Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans

When a cell dies in vivo, the event does not go unnoticed. The host has evolved mechanisms to detect the death of cells and rapidly investigate the nature of their demise. If cell death is a result of natural causes - that is, it is part of normal physiological processes - then there is little threat to the organism. In this situation, little else is done other than to remove the corpse. However, if cells have died as the consequence of some violence or disease, then both defence and repair mechanisms are mobilized in the host. The importance of these processes to host defence and disease pathogenesis has only been appreciated relatively recently. This article reviews our current knowledge of these processes.

How dying cells alert the immune system to danger

Galectins are a family of animal lectins with diverse biological activities. They function both extracellularly, by interacting with cell-surface and extracellular matrix glycoproteins and glycolipids, and intracellularly, by interacting with cytoplasmic and nuclear proteins to modulate signalling pathways. Current research indicates that galectins have important roles in cancer; they contribute to neoplastic transformation, tumour cell survival, angiogenesis and tumour metastasis. They can modulate the immune and inflammatory responses and might have a key role helping tumours to escape immune surveillance. How do the different members of the Galectin family contribute to these diverse aspects of tumour biology?

Galectins as modulators of tumour progression

Galectin-3: an open-ended story.

When cells die in vivo, they trigger an inflammatory response. The ensuing hyperemia, leak of plasma proteins, and recruitment of leukocytes serve a number of useful functions in host defense and tissue repair. However, this response can also cause tissue damage and contribute to the pathogenesis of a number of diseases. Given the key role of inflammation in these processes, it is important to understand the underlying mechanisms that drive this response. Injured cells release danger signals that alert the host to cell death. Some of these molecules are recognized by cellular receptors that stimulate the generation of proinflammatory mediators. Other molecules released by dead cells stimulate the generation of mediators from extracellular sources. The resulting mediators then orchestrate the inflammatory response, eliciting its various vascular and cellular components. Dead cells also release danger signals that activate dendritic cells and promote the generation of immune responses to antigens. Here we review what is presently known about the sterile inflammatory response and its underlying mechanisms.

The Inflammatory Response to Cell Death

Galectin-3 is a beta-galactoside-binding protein implicated in diverse biological processes. We found that galectin-3 induced human monocyte migration in vitro in a dose-dependent manner, and it was chemotactic at high concentrations (1.0 microM) but chemokinetic at low concentrations (10-100 nM). Galectin-3-induced monocyte migration was inhibited by its specific mAb and was blocked by lactose and a C-terminal domain fragment of the protein, indicating that both the N-terminal and C-terminal domains of galectin-3 are involved in this activity. Pertussis toxin (PTX) almost completely blocked monocyte migration induced by high concentrations of galectin-3. Galectin-3 caused a Ca2+ influx in monocytes at high, but not low, concentrations, and both lactose and PTX inhibited this response. There was no cross-desensitization between galectin-3 and any of the monocyte-reactive chemokines examined, including monocyte chemotactic protein-1, macrophage inflammatory protein-1alpha, and stromal cell-derived factor-1alpha. Cultured human macrophages and alveolar macrophages also migrated toward galectin-3, but not monocyte chemotactic protein-1. Finally, galectin-3 was found to cause monocyte accumulation in vivo in mouse air pouches. These results indicate that galectin-3 is a novel chemoattractant for monocytes and macrophages and suggest that the effect is mediated at least in part through a PTX-sensitive (G protein-coupled) pathway.

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Human Galectin-3 Is a Novel Chemoattractant for Monocytes and Macrophages

Macrophage-stimulating protein (MSP) is an 80-kD serum protein with homology to hepatocyte growth factor (HGF). Its receptor, RON tyrosine kinase, is a new member of the HGF receptor family. The MSP-RON signaling pathway has been implicated in the functional regulation of mononuclear phagocytes. However, the function of this pathway in other types of cells has not been elucidated. Here we show that in contrast to the HGF receptor, which was expressed at the basolateral surface, RON was localized at the apical surface of ciliated epithelia in the airways and oviduct. In addition, MSP was found in the bronchoalveolar space at biologically significant concentrations. MSP bound to RON on normal human bronchial epithelial cells with a high affinity (Kd = 0.5 nM) and induced autophosphorylation of RON. Activation of RON by MSP led to a significant increase in ciliary beat frequency of human nasal cilia. These findings indicate that the ciliated epithelium of the mucociliary transport apparatus is a novel target of MSP. Ciliary motility is critical for mucociliary transport. Our findings suggest that the MSP-RON signaling pathway is a novel regulatory system of mucociliary function and might be involved in the host defense and fertilization.

https://dm5migu4zj3pb.cloudfront.net/manuscripts/119000/119214/JCI97119214.pdf

Role of macrophage-stimulating protein and its receptor, RON tyrosine kinase, in ciliary motility.

To clarify the pathogenesis of chronic eosinophilic pneumonia (CEP), the apoptosis of eosinophils from bronchoalveolar lavage (BAL-Eos) was compared with that of eosinophils from peripheral blood (PB-Eos) in six cases of CEP. The survival rate of eosinophils and the percentage of apoptotic cells of both types of eosinophils were examined, and the effects of interleukin 5 (IL-5) were evaluated. The role of Fas expression in apoptosis of these eosinophils was also studied. The survival rate of BAL-Eos on the third day of culture was significantly higher than that of PB-Eos (p < 0.01). This was associated with a lower proportion of apoptotic cells in BAL-Eos than in PB-Eos; the percentages of apoptotic cells in PB-Eos and BAL-Eos after 24 h of incubation were 21.7 +/- 3.4% and 10.6 +/- 1.7% respectively. IL-5 suppressed apoptosis and increased the survival rate of both PB-Eos and BAL-Eos. It was found that the apoptotic character of BAL-Eos differed from that of PB-Eos in at least three ways. Firstly, the positive rate of Fas expression on PB-Eos was increased after 24 h of incubation, whereas that on BAL-Eos did not change. Secondly, the expression of Fas on PB-Eos was suppressed by IL-5 (18.5 +/- 4.2% - 8.3 +/- 3.2%, p < 0.05), whereas IL-5 failed to suppress Fas expression on BAL-Eos (3.3 +/- 1.6% - 3.6 +/- 1.0%). Lastly, binding of antibody to Fas antigen induced apoptosis of PB-Eos, but not of BAL-Eos. These data suggested that Fas seemed to be involved in the apoptosis of PB-Eos, whereas BAL-Eos were Fas-resistant in chronic eosinophilic pneumonia. In conclusion, apoptosis of eosinophils might be suppressed by proinflammatory cytokines such as IL-5 leading to their accumulation in the lung. Chronic stimulation of eosinophils in the alveolar space with IL-5 may play a crucial role chronic eosinophilic disorders.

https://erj.ersjournals.com/content/erj/17/2/190.full.pdf

Apoptotic response of eosinophils in chronic eosinophilic pneumonia

We compared apoptosis in eosinophils from bronchoalveolar lavage (BAL-Eos) with that in eosinophils from peripheral blood (PB-Eos) of 4 patients with chronic eosinophilic pneumonia (CEP). The survival rate of the BAL-Eos on the 3rd day of the culture was significantly higher than that of the PB-Eos (39.1 vs. 1.3%). The percentage of apoptotic cells in the PB-Eos after a 24-hour incubation was higher than that in the BAL-Eos (21.7 vs. 10.6%) according to an analysis with annexin V. We further found that ECF-PI9, an eosinophil chemotactic factor (ECF) derived from an established T cell line (STO-2), significantly suppressed the apoptosis of both PB-Eos and BAL-Eos and prolonged their survival. The expression of Fas on PB-Eos was significantly suppressed by ECF-PI9 (18.5 to 7.37%, p < 0.05), whereas ECF-PI9 failed to suppress the Fas expression on BAL-Eos (3.3 to 3.6%). In addition, an ECF with similar physicochemical properties and biological functions was isolated from the BAL fluid of patients with CEP. These data demonstrate differences between PB-Eos and BAL-Eos, and indicate that ECF-PI9 is involved in the pathogenesis of CEP.

Difference in Apoptotic Function between Eosinophils from Peripheral Blood and Bronchoalveolar Lavage in Chronic Eosinophilic Pneumonia

We examined the expression of apoptosis-related antigens Fas and bcl-2 on eosinophils from peripheral blood (PB) and bronchoalveolar lavage (BAL) in patients with chronic eosinophilic pneumonia (CEP). The expression of those antigens was assessed before and after culture with or without eosinophil chemotactic factors derived from an established T-cell line (STO-2-derived ECFs; ECF-PI5, 6, 7, 8, and 9), granulocyte-macrophage colony stimulating factor, and interleukin 5 (IL-5). We found that the expression of these antigens on eosinophils from PB increased after 24 h culture without any stimulation. In contrast, little or no change was observed even after 24 h culture in eosinophils from BAL. All STO2-derived ECFs and IL-5 suppressed Fas expression on eosinophils from PB. Furthermore, we found that eosinophils which were attracted by ECF-PI9 expressed Fas and bcl-2 more highly than those attracted by other ECFs and IL-5. Such a heterogeneous response of eosinophils to respective ECFs suggests the possibility of a heterogeneous population of eosinophils in patients with CEP.

Tohru Yamanaka

Papers

Human Galectin-3 Is a Novel Chemoattractant for Monocytes and Macrophages

Role of macrophage-stimulating protein and its receptor, RON tyrosine kinase, in ciliary motility.

Apoptotic response of eosinophils in chronic eosinophilic pneumonia

Difference in Apoptotic Function between Eosinophils from Peripheral Blood and Bronchoalveolar Lavage in Chronic Eosinophilic Pneumonia

Expression of apoptosis-related antigen on eosinophils in chronic eosinophilic pneumonia