Sense Danger Research Articles

Research advances of inflammasome and its role in sepsis

Inflammasomes are high-molecular-weight, multiprotein complexes in cells, which are assembled after cytoplasmic nucleotide-binding oligomerization domain like receptors (NLRs) sense pathogens and danger signals. The inflammasome can activate caspase-1, and later makes the pro-IL-1β, proIL-18 precursor mature by cleavaging, thereby mediates the innate immunity. Dysregulation of inflammasomes plays an important role in the development of sepsis and other immune inflammatory diseases, thus inflammasome may be a new target for prevention and treatment of sepsis.

Monogenic IL-1 mediated autoinflammatory and immunodeficiency syndromes: Finding the right balance in response to danger signals

Interleukin-1 was the first cytokine identified and is a powerful inducer of fever and inflammation. The biologically active receptor for IL-1, shares signaling pathways with some pathogen recognition receptors, the Toll-like receptors (TLRs) which early on suggested an important role in innate immune function. The discovery that some intracellular "danger receptors", the NOD like receptors (NLRs) can assemble to form multimolecular platforms, the inflammasomes, that not only sense intracellular danger but also activate IL-1beta, has provided the molecular basis for the integration of IL-1 as an early response mediator in danger recognition. The critical role of balancing IL-1 production and signaling in human disease has recently been demonstrated in rare human monogenic diseases with mutations that affect the meticulous control of IL-1 production, release and signaling by leading to decreased or increased TLR/IL-1 signaling. In diseases of decreased TLR/IL-1 signaling (IRAK-4 and MyD88 deficiencies) patients are at risk for infections with gram positive organisms; and in diseases of increased signaling, patients develop systemic autoinflammatory diseases (cryopyrin-associated periodic syndromes (CAPS), and deficiency of the IL-1 receptor antagonist (DIRA)). Monogenic defects in a number of rare diseases that affect the balance of TLR/IL-1 signaling have provided us with opportunities to study the systemic effects of IL-1 in human diseases. The molecular defects in CAPS and DIRA provided a therapeutic rationale for targeting IL-1 and the impressive clinical results from IL-1 blocking therapies have undoubtedly confirmed the pivotal role of IL-1 in human disease and spurred the exploration of modifying IL-1 signaling in a number of genetically complex common human diseases.

Current concepts of molecular defence mechanisms operative during urinary tract infection

Mucosal tissues such as the gastrointestinal tract are typically exposed to a tremendous number of microorganisms and many of them are potentially dangerous to the host. In contrast, the urogenital tract is rather infrequently colonized with bacterial organisms and also devoid of physical barriers as a multi-layered mucus or ciliated epithelia, thereby necessitating separate host defence mechanisms. Recurrent urinary tract infection (UTI) represents the successful case of microbial host evasion and poses a major medical and economic health problem. During recent years considerable advances have been made in our understanding of the mechanisms underlying the immune homeostasis of the urogenital tract. Hence, the system of pathogen-recognition receptors including the Toll-like receptors (TLRs) is able to sense danger signalling and thus activate the host immune system of the genitourinary tract. Additionally, various soluble antimicrobial molecules including iron-sequestering proteins, defensins, cathelicidin and Tamm-Horsfall protein (THP), as well as their role for the prevention of UTI by modulating innate and adaptive immunity, have been more clearly defined. Furthermore, signalling mediators like cyclic adenosine monophosphate (cAMP) or the circulatory hormone vasopressin were shown to be involved in the defence of uropathogenic microbes and maintenance of mucosal integrity. Beyond this, specific receptors e.g. CD46 or beta1/beta 3-integrins, have been elucidated that are hijacked by uropathogenic E. coli to enable invasion and survival within the urogenital system paving the way for chronic forms of urinary tract infection. Collectively, the majority of these findings offer novel avenues for basic and translational research implying effective therapies against the diverse forms of acute and chronic UTI.

Spinal p38 MAP kinase regulates peripheral cholinergic outflow

Spinal p38 MAP kinase regulates peripheral cholinergic outflow

Psychoneuroimmunology – Cross-talk between the immune and nervous systems

Psychoneuroimmunology is a relatively new field of study that investigates interactions between behaviour and the immune system, mediated by the endocrine and nervous systems. The immune and central nervous system (CNS) maintain extensive communication. On the one hand, the brain modulates the immune system by hardwiring sympathetic and parasympathetic nerves (autonomic nervous system) to lymphoid organs. On the other hand, neuroendocrine hormones such as corticotrophin-releasing hormone or substance P regulate cytokine balance. Vice versa, the immune system modulates brain activity including sleep and body temperature. Based on a close functional and anatomical link, the immune and nervous systems act in a highly reciprocal manner. From fever to stress, the influence of one system on the other has evolved in an intricate manner to help sense danger and to mount an appropriate adaptive response. Over recent decades, reasonable evidence has emerged that these brain-to-immune interactions are highly modulated by psychological factors which influence immunity and immune system-mediated disease.

Réponse inflammatoire et polytraumatisme : mise au point

Multiple organ failure (MOF) remains the leading cause of death after severe trauma. The systemic inflammatory response syndrome (SIRS) and the neutrophils that accumulate in organs are critically involved in early MOF. Late MOF is septic, and associated with a selective decreased capacity of patients' monocytes to produce proinflammatory cytokines in response to endotoxin (LPS) ex vivo. Toll-like receptors (TLRs) are a critical component of innate immunity. Within the TLR family, TLR2 and TLR4 sense specific microbial products and danger associated molecular patterns. TLR4 senses the LPS from Gram negative bacteria, and TLR2 senses bacterial products from Gram positive bacteria. Studying TLRs pathway is of particular interest in the setting of post-traumatic MOF. TLRs on immune cells (neutrophils and monocytes) play a major role in the creation and the control of inflammatory processes through the signaling pathways of NF-κB and MAP kinases. Recently, it was demonstrated that early alterations in leucocytes activation patterns, particularly involving the ability to activate NF-kappaB and regulating kinases after an ex vivo TLR4 stimulation of immune cells, contribute to subsequent clinical course in ARDS and severe trauma. The development of immunomonitoring will help in the selection of patients at risk of post-traumatic complications, and thereby, the choice of the most appropriate treatment protocols. Finally, there is reason to believe that future studies may demonstrate a beneficial role for immunomodulatory therapies in carefull defined groups of patients.

Toll-Like Receptors-Intrarenal Mechanisms beyond Immune Function: Renal-Associated TLR2 Mediates Ischemia/Reperfusion Injury in the Kidney.

Toll-Like Receptors-Intrarenal Mechanisms beyond Immune Function: Renal-Associated TLR2 Mediates Ischemia/Reperfusion Injury in the Kidney.

Epicubenol and Ferruginol induce DC from human monocytes and differentiate IL-10-producing regulatory T cells in vitro

Epicubenol and 19-hydroxyferruginol (Ferruginol) are sesquiterpenes isolated from the black heartwood of Cryptomeria japonica. Dendritic cells (DC) are specialized antigen-presenting cells that monitor the antigenic environment and activate naïve T cells. The role of DC is not only to sense danger but also to tolerize the immune system to antigens encountered in the absence of maturation/inflammatory stimuli. In this study, we attempted to investigate the effects of Epicubenol and Ferruginol on the phenotypic and functional maturation of human monocytes-derived DC in vitro. Human monocytes were cultured with GM-CSF and IL-4 for 6 days under standard conditions, followed by another 2 days with Epicubenol or Ferruginol. The expression levels of CD1a, CD83, and HLA-DR as expressed by mean fluorescence intensity (MFI) on Epicubenol-primed DC or Ferruginol-primed DC were enhanced. Allogeneic Epicubenol-primed DC or Ferruginol-primed DC co-cultured with naïve T cells at 1:5 ratio, secreted IL-10 and TGF-β, but little IL-4. Moreover, T cells that develop in co-culture of Epicubenol-primed DC or Ferruginol-primed DC and naïve T cells at 1:5 ratio suppressed the proliferation of autologous T cells at Treg cells: Ttarget cells and this suppression of proliferation was inhibited by anti-IL-10 mAb. The expression of FoxP3 mRNA on T cells that develop in co-culture of Epicubenol-primed DC or Ferruginol-primed DC and naïve T cells was lower. From these results, Epicubenol and Ferruginol may induce IL-10-producing Treg 1 cells from naïve T cells by modulating DC function. It seems that Epicubenol and Ferruginol appear to be a target for tolerance after transplantation and in autoimmune diseases.

Differentiation of Tr1 cells by immature dendritic cells requires IL-10 but not CD25+CD4+ Tr cells

AbstractDendritic cells (DCs) are specialized antigen-presenting cells that monitor the antigenic environment and activate naive T cells. The role of DCs is not only to sense danger but also to tolerize the immune system to antigens encountered in the absence of maturation/inflammatory stimuli. Indeed, if a naive T cell encounters its antigen on immature DCs (iDCs), it may differentiate into a T-regulatory (Tr) rather than a T-effector cell. However, little is known about the mechanisms by which iDCs differentiate Tr cells. We developed a standardized and highly reproducible protocol to differentiate Tr cells by repetitive exposure of naive peripheral blood CD4+ T cells to allogeneic iDCs. The resultant Tr cells are phenotypically and functionally identical to type 1 Tr (Tr1) cells because their generation requires production of IL-10 by iDCs, and they suppress T-cell responses through an interleukin-10 (IL-10)– and a transforming growth factor β (TGF-β)–dependent mechanism. In addition, Tr1 cells induced by iDCs do not require the presence of CD4+CD25+ Tr cells for their generation, nor do they express high constitutive levels of CD25 or the transcription factor FoxP3. Thus, iDCs can drive the differentiation of Tr1 cells and can be used to generate large numbers of alloantigen-specific Tr1 cells for clinical use as a cellular therapy to restore peripheral tolerance.