Disparate Recruitment and Retention of Plasmacytoid Dendritic Cells to The Small Intestinal Mucosa between Young and Aged Mice.

Plasmacytoid dendritic cells (pDC), a highly specialized class of innate immune cells that serve as rapid sensors of danger signals in circulation or in lymphoid tissue are well studied. However, there remains knowledge gaps about age-dependent changes of pDC function in the intestinal mucosa. Here, we report that under homeostatic conditions, the proportion of pDC expressing C-C chemokine receptor 9 (CCR9) in the intestinal intraepithelial cell (iIEC) population is comparable between young (2-4 months) and aged (18-24 months) mice, but the absolute numbers of iIEC and pDC are significantly lower in aged mice.

TLR9 signaling in fibroblastic reticular cells regulates peritoneal immunity.

Fibroblastic reticular cells (FRCs), a subpopulation of stromal cells in lymphoid organs and fat-associated lymphoid clusters (FALCs) in adipose tissue, play immune-regulatory roles in the host response to infection and may be useful as a form of cell therapy in sepsis. Here, we found an unexpected major role of TLR9 in controlling peritoneal immune cell recruitment and FALC formation at baseline and after sepsis induced by cecal ligation and puncture (CLP). TLR9 regulated peritoneal immunity via suppression of chemokine production by FRCs.

Innate-Like Lymphocytes Are Immediate Participants in the Hyper-Acute Immune Response to Trauma and Hemorrhagic Shock.

Adverse outcomes following severe traumatic injury are frequently attributed to a state of immunological dysfunction acquired during treatment and recovery. Recent genomic evidence however, suggests that the trajectory toward development of multiple organ dysfunction syndrome (MODS) is already in play at admission (<2 h following injury). Improved understanding of the molecular events during the hyper-acute immunological response to trauma, <2 h following injury, may reveal opportunities to ameliorate organ injury and expedite recovery.

Interleukin-33 contributes to ILC2 activation and early inflammation-associated lung injury during abdominal sepsis.

Sepsis is defined as infection with organ dysfunction due to a dysregulated immune response. The lung is one of the most vulnerable organs at the onset of sepsis. Interleukin (IL)-33 can be released by injured epithelial and endothelial cells in the lung and regulate immune activation and infiltration.

Platelet HMGB1 is required for efficient bacterial clearance in intra-abdominal bacterial sepsis in mice.

Thrombocytopenia impairs host defense and hemostasis in sepsis. However, the mechanisms of how platelets regulate host defense are not fully understood. High-mobility group box 1 (HMGB1), a danger-associated molecular pattern protein, is released during infection and contributes to the pathogenesis of sepsis.

Deep vein thrombosis in mice is regulated by platelet HMGB1 through release of neutrophil-extracellular traps and DNA.

Venous thromboembolic (VTE) disease, consisting of deep venous thrombosis (DVT) and pulmonary embolism (PE) is a leading cause of morbidity and mortality. Current prophylactic measures are insufficient to prevent all occurrence in part due to an incomplete understanding of the underlying pathophysiology. Mounting evidence describes interplay between activation of the innate immune system and thrombus development.

IL33-mediated ILC2 activation and neutrophil IL5 production in the lung response after severe trauma: A reverse translation study from a human cohort to a mouse trauma model.

Background: The immunosuppression and immune dysregulation that follows severe injury includes type 2 immune responses manifested by elevations in interleukin (IL) 4, IL5, and IL13 early after injury. We hypothesized that IL33, an alarmin released early after tissue injury and a known regulator of type 2 immunity, contributes to the early type 2 immune responses after systemic injury.

Methods And Findings: Blunt trauma patients admitted to the trauma intensive care unit of a level I trauma center were enrolled in an observational study that included frequent blood sampling.

NK1.1 cells promote sustained tissue injury and inflammation after trauma with hemorrhagic shock.

Various cell populations expressing NK1.1 contribute to innate host defense and systemic inflammatory responses, but their role in hemorrhagic shock and trauma remains uncertain. NK1.

Role of the IL-33-ST2 axis in sepsis.

Sepsis remains a major clinical problem with high morbidity and mortality. As new inflammatory mediators are characterized, it is important to understand their roles in sepsis. Interleukin 33 (IL-33) is a recently described member of the IL-1 family that is widely expressed in cells of barrier tissues.

Graft-infiltrating host dendritic cells play a key role in organ transplant rejection.

Successful engraftment of organ transplants has traditionally relied on preventing the activation of recipient (host) T cells. Once T-cell activation has occurred, however, stalling the rejection process becomes increasingly difficult, leading to graft failure. Here we demonstrate that graft-infiltrating, recipient (host) dendritic cells (DCs) play a key role in driving the rejection of transplanted organs by activated (effector) T cells.

Choosing and remaining in mental health nursing: perceptions of Western Australian nurses.

Mental health nursing has an ageing workforce with a critical shortage of nurses in Western Australia. Additionally, mental health is not the preferred career for many graduate nurses. Current challenges with recruitment and retention suggest that strategies are needed to address this issue.

Toll-like receptor 4 regulates platelet function and contributes to coagulation abnormality and organ injury in hemorrhagic shock and resuscitation.

Background: Growing evidence indicates that the presence of toll-like receptor 4 (TLR4) on platelets is a key regulator of platelet number and function. Platelets exposed to TLR4 agonists may serve to activate other cells such as neutrophils and endothelial cells in sepsis and other inflammatory conditions. The functional significance of platelet TLR4 in hemorrhagic shock (HS), however, remains unexplored.

B cells mediate chronic allograft rejection independently of antibody production.

Chronic rejection is the primary cause of long-term failure of transplanted organs and is often viewed as an antibody-dependent process. Chronic rejection, however, is also observed in mice and humans with no detectable circulating alloantibodies, suggesting that antibody-independent pathways may also contribute to pathogenesis of transplant rejection. Here, we have provided direct evidence that chronic rejection of vascularized heart allografts occurs in the complete absence of antibodies, but requires the presence of B cells.

Combined in silico, in vivo, and in vitro studies shed insights into the acute inflammatory response in middle-aged mice.

We combined in silico, in vivo, and in vitro studies to gain insights into age-dependent changes in acute inflammation in response to bacterial endotoxin (LPS). Time-course cytokine, chemokine, and NO2 (-/)NO3 (-) data from "middle-aged" (6-8 months old) C57BL/6 mice were used to re-parameterize a mechanistic mathematical model of acute inflammation originally calibrated for "young" (2-3 months old) mice. These studies suggested that macrophages from middle-aged mice are more susceptible to cell death, as well as producing higher levels of pro-inflammatory cytokines, vs.

Selective roles for toll-like receptors 2, 4, and 9 in systemic inflammation and immune dysfunction following peripheral tissue injury.

Background: Toll-like receptors (TLRs) detect endogenous ligands released after trauma and contribute to the proinflammatory response to injury. Posttraumatic mortality correlates with the extent of the immunoinflammatory response to injury that is composed of a complex regulation of innate and adaptive immune responses. Although TLRs are known to modulate innate immune responses, their role in the suppression of lymphocyte responses following traumatic tissue injury is unclear.

Cognate antigen directs CD8+ T cell migration to vascularized transplants.

The migration of effector or memory T cells to the graft is a critical event in the rejection of transplanted organs. The prevailing view is that the key steps involved in T cell migration - integrin-mediated firm adhesion followed by transendothelial migration - are dependent on the activation of Gαi-coupled chemokine receptors on T cells. In contrast to this view, we demonstrated in vivo that cognate antigen was necessary for the firm adhesion and transendothelial migration of CD8+ effector T cells specific to graft antigens and that both steps occurred independent of Gαi signaling.

Inducible nitric oxide synthase contributes to immune dysfunction following trauma.

Trauma results in a persistent depression in adaptive immunity, which contributes to patient morbidity and mortality. This state of immune paralysis following trauma is characterized by a change in cell-mediated immunity, specifically a depression in T-cell function and a shift toward TH2 T-cell phenotype. Upregulation of inducible nitric oxide synthase (iNOS) is well recognized after injury and contributes to the inflammatory response and organ damage early after trauma.

Memory T cells migrate to and reject vascularized cardiac allografts independent of the chemokine receptor CXCR3.

Background: Memory T cells migrate to and reject transplanted organs without the need for priming in secondary lymphoid tissues, but the mechanisms by which they do so are not known. Here, we tested whether CXCR3, implicated in the homing of effector T cells to sites of infection, is critical for memory T-cell migration to vascularized allografts.

Methods: CD4 and CD8 memory T cells were sorted from alloimmunized CXCR3 and wildtype B6 mice and cotransferred to congenic B6 recipients of BALB/c heart allografts.

A role for connexin43 in macrophage phagocytosis and host survival after bacterial peritoneal infection.

The pathways that lead to the internalization of pathogens via phagocytosis remain incompletely understood. We now demonstrate a previously unrecognized role for the gap junction protein connexin43 (Cx43) in the regulation of phagocytosis by macrophages and in the host response to bacterial infection of the peritoneal cavity. Primary and cultured macrophages were found to express Cx43, which localized to the phagosome upon the internalization of IgG-opsonized particles.

Systemic inflammation and end organ damage following trauma involves functional TLR4 signaling in both bone marrow-derived cells and parenchymal cells.

Endogenous damage-associated molecular pattern (DAMP) molecules are released from cells during traumatic injury, allowing them to interact with pattern recognition receptors such as the toll-like receptors (TLRs) on other cells and subsequently, to stimulate inflammatory signaling. TLR4, in particular, plays a key role in systemic and remote organ responses to hemorrhagic shock (HS) and peripheral tissue injury in the form of bilateral femur fracture. TLR4 chimeric mice were generated to investigate the cell lineage in which functional TLR4 is needed to initiate the injury response to trauma.

Bone marrow-derived CD8alpha+TCR- cells that facilitate allogeneic bone marrow transplantation are a mixed population of lymphoid and myeloid progenitors.

Objective: We have characterized a hematopoietic cell population isolated from murine bone marrow that can facilitate purified hematopoietic stem cell engraftment across fully allogeneic major histocompatibility complex barriers. These facilitating cells (FCs) are classically identified as CD8alpha(+)TCR(-) by flow cytometry. Prior work has demonstrated that FCs are comprised of a heterogeneous cell population with both lymphoid and myeloid phenotypes.

Leukocyte-derived inducible nitric oxide synthase mediates murine postoperative ileus.

Objective: To provide evidence that iNOS expression solely in leukocytes plays a role in postoperative ileus.

Summary Background Data: Intestinal handling initiates a molecular and cellular muscularis inflammation that has been associated with iNOS expression and ileus. The specific cellular source of iNOS is a matter of speculation.

Hepatic ischemia/reperfusion injury involves functional TLR4 signaling in nonparenchymal cells.

Endogenous ligands from damaged cells, so-called damage-associated molecular pattern molecules, can activate innate immunity via TLR4 signaling. Hepatic warm ischemia and reperfusion (I/R) injury and inflammation is largely TLR4 dependent. We produced TLR4 chimeric mice to assess whether the TLR4-dependent injury required TLR4 expression on liver parenchymal or nonparenchymal cells.

Use of a Clostridium perfringens vector to express high levels of SIV p27 protein for the development of an oral SIV vaccine.

Clostridium perfringens is a normal bacterial flora of the small and large intestines of humans and other animals. The current study investigates the potential use of a noncytotoxic C. perfringens as an oral vaccine vehicle for expression and intestinal delivery of a large amount of SIV antigens.

Carbon monoxide inhibits T lymphocyte proliferation via caspase-dependent pathway.

T lymphocyte activation and proliferation is involved in many pathological processes. We have recently shown that carbon monoxide (CO), an enzymatic product of heme oxygenase-1 (HO-1), confers potent antiproliferative effects in airway and vascular smooth muscle cells. The purpose of this study was to determine whether CO can inhibit T lymphocyte proliferation and then to determine the mechanism by which CO can modulate T lymphocyte proliferation.