Heterogeneity of Macrophage Activation in Anti-Thy-1.1 Nephritis

Abstract

Macrophages infiltrating glomeruli in telescoped nephrotoxic nephritis are programmed. The purpose of this study was to assess whether macrophages infiltrating glomeruli of rats with passively induced injury become similarly programmed, and to determine whether macrophage commitment is an early event. Glomerular macrophages isolated from rats with resolving and proliferative anti-Thy-1 nephritis were examined for nitric oxide (NO) generation and expression of lysosomal hydrolases. After a single injection of Thy-1 antibody the cells generated large amounts of NO that was attenuated ex vivo by transforming growth factor-beta and other anti-inflammatory cytokines. In contrast macrophages infiltrating glomeruli immediately after a second injection of Thy-1 antibody generated NO spontaneously and were unresponsive to alternative activation. beta-Glucuronidase expression was used as a second independent assay for macrophage activation and the results confirmed the observations made for NO. Furthermore, macrophages infiltrating the glomerulus after the second antibody injection exhibited a striking dichotomy in that 70% of the cells behave as programmed by interferon-gamma and 30% by transforming growth factor-beta. The results show that macrophage commitment occurs very early after monocyte migration and that infiltration itself does not invariably induce macrophage programming. It demonstrates that macrophages infiltrating inflamed glomeruli at the same time do not respond uniformly, but are capable of engaging different activation programs. This emphasizes the critical importance of the underlying disease process for macrophage functional development in an inflamed environment.

Unique Expression of Suppressor of Cytokine Signaling 3 Is Essential for Classical Macrophage Activation in Rodents In Vitro and In Vivo

“…Programmed unresponsiveness focuses activation of individual macrophages in a particular direction not only in vitro but also in vivo as demonstrated in models of glomerulonephritis (7,8). Consequently, it is not surprising that macrophages infiltrating inflamed glomeruli can be activated in different ways, presumably stochastically as a result of their initial cytokine contact in the complex microenvironments within inflamed tissue (8).…”

“…Consequently, it is not surprising that macrophages infiltrating inflamed glomeruli can be activated in different ways, presumably stochastically as a result of their initial cytokine contact in the complex microenvironments within inflamed tissue (8). Understanding the molecular mechanisms for such unresponsiveness could unlock new therapeutic approaches and here we have examined the potential role of one of the prime candidates -suppressors of cytokine signaling (SOCS) proteins.…”

The macrophage heterogeneity: Difference between mouse peritoneal exudate and splenic F4/80+ macrophages

“…Macrophages in a different microenvironment display a wide diversity in terms of their function and morphology (Minto et al, 2003;Liu et al, 2005a). The heterogeneity of macrophages may be important for the diversity, flexibility and validity of innate and adaptive immune responses to all kinds of stimuli (Kaufmann and Schaible, 2005).…”

Contrasting Dose–Effects of Multi-glycoside of Tripterygium wilfordii HOOK. f. on Glomerular Inflammation and Hepatic Damage in Two Types of Anti-Thy1.1 Glomerulonephritis

“…Anti-Thy1.1 GN, induced by the injection of anti-Thy1.1 monoclonal antibody (mAb) 1-22-3, is commonly used as the model of human MsPGN (19 -21). It is reported that, the accumulation of macrophages and T lymphocytes into glomeruli is one of the hallmarks of anti-Thy1.1 GN and plays an important pathogenetic role (22). Indeed, the involvement of ED3 + macrophages and CD4 + T helper lymphocytes in the development of the anti-Thy1.1 GN model induced by the injection of mAb 1-22-3 has been reported.…”