Abstract Kupffer cells (KCs) are thought to mediate hepatocyte injury via their production of proinflammatory cytokines and reactive oxygen species in response to stress. In this study, we depleted KCs from the liver to examine their role in total warm hepatic ischemia/reperfusion (I/R) injury with bowel congestion. We injected 8-wk-old C57BL/10J mice with liposome-encapsulated clodronate 48 h before 35 min of hepatic ischemia with bowel congestion, followed by 6 or 24 h of reperfusion. KC-depleted animals had a higher mortality rate than diluent-treated animals and a 10-fold elevation in transaminase levels that correlated with increases in centrilobular necrosis. There was extensive LPS binding to the endothelial cells, which correlated with an upregulation of endothelial adhesion molecules in the KC-depleted animals versus diluent-treated animals. There was an increase in the levels of proinflammatory cytokines in KC-depleted animals, and a concomitant decrease in IL-10 levels. When KC-depleted mice were treated with recombinant IL-10, their liver damage profile in response to I/R was similar to diluent-treated animals, and endothelial cell adhesion molecules and proinflammatory cytokine levels decreased. KCs are protective in the liver subjected to total I/R with associated bowel congestion and are not deleterious as previously thought. This protection appears to be due to KC secretion of the potent anti-inflammatory cytokine IL-10.
Mice were injected intravenously with 2 mg of a bovine gamma globulin-penicilloyl (BGG-Pen) conjugate. Cells producing specific antibodies against the protein carrier bovine gamma globulin (BGG) and cells producing specific antibodies against the hapten penicilloyl (Pen) could be distinguished simultaneously in the same spleen section using a combined peroxidase (HRP) and alkaline phosphatase (AP) immunocytochemical technique. AP-BGG conjugate was used for detection of anti-BGG-producing cells and HRP-human serum albumin (HSA)-Pen conjugate, prepared by coupling penicillin to HRP-HSA conjugate, was used for detection of anti-Pen-producing cells in the same spleen section. After performing both HRP and AP cytochemistry, cells with a blue-stained cytoplasm represent anti-BGG-producing cells and cells with a red-stained cytoplasm represent anti-Pen-producing cells.
Abstract The propensity of a range of parasitic helminths to stimulate a Th2 or regulatory cell-biased response has been proposed to reduce the severity of experimental inflammatory bowel disease. We examined whether infection with Schistosoma mansoni, a trematode parasite, altered the susceptibility of mice to colitis induced by dextran sodium sulfate (DSS). Mice infected with schistosome worms were refractory to DSS-induced colitis. Egg-laying schistosome infections or injection of eggs did not render mice resistant to colitis induced by DSS. Schistosome worm infections prevent colitis by a novel mechanism dependent on macrophages, and not by simple modulation of Th2 responses, or via induction of regulatory CD4+ or CD25+ cells, IL-10, or TGF-β. Infected mice had marked infiltration of macrophages (F4/80+CD11b+CD11c−) into the colon lamina propria and protection from DSS-induced colitis was shown to be macrophage dependent. Resistance from colitis was not due to alternatively activated macrophages. Transfer of colon lamina propria F4/80+ macrophages isolated from worm-infected mice induced significant protection from colitis in recipient mice treated with DSS. Therefore, we propose a new mechanism whereby a parasitic worm suppresses DSS-induced colitis via a novel colon-infiltrating macrophage population.
Abstract In the mucosal immune system, resident dendritic cells are specialized for priming Th2-polarized immunity, whereas the Ag-presenting activity of macrophages has been linked with the development of Th1 phenotype. As an immune switch toward Th1 can protect against Th2-mediated allergic response, this study investigated the capacity of lung macrophages to stimulate Th1 responses during the secondary exposure to inhaled allergen, thereby suppressing Th2-mediated allergic airway inflammation in a murine model of allergic asthma. Following airway macrophage depletion in OVA-sensitized mice, lung T cells defaulted to a phenotype that produced less Th1 (IFN-γ) and more Th2 (IL-4 and IL-5) cytokines, leading to more severe airway hyperreactivity and inflammation after intranasal Ag challenge. After OVA pulsing and adoptive transfer, lung macrophages selectively promoted a Th1 response in Ag-sensitized recipients and did not induce pulmonary eosinophilia. By contrast, OVA pulsing and adoptive transfer of a lung cell preparation, consisting of dendritic cells, B cells, and macrophages, promoted a Th2 response with an associated inflammatory response that was suppressed when macrophages were present and pretreated with IFN-γ, but exacerbated when macrophages were depleted before IFN-γ treatment. In addition, Th1-promoting activity of lung macrophages was not related to the autocrine production of IL-12p40. These results suggest that the Th1-promoting APC activity may be an inherent property of the lung macrophage population, and may play an important role, upon stimulation by IFN-γ, in antagonizing an ongoing Th2 immunity and Th2-dependent allergic responses.
Abstract For many years data on the development of specific antibody‐forming cells in lymph nodes were incomplete, fragmentary, and even contradictory. A number of recent studies have been performed, concerning (1) their overall architecture; (2) migration of B‐lymphocytes; (3) localization of accessory cells and T‐lymphocytes which are believed to be involved in humoral immune responses; and (4) localization patterns of specific antibody‐forming cells developing during thymus dependent and thymus independent immune responses. Comparison of these new results with those of earlier studies suggests a single route of migration followed by all cells which will differentiate into antibody‐forming cells. During their differentiation into antibody‐forming plasma cells, antigen reactive B‐cells migrate along the required accessory cells and/or T‐lymphocytes.
Abstract Macrophages adopt an ‘alternative phenotype’ in a Th2-mediated inflammatory environment. Although identified in a wide variety of disease conditions, alternatively activated macrophages (AAMs) have been functionally best studied in helminth infections. The heterogeneity of functions performed by AAMs is attributed to the diverse molecules they express. Since infection with the fungus, Aspergillus fumigatus induces a chronic allergic response in patients with cystic fibrosis and asthma, we investigated the participation of AAMs in the process. We have found that Aspergillus infection promotes early recruitment of AAMs to the lung and the cells possess features of both AAMs and Th2 cells. The AAMs produce Th2 cytokines, which is independent of Dectin-1 signaling. Interestingly, unlike in helminth infections, both AAM recruitment and Th2 cytokine production were found to be independent of IL-4Rα and STAT6. Besides being part of the innate immune response to A.fumigatus, AAMs were also induced during adaptive immune response to the fungus. However, at this later time, AAM recruitment and their typical features were abolished in the absence of IL-4Rα and STAT6. Collectively, our studies show that different signaling pathways regulate the development of AAMs in the innate and adaptive arms of the immune response to A. fumigatus. Being early producers of Th2 cytokines, the presence of AAMs would be deleterious to the host unless regulated efficiently.
Idiopathic pulmonary fibrosis (IPF) is the most common form of interstitial lung disease characterized by the persistence of activated myofibroblasts resulting in excessive deposition of extracellular matrix proteins and profound tissue remodeling. In the present study, the expression of tumor necrosis factor- (TNF-) related apoptosis-inducing ligand (TRAIL) was key to the resolution of bleomycin-induced pulmonary fibrosis. Both in vivo and in vitro studies demonstrated that Gr-1+TRAIL+ bone marrow-derived myeloid cells blocked the activation of lung myofibroblasts. Although soluble TRAIL was increased in plasma from IPF patients, the presence of TRAIL+ myeloid cells was markedly reduced in IPF lung biopsies, and primary lung fibroblasts from this patient group expressed little of the TRAIL receptor-2 (DR5) when compared with appropriate normal samples. IL-13 was a potent inhibitor of DR5 expression in normal fibroblasts. Together, these results identified TRAIL+ myeloid cells as a critical mechanism in the resolution of pulmonary fibrosis, and strategies directed at promoting its function might have therapeutic potential in IPF.
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