Abstract
Interferon-gamma (Ifnγ), a key macrophage activating cytokine, plays pleiotropic roles in host immunity. In this study, the ability of Ifnγ to induce the aggregation of resident mouse adherent peritoneal exudate cells (APECs), consisting primarily of macrophages, was investigated. Cell-cell interactions involve adhesion molecules and, upon addition of Ifnγ, CD11b re-localizes preferentially to the sites of interaction on APECs. A functional role of CD11b in enhancing aggregation is demonstrated using Reopro, a blocking reagent, and siRNA to Cd11b. Studies with NG-methyl-L-arginine (LNMA), an inhibitor of Nitric oxide synthase (Nos), NO donors, e.g., S-nitroso-N-acetyl-DL-penicillamine (SNAP) or Diethylenetriamine/nitric oxide adduct (DETA/NO), and Nos2 -/- mice identified Nitric oxide (NO) induced by Ifnγ as a key regulator of aggregation of APECs. Further studies with Nos2 -/- APECs revealed that some Ifnγ responses are independent of NO: induction of MHC class II and CD80. On the other hand, Nos2 derived NO is important for other functions: motility, phagocytosis, morphology and aggregation. Studies with cytoskeleton depolymerizing agents revealed that Ifnγ and NO mediate the cortical stabilization of Actin and Tubulin which contribute to aggregation of APECs. The biological relevance of aggregation of APECs was delineated using infection experiments with Salmonella Typhimurium (S. Typhimurium). APECs from orally infected, but not uninfected, mice produce high amounts of NO and aggregate upon ex vivo culture in a Nos2-dependent manner. Importantly, aggregated APECs induced by Ifnγ contain fewer intracellular S. Typhimurium compared to their single counterparts post infection. Further experiments with LNMA or Reopro revealed that both NO and CD11b are important for aggregation; in addition, NO is bactericidal. Overall, this study elucidates novel roles for Ifnγ and Nos2 in regulating Actin, Tubulin, CD11b, motility and morphology during the aggregation response of APECs. The implications of aggregation or “group behavior” of APECs are discussed in the context of host resistance to infectious organisms.
Highlights
Cell-cell interactions, an important mode of communication, are fundamental to an organism’s ability to survive and grow
The ability of adherent peritoneal exudate cells (APECs) consisting primarily of macrophages to interact with each other, the mechanisms involved and the possible physiological significance have not been explored
We demonstrate that Ifnγ induces APECs to form aggregates (Fig 1)
Summary
Cell-cell interactions, an important mode of communication, are fundamental to an organism’s ability to survive and grow. In the context of immune responses, physical interactions and biochemical communications between different leukocytes are essential. Are characterized by the formation of ‘immunological synapses.’. Interactions involving immune cells, e.g. APCs with CD4+ T cells, cytotoxic T cells with target cells etc. These integrate signals and promote molecular interactions for an effective immune response [1]. Immune cells of both innate and adaptive arms are known to interact with endothelial cells in the vasculature before extravasating to the sites of inflammation or infection [2]. Cell-cell interactions involving immune cells are essential for the development of host immunity
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