Alveolar Epithelial Type II Cells Activate Alveolar Macrophages and Mitigate P. Aeruginosa Infection

Although alveolar epithelial type II cells (AECII) perform substantial roles in the maintenance of alveolar integrity, the extent of their contributions to immune defense is poorly understood. Here, we demonstrate that AECII activates alveolar macrophages (AM) functions, such as phagocytosis using a conditioned medium from AECII infected by P. aeruginosa. AECII-derived chemokine MCP-1, a monocyte chemoattractant protein, was identified as a main factor in enhancing AM function. We proposed that the enhanced immune potency of AECII may play a critical role in alleviation of bacterial propagation and pneumonia. The ability of phagocytosis and superoxide release by AM was reduced by MCP-1 neutralizing antibodies. Furthermore, MCP-1−/− mice showed an increased bacterial burden under PAO1 and PAK infection vs. wt littermates. AM from MCP-1−/− mice also demonstrated less superoxide and impaired phagocytosis over the controls. In addition, AECII conditioned medium increased the host defense of airway in MCP-1−/− mice through the activation of AM function. Mechanistically, we found that Lyn mediated NFκB activation led to increased gene expression and secretion of MCP-1. Consequently Lyn−/− mice had reduced MCP-1 secretion and resulted in a decrease in superoxide and phagocytosis by AM. Collectively, our data indicate that AECII may serve as an immune booster for fighting bacterial infections, particularly in severe immunocompromised conditions

Host DNA Repair Proteins in Response to Pseudomonas aeruginosa in Lung Epithelial Cells and in Mice ▿

Although DNA repair proteins in bacteria are critical for pathogens' genome stability and for subverting the host defense, the role of host DNA repair proteins in response to bacterial infection is poorly defined. Here, we demonstrate, for the first time, that infection with the Gram-negative bacterium Pseudomonas aeruginosa significantly altered the expression and enzymatic activity of 8-oxoguanine DNA glycosylase (OGG1) in lung epithelial cells. Downregulation of OGG1 by a small interfering RNA strategy resulted in severe DNA damage and cell death. In addition, acetylation of OGG1 is required for host responses to bacterial genotoxicity, as mutations of OGG1 acetylation sites increased Cockayne syndrome group B (CSB) protein expression. These results also indicate that CSB may be involved in DNA repair activity during infection. Furthermore, OGG1 knockout mice exhibited increased lung injury after infection with P. aeruginosa, as demonstrated by higher myeloperoxidase activity and lipid peroxidation. Together, our studies indicate that P. aeruginosa infection induces significant DNA damage in host cells and that DNA repair proteins play a critical role in the host response to P. aeruginosa infection, serving as promising targets for the treatment of this condition and perhaps more broadly Gram-negative bacterial infections

Cross Talk between Follicular Th Cells and Tumor Cells in Human Follicular Lymphoma Promotes Immune Evasion in the Tumor Microenvironment

The microenvironment of human follicular lymphoma (FL), an incurable B-cell non-Hodgkin lymphoma, is thought to play a major role in its pathogenesis and course. Microenvironmental cells of likely importance include follicular helper T cells (T(FH)) and regulatory T cells (Tregs), and understanding their interactions with FL tumor cells is necessary to develop novel therapeutic strategies. We found that IL-4 and CD40L are expressed by intratumoral T(FH) and induce production of CCL17 and CCL22 by FL tumor cells. IL-4 alone induces only CCL17, but enhances stimulation by CD40L of both CCL17 and CCL22. Consistent with our in vitro results, mRNA transcripts of IL-4 correlated with CCL17 but not CCL22 in gene expression profiling studies of FL biopsies, whereas CD40L correlated with both CCL17 and CCL22. Tumor supernatants induced preferential migration of Tregs and IL-4–producing T cells rather than IFN-γ–producing T cells, and antibodies to CCR4 significantly abrogated the migration of Tregs. Our results suggest that through two distinct mechanisms, intratumoral T(FH) induce production of CCL17 and CCL22 by FL tumor cells and facilitate active recruitment of Tregs and IL-4–producing T cells, which in turn may stimulate more chemokine production in a feed-forward cycle. Thus, T(FH) appear to play a major role in generating an immunosuppressive tumor microenvironment that promotes immune escape and tumor survival and growth. Our results provide novel insights into the cross talk between T(FH), tumor cells, and Tregs in FL and offer potential targets for development of therapeutic strategies to overcome immune evasion