Metallophilic macrophages are lacking in the thymus of lymphotoxin-β receptor-deficient mice

Institute of Histology and Embryology, University of Belgrade Medical School, Visegradska 26, 11000 Belgrade, Serbia and Montenegro.
Histochemie (Impact Factor: 3.05). 01/2007; 126(6):687-93. DOI: 10.1007/s00418-006-0202-5
Source: PubMed


Lymphotoxin-beta receptor (LTbetaR) axis plays a crucial role in development and compartmentalization of peripheral lymphatic organs. But, it is also required for the appropriate function and maintenance of structural integrity of the thymus: in LTbetaR-deficient animals the clonal deletion of autoreactive lymphocytes is impaired and differentiation of thymic medullary epithelial cells is disturbed. In this study, using several markers, we showed that thymic metallophilic macrophages were lacking in LTbetaR-deficient mice. In tumor necrosis factor receptor-I (p55)-deficient mice (which we used as positive control) thymic metallophilic cells were located, similarly as in normal mice, in the thymic cortico-medullary zone at the junction of cortex and medulla. These findings show that LTbetaR is necessary for maintenance of metallophilic macrophages in the thymus and provide further evidence that these cells may represent a factor involved in thymic negative selection.

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    • "This Wnding was concluded by investigating the thymus of Aire-deWcient mice, where these cells are fully developed, compared to mice deWcient in nuclear factor-B-inducing kinase (NIK) which acted as negative control animals. The authors interpreted their Wndings to support an even more important role of lymphotoxin-receptor signaling for the development of metallophilic macrophages, which had been reported previously (Milicevic et al. 2006). Mikkelsen et al. (2008) put particular emphasis on studying the macrophage system in the intestinal muscularis externa during inXammation. "
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    Histochemie 11/2009; 133(1):1-40. DOI:10.1007/s00418-009-0665-2 · 3.05 Impact Factor
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    • "+ (Matsumoto et al. 1997) LTR ¡/¡ – (MiliTeviT et al. 2006) – (Fütterer et al. 1998) NIK ¡/¡ – (This work) – (Koike et al. 1996) Fig. 2 "
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    ABSTRACT: Thymic metallophilic macrophages represent a significant component in the thymus physiology. Recently, we showed their presence to be dependent on functional lymphotoxin-beta receptor (LT beta R) signaling pathway. However, it is unknown whether the development of metallophilic macrophages also requires the Autoimmune regulator (Aire) transcription factor, as suggested by some studies for medullary thymic epithelial cells, or perhaps the presence of Aire-expressing thymic epithelial cells themselves. Therefore, we investigated the presence of metallophilic macrophages in Aire-deficient thymus. Our study shows that the metallophilic macrophages are fully developed in the Aire-deficient thymus; their development is not regulated via Aire transcription factor and does not require the presence of Aire-expressing epithelial cells. On the contrary, in alymphoplasia (ALY) mice (deficient in nuclear factor-kappaB-inducing kinase, NIK), which we used as negative control, thymic metallophilic macrophages are completely lacking, similarly as in LT beta R-deficient animals. Together, these results show that the development/maintenance of thymic metallophilic macrophages is executed via LT beta R circumventing the Aire transcription factor. Thus, we shed a new light on the molecular requirements for development of these cells and also show that LT beta R pathway is a common developmental regulator of metallophilic macrophages in different lymphatic organs (i.e., thymus and spleen).
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