Evidence has suggested that parenchymal-stromal cell interaction is implicated in the development of a variety of metabolic diseases. In obese adipose tissue, saturated fatty acids, which are released as a danger signal from hypertrophied adipocytes, stimulates a pathogen sensor TLR4 in the infiltrating macrophages, thus establishing a vicious cycle that augments adipose tissue inflammation. Histologically, macrophages aggregate to constitute crown-like structures (CLS), where they are thought to scavenge the residual lipid droplets of dead adipocytes. In obese adipose tissue, macrophage-inducible C-type lectin (Mincle) is induced in macrophages constituting CLS, the number of which is correlated with the extent of interstitial fibrosis. Mincle, when activated by an as-yet-unidentified danger signal released from dead or dying adipocytes, may play a key role in adipose tissue inflammation and fibrosis. Free fatty acids, when released from obese visceral fat depots, are transported in large quantities to the liver via the portal vein, where they are accumulated as ectopic fat, thus developing nonalcoholic steatohepatitis (NASH). There is a unique histological feature termed “hepatic CLS (hCLS)” in the NASH liver, where macrophages aggregate to surround dead hepatocytes with large lipid droplets. Notably, the number of hCLS is positively correlated with the extent of liver fibrosis, which suggests that hCLS serves as an origin of hepatic inflammation and fibrosis during the progression from simple steatosis to NASH. We postulate that CLS/hCLS represent the unique microenvironment for parenchymal-stromal cell interaction in metabolic diseases.

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Extracellular adenosine 5'-triphophate (ATP) mediates the immune response. Several ecto-enzymes hydrolyze ATP, including the ecto-nucleoside triphosphate diphosphohydrolase (E-NTPDase) and ecto-nucleotide pyrophosphate/phosphodiesterase (E-NPP) protein families. Among these, E-NTPD1, E-NTPD7, and E-NPP3 have been shown to regulate the immune response. E-NTPD1 is expressed in lymphocytes and myeloid cells and modulates their function. E-NTPD7, which is selectively expressed in the epithelial cells of the small intestine, regulates Th17 responses in the small intestine by controlling ATP levels. E-NPP3 is rapidly induced on activated basophils and mast cells, and regulates ATP-dependent activation in basophils and mast cells to prevent chronic allergic inflammation. Thus, ATP-hydrolyzing ecto-enzymes modulate the immune response through ATP hydrolysis.

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The prevalence of obesity, diabetes and heart failure increases with aging, and there is evidence that these age-related disorders share common pathologic features such as chronic low-grade inflammation and systemic metabolic dysfunction. Cellular senescence was initially discovered by in vitro studies, but it is now widely accepted that this process also occurs in vivo with aging. The p53 signaling pathway has a central role in the regulation of cellular senescence, and several lines of evidence indicate that cellular senescence has a causative role in the progression of age-related disorders. In obesity, chronic low-grade inflammation of visceral fat is characterized by production of pro-inflammatory cytokines and infiltration of immune cells, which induces systemic insulin resistance (hyperinsulinemia) that leads to the development of diabetes. Recently, p53-induced cellular senescence was reported to have a critical role in this process. In murine heart failure models, cellular senescence due to activation of p53 not only contributes to adipose tissue inflammation and systemic insulin resistance, but also to the progression of heart failure. This review outlines the pathological role of cellular senescence occurring in white adipose tissue in the development of obesity, diabetes, and heart failure.

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Chronic inflammation underlies an array of chronic, non-communicable diseases, including various cardiovascular and metabolic diseases and cancer. Recent studies have also shown that the mechanisms involved in regulating immunity and metabolism are intricately linked. The term immunometabolism refers to that linkage. In this review, we will discuss immune cell-mediated regulation of metabolic homeostasis and pathology in major metabolic tissues. A particular focus is on macrophages, which play diverse roles in the inflammatory processes induced in non-communicable diseases.

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Repeated cellular stress due to aging and lifestyle-related activities causes tissue damage. That damage is repaired by a homeostatic process consisting first of acute inflammation and then of adaptive physiologic tissue remodeling meditated by communication between parenchymal and stromal cells. That signaling can occur via cell-to-cell contact or through secreted factors. However, excessive or prolonged stress leads to chronic inflammation and pathologic tissue remodeling, perturbing homeostasis and promoting development of lifestyle-related diseases or cancer. Expression of Angiopoietin-like protein 2 (ANGPTL2) is induced both normally and by disease-associated stresses. In the former, ANGPTL2 promotes proper adaptive inflammation and tissue reconstruction and thus maintains homeostasis; however, in the latter, excess ANGPTL2 activation impairs homeostasis due to chronic inflammation and irreversible tissue remodeling, promoting metabolic and atherosclerotic diseases and some cancers. Thus, it is important to define how ANGPTL2 signaling is regulated in order to understand mechanisms underlying tissue homeostasis and disease development. Here, we focus on ANGPTL2 function in these activities and discuss whether excess ANGPTL2 function is a common molecular mechanism underlying lifestyle diseases and cancer.

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The circulating protein apoptosis inhibitor of macrophage (AIM) is incorporated into normal hepatocytes and inhibits lipid storage within them, thereby decreasing liver steatosis. In contrast, AIM accumulates on the surface of hepatocellular carcinoma (HCC) cells and induces elimination of the cells, thereby preventing HCC tumor development. Based on these findings, we hypothesize the presence of a set of circulating proteins that specifically mark biological garbage, such as cancer cells, dead cell debris, or degenerated proteins/cells, and promote efficient elimination of such undesired substances, thereby preventing progression to multiple diseases. We propose designating these marker proteins as “soluble scavenger proteins” (SSPs), and their potential therapeutic application to various refractory diseases.

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Introduction: Dentinogenesis is regulated by cytokines and growth factors, and modulated by alterations in the extracellular microenvironment. Dental matrix protein-1 (DMP-1), which is predominantly expressed in odontoblasts, is required during the early and late stages of odontogenesis. In the present study, we examined the involvement of proinflammatory cytokines in the expression of odontogenic markers in the rat odontoblast-like cell line KN-3.
Methods: The expression of DMP-1 and p38 mitogen-activated protein kinase (MAPK) in proinflammatory cytokine-treated KN-3 cells was evaluated by immunoblot analysis. Alkaline phosphatase (ALP) activity in proinflammatory cytokine-treated KN-3 cells was measured by ALP staining and a colorimetric assay.
Results: DMP-1 protein was downregulated in KN-3 cells treated with interferon-γ (IFN-γ) for 3 days, but not in interleukin-1β (IL-1β)-treated cells. The IFN-γ-induced downregulation of DMP-1 was rescued by treatment with IL-1β for 3 days. Interestingly, ALP activity was also suppressed in IFN-γ-treated KN-3 cells and no significant change was induced by IL-1γ treatment for 5 days. In addition, IFN-γ treatment for 3 days remarkably upregulated the phosphorylation of p38 MAPK in KN-3 cells.
Conclusions: INF-γ treatment downregulated DMP-1 expression and ALP activity in KN-3 cells through prolonged phosphorylated p38 MAPK. IL-1β treatment restored these odontogenic reactions mediated by IFN-γ. Taken together, these findings suggest that IFN-γ and IL-β may be involved in the complex regulation of odontogenesis in the microenvironment of dental pulp.

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