Absence of CC chemokine receptor 8 enhances innate immunity during septic peritonitis

An effective clearance of microbes is crucial in host defense during infection. In the present study, we demonstrate that CC chemokine receptor 8 (CCR8) skews innate immune response during septic peritonitis induced by cecal ligation and puncture (CLP). CCR8 was expressed in resident peritoneal macrophages and elicited leukocytes during CLP in the wildâ type CCR8+/+ mice. CCR8â /â mice were resistant to CLPâ induced lethality relative to CCR8+/+ mice, and this resistance was associated with an augmented bacterial clearance in CCR8â /â mice. In vitro, peritoneal macrophages from CCR8â /â mice, but not neutrophils, exhibited enhanced bactericidal activities relative to those from CCR8+/+ mice. Upon stimulation with the bacterial component LPS, elevated levels of superoxide generation, lysosomal enzyme release, and nitric oxide generation, effector molecules for bacterial killing were detected in CCR8â /â macrophages relative to CCR8+/+ macrophages. In addition, CCR8â /â macrophages produced significantly higher levels than CCR8+/+ macrophages of several cytokines and chemokines known to augment bactericidal activities of leukocytes that include TNFâ α, ILâ 12, macrophageâ derived chemokine (MDC/CCL22), macrophage inflammatory protein (MIP)â 2, and KC. Altogether, these results indicate that CCR8 may have a negative impact on host defense during septic peritonitis, providing a new paradigm for the role of CCR8 in innate immunity.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154456/1/fsb2fj041728fje.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154456/2/fsb2fj041728fje-sup-0001.pd

IL-4-secreting CD4+ T cells are crucial to the development of CD8+ T-cell responses against malaria liver stages.

CD4+ T cells are crucial to the development of CD8+ T cell responses against hepatocytes infected with malaria parasites. In the absence of CD4+ T cells, CD8+ T cells initiate a seemingly normal differentiation and proliferation during the first few days after immunization. However, this response fails to develop further and is reduced by more than 90%, compared to that observed in the presence of CD4+ T cells. We report here that interleukin-4 (IL-4) secreted by CD4+ T cells is essential to the full development of this CD8+ T cell response. This is the first demonstration that IL-4 is a mediator of CD4/CD8 cross-talk leading to the development of immunity against an infectious pathogen

Early self-regulatory mechanisms control the magnitude of CD8+ T cell responses against liver stages of murine malaria.

Following immunization with Plasmodium yoelii sporozoites, the CD8(+) T cell population specific for the SYVPSAEQI epitope expressed in sporozoite and liver stages of this malaria parasite revealed the existence of a short term Ag presentation process that translated into a single clonal burst. Further expansion of this CD8(+) T cell population in conditions of sustained Ag exposure and additional supply of naive cells was inhibited by regulatory mechanisms that were developed as early as 24-48 h after priming. Studies using mouse models for Plasmodium or influenza virus infections revealed that this mechanism is Ag specific and is mediated by activated CD8(+) T cells that inhibit the priming of naive cells. This interference of the priming of naive cells appeared to result from limited access to Ag-presenting dendritic cells, which become disabled or are eliminated after contact with activated cells. Thus, concomitantly with the development of their effector antimicrobial capacity, CD8(+) T cells also acquire a self-regulatory role that is likely to represent one of the earliest mechanisms induced in the course of an immune response and that limits the magnitude of the early expansion of CD8(+) T lymphocytes reactive to microorganisms

c-Fos-Deficient Mice Are Susceptible to Salmonella enterica Serovar Typhimurium Infection

c-Fos is a component of transcription factor AP-1. We show that macrophages lacking c-Fos exhibit enhanced production of proinflammatory cytokines, potentiated NF-κB phosphorylation, and increased cell death following Salmonella enterica serovar Typhimurium infection. Furthermore, mice lacking c-Fos are highly susceptible to infection, suggesting that c-Fos confers resistance to Salmonella infection in mice

Flagella Facilitate Escape of Salmonella from Oncotic Macrophages▿ †

The intracellular parasite Salmonella enterica serovar Typhimurium causes a typhoid-like systemic disease in mice. Whereas the survival of Salmonella in phagocytes is well understood, little has been documented about the exit of intracellular Salmonella from host cells. Here we report that in a population of infected macrophages Salmonella induces “oncosis,” an irreversible progression to eukaryotic cell death characterized by swelling of the entire cell body. Oncotic macrophages (OnMφs) are terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling negative and lack actin filaments (F-actin). The plasma membrane of OnMφs filled with bacilli remains impermeable, and intracellular Salmonella bacilli move vigorously using flagella. Eventually, intracellular Salmonella bacilli intermittently exit host cells in a flagellum-dependent manner. These results suggest that induction of macrophage oncosis and intracellular accumulation of flagellated bacilli constitute a strategy whereby Salmonella escapes from host macrophages

Cytoplasmic Kinase Network Mediates Defense Response to <i>Spodoptera litura</i> in Arabidopsis

Plants defend against folivores by responding to folivore-derived elicitors following activation of signaling cascade networks. In Arabidopsis, HAK1, a receptor-like kinase, responds to polysaccharide elicitors (Frα) that are present in oral secretions of Spodoptera litura larvae to upregulate defense genes (e.g., PDF1.2) mediated through downstream cytoplasmic kinase PBL27. Here, we explored whether other protein kinases, including CPKs and CRKs, function with PBL27 in the intracellular signaling network for anti-herbivore responses. We showed that CRK2 and CRK3 were found to interact with PBL27, but CPKs did not. Although transcripts of PDF1.2 were upregulated in leaves of wild-type Arabidopsis plants in response to mechanical damage with Frα, this failed in CRK2- and PBL27-deficient mutant plants, indicating that the CRK2/PBL27 system is predominantly responsible for the Frα-responsive transcription of PDF1.2 in S. litura-damaged plants. In addition to CRK2-phosphorylated ERF13, as shown previously, ethylene signaling in connection to CRK2-phosphorylated PBL27 was predicted to be responsible for transcriptional regulation of a gene for ethylene response factor 13 (ERF13). Taken together, these findings show that CRK2 regulates not only ERF13 phosphorylation but also PBL27-dependent de novo synthesis of ERF13, thus determining active defense traits against S. litura larvae via transcriptional regulation of PDF1.2