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Fast growing macrophage-MR M1/M2 polarization science finds M2 forming a protective ring/crown triggering caloric overload storing fat and reducing insulin sensitivity..inflammation linkage of diabetes-obesity-NASH and a luring therapeutics target..India India Feb 2021.. First, this study is way too complex for my novice comprehension, so in a purely layman's description and terminology the studies case is made for inflammation linkage and therapeutic potential between diabetics, obesity and NASH from M1 and M2 activation/polarization along with ATM (macrophages) and SAM (macrophages) energy storage misfiring and secretion of IL-1β, TNF-α and IL-10. In turn the misfiring and secretions possibly activate CD206 M2 macrophages to form tissue remodeling or a protective ring or what is termed a crown (my description is picture TAMs protecting cancer cells) to trigger caloric overload storing fat and reducing insulin sensitivity and all in all inflammatory signalling activating/polarizing liver Kupffer macrophages resulting in some level of NASH...Also a side note the role of islets macrophages with regard to islets homeostasis or type 1 diabetes has only started to gain significance. Imaging done in situ showed that macrophages are very near to both β cells as well as vasculature, in mice.40 Islets Macrophages are the ones that keep checking the β cells insulin secretion relating to glucose by finding endogenous ATP which gets released along with insulin, so could this have an influence on Type 1 diabetes... "Macrophage
metabolism is a luring therapeutic target which will manipulate
inflammation without markedly influencing effector functions by turning
the immune response ‘’ on’’ or ‘’off’" Macrophages from pancreatic islets Pancreatic islets are the ones distributed throughout the exocrine pancreas; represent micro-organs necessary for systemic glucose homeostasis. Maximum of these Islets are composed of β cells that respond to glucose within seconds by liberating proper levels of insulin needed for appropriate energy supply to insulin sensitive tissues. Innate immune cells form part of pancreatic Islets also. In case of steady state, Macrophages represent the instant immune cells in both mice as well as humans.28,37,38 Following greater than 20yrs of their finding, islets macrophages phenotype is still not known. Converse to adipose tissue macrophages (ATM) as well as liver macrophages islets macrophages don’t stick to M1 as well as M2 polarization paradigm related to metabolic protection as well as dysfunction, respectively. Actually M1 indicators (like CD11c, MHC II) get constitutively expressed by macrophages on healthy pancreatic Islets, along with the high expression of IL-1β, TNF-α as well as other proinflammatory transcription factor interferon regulatory factor (IRF)-5 in the same.28,37,39 Further no expression of M2 pointers (CD206), as compared to stromal Macrophages of the exocrine pancreasis are seen.37 Role of islets macrophages with regard to islets homeostasis has only started to gain significance. Imaging done in situ showed that macrophages are very near to both β cells as well as vasculature, in mice.40 Islets Macrophages are the ones that keep checking the β cells insulin secretion relating to glucose by finding endogenous ATP which gets released along with insulin.41 Macrophages, in turn might directly stimulate or escalate insulin secretion via production of factors like retinoic acid.28 In contrast to any other tissues β cells express the maximum IL-1 receptor 1 (IL-1R1)that markedly points to a physiological part of IL-1β in β cells function.42 Now it is well known that that acute but not chronic exposure to IL-1β stimulates insulin secretion in mice as well as humans.43 Basic mechanism is not known, although might have a greater than insulin granule docking at the plasma membrane following escalated exocytosis.43 For corroborating this posit using transgenic murine models β cells targeted removal of IL-1R1 interferes with peripheral glucose tolerance through decreased glucose stimulated insulin secretion via 2 studies.44 Others show that feeding stimulates a physiological enhancement of circulating IL-1β, that further escalates insulin secretion.45 It was said that peritoneal macrophages are the ones responsible for IL-1β secretion, that responded in response to glucose metabolism as well as bacterial products, liberated IL-1β, which then in turn stimulated the β cells.45It is not yet been sure that probably Islets resident macrophages might also synthesize IL-1β Post prandially, actually these macrophages might turn out to be the major IL-1β source in Islets microenvironment. In to these findings prove that physiological IL-1β amounts have a key role in exaggerating insulin secretion. ....Macrophages from AT-metabolic homeostasis Physiologically AT controls longtime energy stores, appetite via endocrine signaling as well as body temperature in case of brown adipose tissue (BAT). Adipose Tissue Macrophages (ATM), usually express an M2 prole during steady state during physiological conditions. They express mannose receptor CD206, CD301 along pan- macrophage markers like F4/80 in mice, CD14 (in humans) CD68 as well as CD11b. ATM homeostasis signaling has expression of arginase (ARG1), IL-10, as well as other type2 eectors and catecholamines. The transcription factor PPAR-ƴ is expressed greater in these cells as well as regulates oxidative metabolism ability to deal with a lipid–rich environment. In this niche ATM’s crosstalk with other immune cells as well as give signals regarding stimulation as well as repression of B as well as T cells, neutrophils, NK cells, as well as ILCs.50 ATM’s control tissue Homeostasis by removal of adipocytes that are in process of death as well as dead cells, the eerocytic mode sustains an anti-inammatory environment. Actually murine AT that presents escalated dying adipocytes in view of targeted stimulation of caspase 8 have the property of enhanced number of alternately activated anti- inammatory macrophages (M2, CD206+), surrounding both dead as well as dying adipocytes.51 This group of cells surrounding adipocytes in a ring like structure is known as crown like structures (CLS). In lean AT CLS are occasional. During physiological changes, AT homeostasis gets challenged every day during feeding times, hence expansion as well as storage of lipids, or mobilization of lipids that are stored during fasting or cold exposure. Escalated lipid buering ability is present in ATM’s which aids in capturing of lipids liberated by dead adipocytes, even at the time of physiological conditions like weight loss, fasting stimulated lipolysis,52 or thermogenesis.53 Intriguingly, in case of obesity macrophages-related excess lipid capture controls systemic glucose tolerance. Lipids get stored within macrophages and get liberated into circulation in a regulated way54 Figure 2 & Figure 3. This lipid buering ability of ATM’s prevents ectopic lipid getting preserved, proinammatory collection of lipids as well as systemic lipotoxicity/dyslipidaemia. Within M2 macrophages of AT lysosomal activity gets stimulated for dealing with environmental lipid overload. Intriguingly, inhibiting lysosomal biogenesis and hence lipid collection as well as catabolism within ATM’s reduces adipocytes lipolysis.55 Innovative pathways of lipid liberation independent of canonical lipolysis have been shown. Adipocytes liberating exosome– sized lipid enriched vesicles that have to be picked up as well as stored via ATM’s.56 This lipid capture gets aided by ATM’s expressing FA transporter (CD36) as well as lipid scavenger receptor MSRI.55 Most of insight regarding macrophages crosstalk with environmental lipids as well as their modes of stimulation have arrived via the atherosclerosis eld as well as studying the foam cells. Actually initial work done by Nagy et al.,57 emphasized on the signicance of receptors like CD36, letting macrophages to internalize oxidized lipids that in turn work as nuclear receptor ligands (PPARƴ here). These Nagy et al.,57 modes turned out to be the rst to bring about connection between metabolic stress, transcriptional control as well as phenotypical plasticity. ATM’s part in thermogenesis is a budding topic as well as pathways causing stimulation of ATM’s are under evaluation.50 An innovative population of macrophages having role in AT thermogenesis has been isolated; namely sympathetic neuron correlated macrophages (SAM).58 These SAM vary morphologically from ATM’s as well as are located at the bers of the sympathetic nervous system in AT. In contrast to ATM’s, SAMs possess molecular apparatus for uptake as well as catabolism of norepinephrine that blunts catacholamine stimulated lipolysis. ATM’s further possess part in iron homeostasis, where intracellular iron is a source of free radicals as well as cofactor for a lot of proteins. 25% of macrophages via lean AT are thought to be ferromagnetic.i.e. iron loaded, with this percentage decreasing with obesity.59 Recycling of iron via ATM’s aids in AT homeostasis, where an up regulation of iron-associated genes takes place at the time of adipogenesis, with an extra iron causing adipocytes IR.60 In adipogenesis, a greater direct part is played via ATM’s, where alternatively activated macrophages (AAM) via a niche for the formation of adipocytes as well as in vascularization of AT.61 The collection of M2 ATM’s in the CLS surrounding dead adipocytes results in the pre adipocytes recruitment via response to osteopontin (OPN). But recently it was shown that M2 like ATM’s inhibit the replication of adipocytes progenitors via TGF β signaling. A signicant study via Bourlier et al.,61 showed that subcutaneous ATM’s are the predominantly CD206+), being a main source of matrix degrading enzymes, and thus they become main source for tissue remodeling. Secreted factors via ATM’s were observed to be aiding angiogenesis as well as inhibit adipogenesis in stromal vascular fraction (SVF) progenitor cells.61 Regulation of angiogenesis is crucial in sustenance of tissue homeostasis since it limits hypoxic sites and ensures proper irrigation giving nutrients as well as O2 to the microenvironment .This work displays that ATM’s are basically protective as well as in early stages of caloric overload, aid in coordinating AT adaptation.61 Lastly AAM have the property of synthesizing IL-10, an anti-inammatory cytokine signicant for modulation of insulin sensitivity.62 Actually IL-10 therapy enhances global insulin sensitivity in vivo63 as well as its expression is positively associated with insulin sensitivity in humans.64 Intriguingly haematopoietic removal of IL-10 does not promote obesity nor are IR, pointing that other factors as well as pathways there for manteinance of metabolic health.65 Moreover ATM’s can liberate exosome possessing miRNA like miR155, which controls insulin sensitivity. These ATM’s derived exosome from lean mice improve glucose intolerance as well as insulin sensitivity when given to obese mice.66....
... Metabolic inammation-liver macrophages Once there is extension of inammation via AT it results in escalation of proinammatory mediators within the circulation and thus escalation in obesity. IR, constant glucolipotoxicity as well as systemic inammation go parallel with ectopic lipid fat accumulation, main site of that being liver. In cases of obesity as well as T2D varying changes take place in liver extending from benign steatosis to brosis as well as cirrhosis83 reviewed.23 These are referred to as nonalcoholic fatty liver disease (NAFLD), in which this lipotoxicity, inammation as well as brosis represent the greater than advanced stages of nonalcoholic steatohepapititis (NASH). Role of liver macrophages, KC’s are crucial in the propagation of NASH, in view of their proapoptotics as well as proinammatory responses towards lipotoxic hepatocytes as well as their ability of activation of matrix producing hepatic stellate cells (HSC’s). This ectopic lipid fat accumulation stimulates activation of immune cells as well as an inammatory environment that stimulates IR. Intriguingly, when a nonbiased transcriptomic signature evaluation was done, no variations as far as expression of genes correlated with proinammatory signatures, among liver Macrophages via lean as well as obese (same data obtained from mice fed 9 wks of high fat diet (HFD). Metabolic alterations do not correlate with a proinammatory stimulation of liver macrophages.84 But the transcriptomic signature varies among dierent benign steatosis stage to that of NASH. During the conversion from steatosis to NASH, liver macrophages attack lipotoxic hepatocytes and thus stimulation of apoptosis as well as signal to HSC’s for stimulation of their activation.83 Chronically damage to liver will end in brosis with extensive scarring response to dead or dying hepatocytes, with continuing brosis inuencing liver function.83 At the NASH stage liver Macrophages pool is markedly heterogenous, with M1 like macrophages stimulating hepatocyte apoptosis, while M2 like macrophages aid in HSC’s activation as well as brogenesis.83,85 The pro inammatory transcription factor Interferon regulatory factor 5 (IRF5) has been demonstrated to have a key part in liver macrophages, that brings about the shift from benign steatosis to NASH. Hepatoprotection occurs once IRF5 expression is blunted via early up regulation of anti-apoptotic as well as immunoregulatory signaling, escalating Treg dierentiation as well as IL-10 liberation on hepatocellular stress.85 Current research is trying to get insight into potential non inammatory or no immune signaling eerent from KC’s, especially eector molecules like insulin like growth factor binding protein -7 (IGFBP-7), controls insulin sensitivity in relation to obesity.86 Development as well as manteinance of macrophages polarization in T2D Currently trying to dene extracellular metabolic as well as molecular signals related to macrophages Polarization in metabolic inammation as well as IR, is being actively worked .The Candidate metabolic immunogens that might be candidates are lipids, hypoxia, cell death as well as stress.52,73,87 In genetically obese mice 90% of adipose tissue macrophages (ATM’s) surround dead adipocytes in fat depots,88 that points that dead adipocytes are the ones that contribute to damage associated molecular patterns (DAMP’s) which results in crown like structures (CLS) development and/or collection of ATM’s. Further hypoxic areas exist in obese AT along with expression of hypoxia related genes, that include hypoxia inducible factor 1 alpha (HIF 1-α).This transcription factor further facilitates the proinammatory abilities of ATM’s in relation to obesity.89 Moreover, lipolytic products as well generally lipids whose levels are escalated in obesity are very good candidates for stimulation of inammatory response in ATM’s. Nutritional Fatty acids activate TLR-4 in Macrophages which states signaling pathways.90 Triglyceride–rich lipids like palmitate or very low density lipoprotein (VLDL) activate macrophages, those up regulate intracellular amounts of ceramides and further accelerate proinammatory responses.91 These modes activate NLRP3ASC inassome that states caspase 1 modulated cleavage of pro IL-1β as well as pro IL-18 into their active states. Intriguingly saturated Fatty acids like palmitate have been demonstrated to activate the NLRP3 inassome via an AMPK-autophagy– mitochondrial-ROS signaling axis, resulting in liberation of IL-1β as well as IL-18.92 Notably this IL-1β liberation by itself correlates with insulin resistance. Actually IL-1β avoids signaling via Tumor necrosis factor alpha dependent as well as in dependent modes.93 On getting established these proinammatory environmental factor, the formation of proinammatory cytokines which recruit monocytes as well as other immune cells which maintain low grade chronic inammation. Proinammatory cytokines represent crucial factors in disrupting insulin signaling resulting in IR.94 They work via paracrine modes on insulin sensitive cells like adipocytes. Physiologically, On insulin binding to its receptor the phosphorylation of tyrosine residues of insulin receptor substrate 1 (IRS1) activates intercellular signaling pathways bringing about insulin action.95 With regards to metabolic inammation, JNK1 as well as IKK have the ability of inuencing insulin signaling by phosphorylation of inhibitory serine /threonine residues of IRS1,thus disrupting insulin signaling.96 On the same hand, pathways involving JNK1 as well as IKK might be activated via binding of fatty acids (FA’s) to TLR’s. Further IL-1β that also signals via IKK β as well as NFκB, stimulates IR by repressing IRS1 expression at both transcriptional as well as post transcriptional levels.97 IL-6 signaling inhibits insulin sensitivity via separate modes that involve JAK-STAT pathway which regulates the transcription of its own suppressor, called suppressors of cytokine signaling (SOCS3). High amounts IL-6 stimulate greater than expression of SOCS3 that physically cross acts with tyrosine phosphorylated residues and this inhibits IRS1 binding to the insulin receptor.98 Macrophages polarization-metabolic modes Just like any other cell Macrophages possess their own Metabolic needs and are dependent on similar bioenergetic pathways like the no immune cells–which are widely divided into glycolytic or mitochondrial Figure 5. Besides proinammatory signaling as well as transcriptional regulation, cellular metabolism is getting recognized for its crucial role that it has in macrophages terminal dierentiation. Metabolic pathways mobilization besides producing energy, further inuences the degree of Macrophages eector function.13 Initial studies on immunometabolism gave basic modes that fuel Macrophage in models systems having canonical activators. These studies aided in proper correlation of bioenergetic proles to polarization status. Recent work is further working on this basis by evaluation of bioenergetic proles as well as metabolic adaptations of tissue particular macrophage niches under both Physiological as well as pathological scenario and in response to varied stimuli. Funnily, the metabolic classication of macrophages was initially done with the 1st seeing that M2 macrophages were able to metabolize arginine...
.... Conclusion Lot of advances has been made in last decades that implicated tissue macrophages in IR formation. Actually macrophages have been found to be the central players in sustaining tissue as well as organism homeostasis in response to every day challenges of temporary over as well as under nutrition-from inammatory signaling essential for insulin liberation, to the house keeping part they have in buering AT lipolysis as well as non inammatory signaling in NAFLD. Till date concentration of studies had been on getting to know the molecular modes which regulate macrophage responses to dysmetabolism, basically restricting classication into M1 like vs M2 like macrophages. With the recent technological improvement of single cell sequencing have given us to give a much >in depth classifying macrophage subsets, i.e. immune cell ontogeny, hence single cell sequencing has resulted in a functional reclassication of innate immune subtypes.16 Signicance of these studies lies in giving the properties of macrophages in tissue niches which had been overlooked till now, like pancreatic islet macrophages or SNS related macrophages. This switch in paradigm in macrophage functional reclassication can further be extended to their metabolic properties, their bioenergetic needs as well as adaptations to the particular challenges of IR. Various studies of infection as well as immunity have mostly used typical immune cell activation. Tissue macrophage bioenergetics needs to be found at the formation stage, at steady state as well as at onset of IR. Macrophage metabolism is a luring therapeutic target which will manipulate inflammation without markedly influencing effector functions by turning the immune response ‘’ on’’ or ‘’off’. After recent ndings of non immune as well as non inammatory signaling via macrophages, we have gained insight into noncanonical part of the innate immune cells, like dendritic cells, NK cells, as well as ILC’s. Since innate immunity, with all its diverseness, we know maintains homeostasis, without denitely engaging inammation, steady state characteristics as well as responses to physiological variation need to be mapped to get more understanding of deregulation of innate immune eector function that causes metabolic pathology. Inspite of consistent strong correlations as well as modes relation between inammation as well as IR there have been relatively little successful translation innovations....
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