Studies on both TCDD treated mice and AhR null

Studies on both TCDD treated mice and AhR null mice have also pointed to a role of AhR in hematopoiesis [65], [66]. Singh et al. showed that AhR is a negative regulator of HSC (hematopoietic stem cell) proliferation, while deletion of AhR leads to spleen enlargement in juvenile and adult mice [67]. In contrast, activation of AhR by TCDD leads to aberrant expression of AhR target genes which blocks progenitor cell differentiation, depletes HSC compartment by stem cell exhaustion, and alters HSC/stroma microenvironment interactions [65]. Consistent with these toxic endpoints seen in TCDD treated mice, accidental exposure to TCDD and related PAHs in humans is associated with increased incidence of respiratory cancer, leukemia and lymphoma [68], [69]. Defense against external insults in humans is an extremely complicated and highly regulated process. In a simplified model, immune defense can be broadly divided into three major mechanisms, composed of the barrier organs such as the skin and gastrointestinal mucosal membrane, as well as innate and adaptive immunity [for a recent review, see 70]. Recently, a role of AhR in the postnatal maintenance of skin-resident dendritic epidermal γδ T Piroxicam has been revealed [71], providing a potential link between AhR and wound healing. It appears that AhR controls the proliferation and expansion of DETC via directly modulating the expression of c-Kit, a receptor tyrosine kinase that promotes DETC growth. As DETC is the major source of GM-CSF (granulocyte/macrophage colony stimulating factor) in the skin that is required for Langerhans cell maturation, AhR deficiency also leads to impaired Langerhans cell maturation and a significantly weakened contact hypersensitivity response against a fluorescent compound FITC [72]. In addition, AhR also appeared to be indispensable in the homeostasis of intestinal RORγt+ innate lymphoid follicle (ILF) and IEL cells [73], [74]. Mouse knock out studies indicated that AhR is critically important for the survival of γδ T cells in small intestine, and the level of TCR γδ IELs in AhR null mice is only ∼5% compared to their wild type littermates. Furthermore, AhR null mice were also highly susceptible to dextran sodium sulfate (DSS) induced colitis and Citrobacter rodentium infection [73]. Moving on from barrier organs, the innate immune system represents the second layer of defense against external pathogens. It is composed of both tissue-resident macrophages and dendritic cells (DCs), and mobile immune cells such as neutrophils, eosinophils, mast cells and natural killer cells that constantly circulate through the body via the bloodstream and lymphatic system. In contrast to adaptive immunity (see below), the innate immune response is nonspecific, which does not lead to the development of immunological memory. Switching from innate to adaptive immunity results in clonal expansion of TCRαβ T cells and B lymphocytes, which accelerate pathogen clearance and promote the generation of memory cells capable of mounting a faster and stronger attack each time the same pathogen is encountered. Not surprisingly, cells from both innate and adaptive immune systems are vulnerable targets of TCDD toxicity [75], [76], [77]. For the rest of this section, the functions of AhR with respect to each of these immune cell types will be discussed.
Concluding remarks First of all, given the recent boost on the role of AhR and immunomodulation, a detailed understanding on the endogenous and physiologic relevant ligands of AhR is becoming increasingly important. Numerous studies have suggested the existence of endogenous AhR ligands [4]. It appeared that the endogenous AhR ligands, if any, are likely to be tissue specific and are much more labile than xenobiotic ligands. One possibility for identifying candidate endogenous AhR ligands is to utilize reconstituted AhR hepatocyte cell lines [8], from which the AhR could be readily purified by affinity chromatography and analyzed for small bound molecules by mass spectrometry. This approach was successful in identifying physiologically relevant endogenous ligands of another signal regulated transcriptional factor, PPARα [114].