Effects of Chronic Ethanol Feeding on Murine Dendritic Cell Numbers, Turnover Rate, and Dendropoiesis

Autor: Michelle Edsen-Moore, Jacquie Marietta, Ji Fan, Kristin J. Ness, Annette J. Schlueter, Robert T. Cook
Rok vydání: 2008
Předmět:
Zdroj: Alcoholism: Clinical and Experimental Research. 32:1309-1320
ISSN: 1530-0277
0145-6008
Popis: Alcoholism is A serious disease that currently affects nearly 18 million Americans. Chronic alcoholics have increased susceptibility to and severity of infection (reviewed in Cook, 1998; MacGregor and Louria, 1997; Szabo, 1999), and evidence is strong that this is because of impaired innate and adaptive immunity. Dendritic cells (DC) play a key role in the initiation of adaptive immune responses, and various aspects of DC function are negatively impacted by acute and chronic ethanol (EtOH) exposure in humans (Dolganiuc et al., 2003; Laso et al., 2007; Mandrekar et al., 2004) and mice (Aloman et al., 2007; Heinz and Waltenbaugh, 2007; Lau et al., 2006, 2007; Ness et al., 2008). In addition to dysfunction of individual DC, alterations in DC numbers could contribute to impaired immune responses because of lack of sufficient antigen presentation interactions to stimulate a robust T cell response or because of increased induction of regulatory T cells (Treg). Dendritic cells are bone marrow (BM)-derived leukocytes responsible for uptake, processing, and presentation of antigen to T cells (reviewed in Banchereau and Steinman, 1998; Bell et al., 1999; Lanzavecchia and Sallusto, 2001). Immature DC continuously sample the environment. When pathogens are encountered in an inflammatory environment, DC migrate to T cell zones of lymph nodes (LN) or spleen, and undergo maturational changes making them effective and unique activators of naive T cells. DC are also found in the thymus, where they play an important role in negative selection of developing T cells (Anderson et al., 1998; Brocker et al., 1997; Gallegos and Bevan, 2004). Murine DC are identified by the expression of CD11c and major histocompatability complex (MHC) class II. In the spleen, immunostimulatory DC can be divided into conventional DC (cDC) and plasmacytoid DC (pDC) subsets based on differential expression of B220; cDC are B220- and pDC are B220+ (Anjuere et al., 1999; Martin et al., 2002; Vremec and Shortman, 1997; Vremec et al., 1992). Classical DC can be further subdivided based on CD11b, CD4, and CD8 expression (Heath et al., 2004; Kamath et al., 2002). Whereas all of these DC populations present antigen to T cells, some specialized functions have been described for various subsets. For example, CD8-cDC produce high levels of interferon (IFN)γ, whereas CD8+ cDC secrete high levels of interleukin (IL)-12 p40/p70 (Hochrein et al., 2001). pDC are the major source of IFNα following viral stimulation, leading to cytotoxic T lymphocyte activation (Dalod et al., 2003). CD8+ DC are the main DC subset found in the thymus (Wu et al., 1995) where they play a role in negative selection of thymocytes (Gallegos and Bevan, 2004). pDC have also been described in the thymus, but their function in that location is currently unclear (Asselin-Paturel et al., 2003). While the detailed lineage of DC subsets is not entirely understood, it is clear that DC share a common origin with other hematopoietic cells at early BM precursor stages (Reid, 1997). Turnover rates of these DC subsets differ, although in general, all are quite short-lived compared with some B and T cell populations. Splenic cDC have a very rapid turnover rate of 3 to 4 days (Kamath et al., 2000), whereas thymic CD8+ DC and pDC have slightly longer lifespans with turnover rates of 10 and 14 days, respectively (Kamath et al., 2002; O’Keeffe et al., 2002). The purpose of this study was to examine the effects of chronic EtOH exposure on DC numbers in various lymphoid tissues, and the mechanisms potentially responsible for observed changes. The Meadows-Cook EtOH in water model was employed (Blank et al., 1992; Meadows et al., 1992; Song et al., 2002), which allows long-term maintenance of mice on EtOH with appropriate weight gain and no evidence of steroid-induced stress (Cook et al., 2007). The results show that EtOH-fed mice had decreased numbers and frequencies of splenic DC but increased thymic DC numbers. Chronic EtOH exposure does not affect BM DC precursor numbers, and an EtOH environment does not influence the differentiation of DC from non-EtOH exposed BM precursors. Furthermore, DC turnover rates were unchanged by chronic EtOH feeding in both spleen and thymus, indicating that altered DC lifespan is not responsible for changes in DC numbers. Total cellularities of spleen and thymus were altered by EtOH feeding, and the size of the splenic or thymic compartment appears to play a substantial role in determining total DC numbers in these organs. Loss of splenic DC provides a potential mechanism for suboptimal T cell activation in response to pathogens, and increased thymic DC numbers could be a contributing factor to increased Treg in chronic EtOH-fed mice. Thus, both of these changes may provide novel means by which alcoholics are more susceptible to severe infections.
Databáze: OpenAIRE
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