A quantitative comparison of rates of phagocytosis and digestion of apoptotic cells by macrophages from normal (BALB/c) and diabetes-prone (NOD) mice

Abstract

Macrophages play an important role in clearing apoptotic debris from tissue. Defective or reduced clearance, seen, for instance, in non-obese diabetic (NOD) mice, has been correlated with initiation of autoimmune (Type 1) diabetes (T1D) (O'Brien BA, Huang Y, Geng X, Dutz JP, Finegood DT. Diabetes 51: 2481-2488, 2002). To validate such a link, it is essential to quantify the reduced clearance (for example, by comparison to BALB/c control mice) and to determine which elements of that clearance are impaired. Recently, we fit data for the time course of in vitro macrophage feeding experiments to basic models of macrophage clearance dynamics, thus quantifying kinetics of uptake and digestion of apoptotic cells in both mouse strains (Marée AFM, Komba M, Dyck C, Łabeçki M, Finegood DT, Edelstein-Keshet L. J Theor Biol 233: 533-551, 2005). In the cycle of modeling and experimental investigation, we identified the importance of 1) measuring short-, intermediate-, and long-time data (to increase the accuracy of parameter fits), and 2) designing experiments with distinct observable regimes, including engulfment-only and digestion-only phases. Here, we report on new results from experiments so designed. In comparing macrophages from the two strains, we find that NOD macrophage engulfment of apoptotic cells is 5.5 times slower than BALB/c controls. Significantly, our new data demonstrate that digestion is at least two times slower in NOD, in contrast with previous conclusions. Moreover, new data enable us to detect an acceleration in engulfment (after the first engulfment) in both strains, but much smaller in NOD macrophages.

Rescuing of deficient killing and phagocytic activities of macrophages derived from non-obese diabetic mice by treatment with geldanamycin or heat shock: potential clinical implications

“…Genetic and environmental factors that affect their responses have been linked to the pathogenesis of DMT1, although the exact mechanisms remain unknown (Fan et al 2004;Shultz et al 1995). It has been suggested that deficient internalization and/or clearance of AC by Mfs may be linked to the development of autoimmunity (O'Brien et al 2006;Trudeau et al 2000;Marée et al 2008;Mohammad et al 2006). Both AC and pathogens are internalized by phagocytosis, although the cell surface receptors involved in these processes are different.…”

“…It is well accepted that the initiation and the progression of DMT1 is linked to intrinsic dysfunction in professional phagocytes (i.e., Mfs), which results in a compromised mounting of immune and inflammatory responses (Fan et al 2004;Shultz et al 1995;O'Brien et al 2006;Trudeau et al 2000;Marée et al 2008;Mohammad et al 2006). For example, it has been shown that deficient internalization of AC by Mfs derived from diabetic individuals is accompanied by decreased production of IL-10 and increased secretion of pro-inflammatory cytokines, generating an unusual pro-inflammatory environment in response to AC (O'Brien et al 2006;Trudeau et al 2000;Marée et al 2008;Mohammad et al 2006). On the contrary, incubation of DMT1-derived Mfs with pro-inflammatory stimuli has been shown to produce unusually high levels of PGE 2 , which leads to down-regulation of cellular immune activation and therefore a decrease in inflammation (Benhamou et al 1995).…”

M2b Monocytes Provoke Bacterial Pneumonia and Gut Bacteria–Associated Sepsis in Alcoholics

“…As a control, gNSG mice were inoculated with nonalcoholic PBMCs in the same fashion (control PBMC chimeras). Because gNSG mice do not carry any functional T cells, B cells, NK cells, macrophages, or neutrophils (36)(37)(38)(39), the chimeras display similar antibacterial resistance shown by the PBMC donors (35). To standardize the severity of infection with these two pathogens in humanized murine chimeras, control PBMC chimeras created with various numbers of PBMCs were exposed to various doses of the pathogens.…”

“…NSG mice are described as mice lacking functional T cells, B cells, and NK cells (35)(36)(37)(38)(39). Also, NSG mice are carriers of macrophages with defective functions for phagocytosis, digestion, and Ag presentation (35)(36)(37)(38)(39). All NSG mice were exposed to whole-body gamma radiation (4 Gy) to deplete neutrophils (gNSG mice).…”

Role of M2b Macrophages in the Acceleration of Bacterial Translocation and Subsequent Sepsis in Mice Exposed to Whole Body [137Cs] Gamma-Irradiation

“…NOD/scid IL-2Rg null mice have been defined as immunodeficient mice lacking functional T cells, B cells, and NK cells. Also, these mice have reduced dendritic functions and defective Mf (14)(15)(16)(17). These mice were treated i.p.…”