The essential role of the intestinal microbiota in facilitating acute inflammatory responses

The restoration of blood flow, i.e., reperfusion, is the treatment of choice to save viable tissue following acute ischemia of a vascular territory. Nevertheless, reperfusion can be accompanied by significant inflammatory events that limit the beneficial effects of blood flow restoration. To evaluate the potential role of the intestinal microbiota in facilitating the development of tissue injury and systemic inflammation, germ-free and conventional mice were compared in their ability to respond to ischemia and reperfusion injury. In conventional mice, there was marked local (intestine) and remote (lung) edema formation, neutrophil influx, hemorrhage, and production of TNF-alpha, KC, MIP-2, and MCP-1. Moreover, there was an increase in the concentration of serum TNF-alpha and 100% lethality. In germ-free mice, there was no local, remote, or systemic inflammatory response or lethality after intestinal ischemia and reperfusion and, in contrast to conventional mice, germ-free animals produced greater amounts of IL-10. Similar results were obtained after administration of LPS, i.e., little production of TNF-alpha or lethality and production of IL-10 after LPS in germ-free mice. Blockade of IL-10 with Abs induced marked inflammation and lethality in germ-free mice after ischemia and reperfusion or LPS administration, demonstrating that the ability of these mice to produce IL-10 was largely responsible for their "no inflammation" phenotype. This was consistent with the prevention of reperfusion-associated injury by the exogenous administration of IL-10 to conventional mice. Thus, the lack of intestinal microbiota is accompanied by a state of active IL-10-mediated inflammatory hyporesponsiveness.     

The role of hyperglycemia in mechanisms of exacerbated inflammatory responses within the oral cavity

Immune modulating factors are necessary for pathogen clearance, but also contribute to host tissues damage, as those seen in periodontal diseases. Many of these responses can be exacerbated by host conditions including type 2 diabetes [T2D], where toll-like receptor 4 [TLR4] and the receptor for advanced glycated end products [RAGE] play a significant role. Here we investigate causality associated with the increase in inflammatory markers observed in periodontally diseased patients with T2D using multi-variant correlation analysis. Inflammation associated with periodontal diseases, characterized by elevated pro-inflammatory cytokines, innate immune receptor expression, and cellular infiltrate was exacerbated in patients with T2D. In addition, a feed forward loop regulated by poor glycemic control was associated with a loss of mucosal barrier integrity and accumulation of innate immune receptor ligands resulting in an exacerbation of ongoing inflammation, where RAGE and TLR4 cooperated to induce responses in oral epithelial cells, which were exacerbated by hyperglycemia.     

Selective role of PI3K delta in neutrophil inflammatory responses

Although members of the class I phosphoinositide 3-kinases (PI3Ks) have been implicated in neutrophil inflammatory responses, the contribution of the individual PI3K isoforms in neutrophil activation has not been tractable with the non-selective inhibitors, LY294002 and wortmannin. We have developed a novel series of PI3K inhibitors that is selective for PI3K delta, an isoform expressed predominantly in hematopoietic cells. In addition to being selective between members of class I PI3Ks, representatives of these inhibitors such as IC980033 and IC87114 did not inhibit any protein kinases tested. Utilizing these inhibitors we report here a novel role for PI3K delta in neutrophil activation. Inhibition of PI3K delta with IC980033 and IC87114 blocked both fMLP- and TNF1 alpha-induced neutrophil superoxide generation and elastase exocytosis. The PI3K delta inhibitor IC87114 also blocked TNF1 alpha-stimulated elastase exocytosis from neutrophils in a mouse model of inflammation. To our knowledge, this is the first in vivo efficacy demonstration of a PI3K delta inhibitor in an animal model. Inhibition of PI3K delta, however, had no effect on in vitro neutrophil bactericidal activity and Fc gamma R-stimulated superoxide generation. Thus, PI3K delta plays an essential role in certain signaling pathways of neutrophil activation and appears to be an attractive target for the development of an anti-inflammatory therapeutic.     

A new role for T cells in dampening innate inflammatory responses

<正>The inflammatory response is an attempt by a host to protect itself against injurious stimuli and initiate the tissue healing process [1,2]. Although the production of both pro-and anti-inflammatory mediators which occurs mainly within tissues is a systemic process,     

The role of IFN-gamma in immune responses to viral infections of the central nervous system

Interferon (IFN)-γ, is not only a marker of T_H1 CD4, CD8 and natural killer (NK) cells, it is also a critical antiviral mediator which is central to the elimination of viruses from the CNS. In this review, we describe IFN-γ, its receptor, signal transduction from receptor engagement, and antiviral downstream mediators. We demonstrate that although neurons are post-mitotic and non-renewing, they respond to IFN-γ in a fashion similar to peripheral fibroblasts or lymphocytes. We have illustrated this review with details about studies on the role(s) of IFN-γ in the pathogenesis of measles virus (MV), herpes simplex virus (HSV) type 1, and vesicular stomatitis virus (VSV) infections of the CNS. For VSV infection, IFN-γ signals through Jaks 1 and 2 and STAT1 to activate (interferon regulatory factor) IRF-1; although viral protein synthesis is inhibited, PKR is not a critical mediator in the antiviral response to VSV in murine neurons. In contrast, induction of nitric oxide synthase (NOS) type 1 and its production of nitric oxide is essential in the elimination of viruses from neurons.     

The role of osteopontin in inflammatory processes

Osteopontin (OPN) is a matricellular protein that mediates diverse biological functions. OPN is involved in normal physiological processes and is implicated in the pathogenesis of a variety of disease states, including atherosclerosis, glomerulonephritis, cancer, and several chronic inflammatory diseases. Through interactions with several integrins, OPN mediates cell migration, adhesion, and survival in many cell types. OPN also functions as a Th1 cytokine, promotes cell-mediated immune responses, and plays a role in chronic inflammatory and autoimmune diseases. Besides its function in inflammation, OPN is also a regulator of biomineralization and a potent inhibitor of vascular calcification.     

The early development of the lymphatic system in mouse embryos.

The early development of the lymphatic system was studied in embryos of an inbred strain of the laboratory mouse. During the first stage of its development the system is represented by a more or less regular series of small and blind-ending outgrowths of the major embryonic veins which develop in a cranio-caudalward direction from the jugular to the pelvic region. As a result of differences in growth rates of adjacent anatomical structures this series of early lymphatic primordia becomes subdivided into 4 singular primordia and 12 groups of primordia. After the constituents of each group of early primordia have fused, 16 isolated lymphatic plexuses (sacs) are formed of which 14 are in bilaterally symmetric and 2 are in a median line position: i.e. bilaterally: (1) the jugulo-axillary lymph sac situated lateral to the anterior cardinal vein and dorsal to the primitive ulnar vein and its major branch, the external mammary vein, (2) the paratracheal lymph plexus situated medial to the anterior cardinal vein, (3) the internal thoracic lymph plexus situated lateral to the thoracic part of the posterior cardinal vein, (4) the thoracic ducts situated medial to the thoracic part of the posterior cardinal vein, (5) the lumbar lymph plexus situated dorso-lateral to the abdominal part of the posterior cardinal vein, (6) the subcardinal lymph plexus and (7) the iliac lymph plexus situated ventro-lateral to the abdominal part of the posterior cardinal vein; and in the median line: (8) the subtracheal lymph plexus situated at the confluence of the pulmonary veins and (9) the mesenteric lymph plexus situated near the confluence of the splenic and the superior mesenteric veins. Except for some openings at the jugulo-subclavian confluence all connections with the veins disappear. From the primordia extensions grow out centrifugally. They invade the surrounding tissues and, in part, fuse with similar sprouts of adjacent primordia. In this way a continuous system of lymph truncs is formed that opens into the venous system at the jugulo-subclavian confluence.     

The role of albendazole in programmes to eliminate lymphatic filariasis.

Citing earlier advances in the treatment of lymphatic filariasis [particularly the effectiveness of single-dose diethylcarbamazine (DEC) in reducing microfilaraemia and its enhanced effectiveness when co-administered with single-dose ivermectin], Eric Ottesen, Mahroof Ismail and John Horton consider recent studies on the antifilarial activity of albendazole that have led to the current recommendations for its use in single-dose regimens in conjunction with either DEC or ivermectin for large-scale control/elimination programmes. Furthermore, the potential of albendazole as a macrofilaricide for treating individual patients with lymphatic filarial infections is emphasized as one of a number of important research questions that remain to be explored.     

Microanatomy of the intestinal lymphatic system

The intestinal lymphatic system comprises two noncommunicating lymphatic networks: one containing the lacteals draining the villi and the connecting submucosal lymphatic network and one containing the lymphatics that drain the intestine muscular layer. These systems deliver lymph into a common network of collecting lymphatics originating near the mesenteric border. The intestinal lymphatic system serves vital functions in the regulation of tissue fluid homeostasis, immune surveillance, and the transport of nutrients; conversely, this system is affected by, and directly contributes to, disease processes within the intestine. Recent discoveries of specific lymphatic markers, factors promoting lymphangiogenesis, and factors selectively affecting the development of intestinal lymphatics, hold promise for unlocking the role of lymphatics in the pathogenesis of diseases affecting the intestine and for intestinal lymphatic selective therapies. Vital to progress in understanding how the intestinal lymphatic system functions is the integration of recent advances identifying molecular pathways for lymphatic growth and remodeling with advanced imaging modalities to observe lymphatic function and dysfunction in vivo.