Implementation of wildfire- and climate-adaptation strategies in seasonally dry forests of western North America is impeded by numerous constraints and uncertainties. After more than a century of ...resource and land use change, some question the need for proactive management, particularly given novel social, ecological, and climatic conditions. To address this question, we first provide a framework for assessing changes in landscape conditions and fire regimes. Using this framework, we then evaluate evidence of change in contemporary conditions relative to those maintained by active fire regimes, i.e., those uninterrupted by a century or more of human-induced fire exclusion. The cumulative results of more than a century of research document a persistent and substantial fire deficit and widespread alterations to ecological structures and functions. These changes are not necessarily apparent at all spatial scales or in all dimensions of fire regimes and forest and nonforest conditions. Nonetheless, loss of the once abundant influence of low- and moderate-severity fires suggests that even the least fire-prone ecosystems may be affected by alteration of the surrounding landscape and, consequently, ecosystem functions. Vegetation spatial patterns in fire-excluded forested landscapes no longer reflect the heterogeneity maintained by interacting fires of active fire regimes. Live and dead vegetation (surface and canopy fuels) is generally more abundant and continuous than before European colonization. As a result, current conditions are more vulnerable to the direct and indirect effects of seasonal and episodic increases in drought and fire, especially under a rapidly warming climate. Long-term fire exclusion and contemporaneous social-ecological influences continue to extensively modify seasonally dry forested landscapes. Management that realigns or adapts fire-excluded conditions to seasonal and episodic increases in drought and fire can moderate ecosystem transitions as forests and human communities adapt to changing climatic and disturbance regimes. As adaptation strategies are developed, evaluated, and implemented, objective scientific evaluation of ongoing research and monitoring can aid differentiation of warranted and unwarranted uncertainties.
Removal of apoptotic cells is essential for maintenance of tissue homeostasis, organogenesis, remodeling, development, and maintenance of the immune system, protection against neoplasia, and ...resolution of inflammation. The mechanisms of this removal involve recognition of the apoptotic cell surface and initiation of phagocytic uptake into a variety of cell types. Here we provide evidence that C1q and mannose binding lectin (MBL), a member of the collectin family of proteins, bind to apoptotic cells and stimulate ingestion of these by ligation on the phagocyte surface of the multifunctional protein, calreticulin (also known as the cC1qR), which in turn is bound to the endocytic receptor protein CD91, also known as the alpha-2-macroglobulin receptor. Use of these proteins provides another example of apoptotic cell clearance mediated by pattern recognition molecules of the innate immune system. Ingestion of the apoptotic cells through calreticulin/CD91 stimulation is further shown to involve the process of macropinocytosis, implicated as a primitive and relatively nonselective uptake mechanism for C1q- and MBL-enhanced engulfment of whole, intact apoptotic cells, as well as cell debris and foreign organisms to which these molecules may bind.
Phagocytic clearance of apoptotic cells may be considered to consist of four distinct steps: accumulation of phagocytes at the site where apoptotic cells are located; recognition of dying cells ...through a number of bridge molecules and receptors; engulfment by a unique uptake process; and processing of engulfed cells within phagocytes. Here, we will discuss these individual steps that collectively are essential for the effective removal of apoptotic cells. This will illustrate our relative lack of knowledge about the initial attraction signals, the specific mechanisms of engulfment and processing in comparison to the extensive literature on recognition mechanisms. There is now mounting evidence that clearance defects are responsible for chronic inflammatory disease and contribute to autoimmunity. Therefore, a better understanding of all aspects of the clearance process is required before it can truly be manipulated for therapeutic gain.
Recently it was shown that circulating Ly6C(+) monocytes traffic from tissue to the draining lymph nodes (LNs) with minimal alteration in their overall phenotype. Furthermore, in the steady state, ...Ly6C(+) monocytes are as abundant as classical dendritic cells (DCs) within the draining LNs, and even more abundant during inflammation. However, little is known about the functional roles of constitutively trafficking Ly6C(+) monocytes. In this study we investigated whether Ly6C(+) monocytes can efferocytose (acquire dying cells) and cross-present cell-associated antigen, a functional property particularly attributed to Batf3(+) DCs. We demonstrated that Ly6C(+) monocytes intrinsically efferocytose and cross-present cell-associated antigen to CD8(+) T cells. In addition, efferocytosis was enhanced upon direct activation of the Ly6C(+) monocytes through its corresponding TLRs, TLR4 and TLR7. However, only ligation of TLR7, and not TLR4, enhanced cross-presentation by Ly6C(+) monocytes. Overall, this study outlines two functional roles, among others, that Ly6C(+) monocytes have during an adaptive immune response.
The culmination of apoptosis in vivo is phagocytosis of cellular
corpses. During apoptosis, the asymmetry of plasma membrane phospholipids
is lost, which exposes phosphatidylserine externally.
The ...phagocytosis of apoptotic cells can be inhibited stereospecifically by
phosphatidylserine and its structural analogues, but not by other anionic
phospholipids, suggesting that phosphatidylserine is specifically recognized. Using phage display, we have cloned a gene that
appears to recognize phosphatidylserine on apoptotic cells. Here we show that
this gene, when transfected into B and T lymphocytes, enables them to recognize
and engulf apoptotic cells in a phosphatidylserine-specific manner. Flow cytometric
analysis using a monoclonal antibody suggested that the protein is expressed
on the surface of macrophages, fibroblasts and epithelial cells; this antibody,
like phosphatidylserine liposomes, inhibited the phagocytosis of apoptotic
cells and, in macrophages, induced an anti-inflammatory state. This candidate
phosphatidylserine receptor is highly homologous to genes of unknown function
in Caenorhabditis elegans and Drosophila melanogaster, suggesting
that phosphatidylserine recognition on apoptotic cells during their removal
by phagocytes is highly conserved throughout phylogeny.
Apoptosis and other forms of programmed cell death are important contributors to lung pathophysiology. In this brief review, we discuss some of the implications of finding apoptotic cells in the lung ...and methods for their detection. The balance between induction of apoptosis and the normally highly efficient clearance of such cells shows that these are highly dynamic processes and suggests that abnormalities of apoptotic cell clearance may be an alternative explanation for their detection. Because recognition of apoptotic cells by other lung cells has additional effects on inflammation, immunity, and tissue repair, local responses to the dying cells may also have important consequences in addition to the cell death itself.
Resolution of Lung Inflammation by CD44 Teder, Priit; Vandivier, R William; Jiang, Dianhua ...
Science (American Association for the Advancement of Science),
04/2002, Letnik:
296, Številka:
5565
Journal Article
Recenzirano
Successful repair after tissue injury and inflammation requires resolution of the inflammatory response and removal of extracellular matrix breakdown products. We have examined whether the ...cell-surface adhesion molecule and hyaluronan receptor CD44 plays a role in resolving lung inflammation. CD44-deficient mice succumb to unremitting inflammation following noninfectious lung injury, characterized by impaired clearance of apoptotic neutrophils, persistent accumulation of hyaluronan fragments at the site of tissue injury, and impaired activation of transforming growth factor-β1. This phenotype was partially reversed by reconstitution with CD44+cells, thus demonstrating a critical role for this receptor in resolving lung inflammation.
After weaning, during mammary gland involution, milk-producing mammary epithelial cells undergo apoptosis. Effective clearance of these dying cells is essential, as persistent apoptotic cells have a ...negative impact on gland homeostasis, future lactation and cancer susceptibility. In mice, apoptotic cells are cleared by the neighboring epithelium, yet little is known about how mammary epithelial cells become phagocytic or whether this function is conserved between species. Here we use a rat model of weaning-induced involution and involuting breast tissue from women, to demonstrate apoptotic cells within luminal epithelial cells and epithelial expression of the scavenger mannose receptor, suggesting conservation of phagocytosis by epithelial cells. In the rat, epithelial transforming growth factor-β (TGF-β) signaling is increased during involution, a pathway known to promote phagocytic capability. To test whether TGF-β enhances the phagocytic ability of mammary epithelial cells, non-transformed murine mammary epithelial EpH4 cells were cultured to achieve tight junction impermeability, such as occurs during lactation. TGF-β3 treatment promoted loss of tight junction impermeability, reorganization and cleavage of the adherens junction protein E-cadherin (E-cad), and phagocytosis. Phagocytosis correlated with junction disruption, suggesting junction reorganization is necessary for phagocytosis by epithelial cells. Supporting this hypothesis, epithelial cell E-cad reorganization and cleavage were observed in rat and human involuting mammary glands. Further, in the rat, E-cad cleavage correlated with increased γ-secretase activity and β-catenin nuclear localization. In vitro, pharmacologic inhibitors of γ-secretase or β-catenin reduced the effect of TGF-β3 on phagocytosis to near baseline levels. However, β-catenin signaling through LiCl treatment did not enhance phagocytic capacity, suggesting a model in which both reorganization of cell junctions and β-catenin signaling contribute to phagocytosis downstream of TGF-β3. Our data provide insight into how mammary epithelial cells contribute to apoptotic cell clearance, and in light of the negative consequences of impaired apoptotic cell clearance during involution, may shed light on involution-associated breast pathologies.
On Nov 11-12, the Early Detection Branch of the National Cancer Institute convened an international workshop to clarify the role of genetics in the pathology of hereditary nonpolyposis colorectal ...cancer (HNPCC). Issues that arose during the workshop are discussed.
Apoptotic cell removal Henson, Peter M; Bratton, Donna L; Fadok, Valerie A
CB/Current biology,
10/2001, Letnik:
11, Številka:
19
Book Review, Journal Article
Recenzirano
Odprti dostop
Ingestion by professional or amateur phagocytes is the fate of most cells that undergo apoptosis. Studies in both Caenorhabditis elegans and mammals are now converging to reveal some of the key ...mechanisms and consequences of this removal process. At least seven corpse removal genes in nematodes have mammalian equivalents, and represent elements of signaling pathways involved in uptake. In mammals, a wide variety of apoptotic cell recognition receptors has been implicated and appears to be divided into two categories, involved in tethering the apoptotic cell or triggering an uptake mechanism related to macropinocytosis. Apoptotic cell removal is normally efficient and non-inflammatory. By contrast, the process may become subverted by parasites to yield a more favorable growth environment, or in other cases lead to fibrosis. Removal may also clinch the apoptotic process itself in cells not yet completely committed to death.
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