phenotype; they are CD14neg, are extremely anergic and do not produce inflammatory cytokines or nitric oxide in response to invading pathogens, but still retain potent phagocytic and bactericidal capabilities. However in diseased conditions such as inflammatory bowel disease (IBD), human immunodeficiency virus (HIV) and necrotising enterocolitis (NEC), intestinal macrophages alter their phenotype and functions resulting in intestinal inflammation. Patients with decompensated cirrhosis frequently develop infections which are associated with the translocation of bacterial products across the epithelial barrier to extra-intestinal sites, defined as bacterial translocation. Reasons why the epithelial barrier fail and permit BT in cirrhosis is currently not completely understood. We could show that intestinal macrophages in cirrhosis have a distinct phenotype similar to other inflammatory states. These CD14+Trem-1+ macrophages expressed iNOS and secrete NO and are the main cell source of cytokines/chemokines, associated with inflammatory cell recruitment. Increased duodenal release of IL-6, NO by activated intestinal macrophages and altered claudin-2 levels strongly suggest that these factors enhance intestinal permeability to bacterial products in patients with decompensated cirrhosis with ascites. Regulating metabolic homeostasis is an important function of macrophage. In lean adipose tissue, macrophages are mostly alternatively activated macrophages and can regulate insulin action, have the ability to store iron and can produce catecholamines. In obesity however, classically activated macrophages infiltrate the tissue, form crown-like structures surrounding necrotic adipocytes and produce pro-inflammatory cytokines. Obesity is closely associated with fatty liver disease and NAFLD is regarded as the hepatic manifestation of the metabolic syndrome. We aimed to explore this relationship further by analysing the transcriptional profiles of subcutaneous and visceral adipose tissue, and determining the phenotypes and functional characteristics of adipocyte tissue macrophages (ATM), in obese patients undergoing bariatric surgery stratified into well-delineated histological subgroups. We observed an increase in the expression of genes that regulate inflammation in adipose tissues from patients with NAFLD and NASH; expression of these genes increased as disease progressed from NAFLD to NASH. We could also show an increased frequency of CD206pos CD11cpos and CCR2pos macrophages in visceral adipose tissue of patients with NASH and NASH with fibrosis and could demonstrate that these macrophages produced more inflammatory cytokines compared to adipose tissue from controls. Our study strongly suggests that adipose tissue inflammation may be a prerequisite for the development of NAFLD in humans. In the absence of adipose tissue inflammation, no inflammation was observed in liver tissue suggesting that adipose tissue macrophages play an important role in the pathogenesis and progression of NAFLD. Fighting infections is an important function of monocytes and macrophages. During the development of systemic inflammation this response may become exaggerated resulting in distant organ injury or conversely may be overwhelmed leading to recurring infections. Systemic inflammatory response syndrome is characterized by a “cytokine storm“and multi-organ failure. Under certain conditions anti-inflammatory mediators such as IL4, IL10 and TGFβ may be secreted to compensate for prolonged immune stimulation. Failure to resolve this disequilibrium can result in persistent immune cell dysfunction with an increased risk to develop infections. An increased risk to develop infections and organ failure are common manifestations of chronic liver disease. Circulating monocytes are central in the development of sepsis. Following repetitive insults monocytes can change their function and switch from predominantly producing inflammatory cytokines to producing anti-inflammatory cytokines. Under such conditions there is a reduction in the surface expression of HLA-DR by circulating monocytes, resulting in an impaired ability to communicate with the adaptive immune system. A decrease in HLA-DR expression is the hallmark of immune paralysis. Acute-on-Chronic liver failure is defined as acute decompensation of liver function in a patient with underlying cirrhosis accompanied by organ failure(s). This condition is associated with very high short-term mortality. These patients commonly develop infections and share many similarities to patients with severe sepsis. We aimed to determine monocyte phenotype and function in patients with ACLF and compare this syndrome to patients with decompensation cirrhosis and alcoholic hepatitis. We also investigated the ICU course of ACLF by comparing this condition to a propensity matched ICU sepsis cohort without liver disease assessing various clinical parameters and plasma cytokine profiles between these populations. We could show that monocytes subsets in patients with alcoholic liver disease in general are significantly different compared to healthy controls. Patients with liver disease had a significant increase in the intermediate monocyte subset population compared to controls. This subset is the mainly responsible for the production of the anti-inflammatory cytokine IL10. In addition HLA-DR expression was decreased and monocyte function significantly impaired in patients with ACLF displaying a decrease in phagocytosis and oxidative burst capacities. Further we observed an increase in IL10 expression at the transcriptional level as well as elevated plasma IL10 levels in patients with ACLF. Importantly IL 10 levels negatively correlated with phagocytosis capacity suggesting that IL10 might be an important factor in the immune dysfunction associated with ACLF. Monocyte and macrophages are not merely cells of the innate immunity with a limited repertoire of immune functions. Instead these cells are important in regulating normal tissue homeostasis but, can under certain conditions also contribute to disease. Our studies indicate that monocytes and macrophages at varies tissue sites are profoundly phenotypically and functionally altered in cirrhosis. Current evidence suggests that these cells may also actively contribute to the progression of liver disease. If we can develop a better understand of macrophage biology and how these cells change and function it will allow us to exploit opportunities in manipulating these cell populations which could be attractive targets for future therapies.status: publishe