M-CSF Induces Monocyte Survival by Activating NF-κB p65 Phosphorylation at Ser276 via Protein Kinase C

Macrophage colony-stimulating factor (M-CSF) promotes mononuclear phagocyte survival and proliferation. The transcription factor Nuclear Factor-kappaB (NF-κB) is a key regulator of genes involved in M-CSF-induced mononuclear phagocyte survival and this study focused at identifying the mechanism of NF-κB transcriptional activation. Here, we demonstrate that M-CSF stimulated NF-κB transcriptional activity in human monocyte-derived macrophages (MDMs) and the murine macrophage cell line RAW 264.7. The general protein kinase C (PKC) inhibitor Ro-31-8220, the conventional PKCα/β inhibitor Gö-6976, overexpression of dominant negative PKCα constructs and PKCα siRNA reduced NF-κB activity in response to M-CSF. Interestingly, Ro-31-8220 reduced Ser276 phosphorylation of NF-κBp65 leading to decreased M-CSF-induced monocyte survival. In this report, we identify conventional PKCs, including PKCα as important upstream kinases for M-CSF-induced NF-κB transcriptional activation, NF-κB-regulated gene expression, NF-κB p65 Ser276 phosphorylation, and macrophage survival. Lastly, we find that NF-κB p65 Ser276 plays an important role in basal and M-CSF-stimulated NF-κB activation in human mononuclear phagocytes

Human Natural Killer T Cells Are Heterogeneous in Their Capacity to Reprogram Their Effector Functions

BACKGROUND: Natural killer T (NKT) cells are a subset of T cells that help potentiate and regulate immune responses. Although human NKT cell subsets with distinct effector functions have been identified, it is unclear whether the effector functions of these subsets are imprinted during development or can be selectively reprogrammed in the periphery. RESULTS: We found that neonatal NKT cells are predominantly CD4+ and express higher levels of CCR7 and CD62L and lower levels of CD94 and CD161 than adult CD4+ or CD4− NKT cell subsets. Accordingly, neonatal NKT cells were more flexible than adult CD4+ NKT cells in their capacity to acquire Th1- or Th2-like functions upon either cytokine-mediated polarization or ectopic expression of the Th1 or Th2 transcription factors T-bet and GATA-3, respectively. Consistent with their more differentiated phenotype, CD4- NKT cells were predominantly resistant to functional reprogramming and displayed higher cytotoxic function. In contrast to conventional T cells, neither the expression of CXCR3 nor the cytotoxic capacity of neonatal NKT cells could be reprogrammed. CONCLUSIONS AND SIGNIFICANCE: Together, these results suggest that neonatal CD4+, adult CD4+, and adult CD4− NKT may represent unique states of maturation and that some functions of human NKT cells may be developmentally imprinted, while others are acquired similar to conventional T cell subsets during peripheral maturation and differentiation. Given the potent immuno-regulatory functions of NKT cells, these findings have important implications for the development of novel NKT cell-based therapeutics and vaccines

CNS Infiltration of Peripheral Immune Cells: D-Day for Neurodegenerative Disease?

While the central nervous system (CNS) was once thought to be excluded from surveillance by immune cells, a concept known as “immune privilege,” it is now clear that immune responses do occur in the CNS—giving rise to the field of neuroimmunology. These CNS immune responses can be driven by endogenous (glial) and/or exogenous (peripheral leukocyte) sources and can serve either productive or pathological roles. Recent evidence from mouse models supports the notion that infiltration of peripheral monocytes/macrophages limits progression of Alzheimer's disease pathology and militates against West Nile virus encephalitis. In addition, infiltrating T lymphocytes may help spare neuronal loss in models of amyotrophic lateral sclerosis. On the other hand, CNS leukocyte penetration drives experimental autoimmune encephalomyelitis (a mouse model for the human demyelinating disease multiple sclerosis) and may also be pathological in both Parkinson's disease and human immunodeficiency virus encephalitis. A critical understanding of the cellular and molecular mechanisms responsible for trafficking of immune cells from the periphery into the diseased CNS will be key to target these cells for therapeutic intervention in neurodegenerative diseases, thereby allowing neuroregenerative processes to ensue

Mechanisms of activation of innate-like intraepithelial T lymphocytes

Intraepithelial T lymphocytes (T-IEL) contain subsets of innate-like T cells that evoke innate and adaptive immune responses to provide rapid protection at epithelial barrier sites. In the intestine, T-IEL express variable T cell antigen receptors (TCR), with unknown antigen specificities. Intriguingly, they also express multiple inhibitory receptors, many of which are normally found on exhausted or antigen-experienced T cells. This pattern suggests that T-IEL are antigen-experienced, yet it is not clear where, and in what context, T-IEL encounter TCR ligands. We review recent evidence indicating TCR antigens for intestinal innate-like T-IEL are found on thymic or intestinal epithelium, driving agonist selection of T-IEL. We explore the contributions of the TCR and various co-stimulatory and co-inhibitory receptors in activating T-IEL effector functions. The balance between inhibitory and activating signals may be key to keeping these highly cytotoxic, rapidly activated cells in check, and key to harnessing their immune surveillance potential

Bovine cryptosporidiosis: impact, host-parasite interaction and control strategies

International audienceAbstractGastrointestinal disease caused by the apicomplexan parasite Cryptosporidium parvum is one of the most important diseases of young ruminant livestock, particularly neonatal calves. Infected animals may suffer from profuse watery diarrhoea, dehydration and in severe cases death can occur. At present, effective therapeutic and preventative measures are not available and a better understanding of the host–pathogen interactions is required. Cryptosporidium parvum is also an important zoonotic pathogen causing severe disease in people, with young children being particularly vulnerable. Our knowledge of the immune responses induced by Cryptosporidium parasites in clinically relevant hosts is very limited. This review discusses the impact of bovine cryptosporidiosis and describes how a thorough understanding of the host–pathogen interactions may help to identify novel prevention and control strategies

Permeabilization of Kluyveromyces marxianus with Mild Detergent for Whey Lactose Hydrolysis and Augmentation of Mixed Culture

Cheese whey is a by-product of cheese-manufacturing industries, and the utilization of whey is a challenging problem either to use it or dispose it, because only few microorganisms can metabolize the whey lactose. Enzymatic hydrolysis of whey lactose to glucose and galactose by β-galactosidase is the approach for biotechnological application. Kluyveromyces marxianus cells were permeabilized with non-toxic, biodegradable, anionic detergent N-lauroyl sarcosine (N-LS) for the enzyme activity. The permeabilization process parameters (N-LS concentration, solvent volume, temperature and incubation time) were optimized. The maximum β-galactosidase activity of 1,220 IU/g dry weight was obtained using permeabilized cells under optimized conditions. Moreover, viability of the permeabilized cells was also evaluated, which showed that cells were alive; however, viability was reduced by two log cycles. The permeabilized cells were evaluated for whey lactose hydrolysis. The maximum lactose hydrolysis of 91 % was observed with 600 mg (dry cell weight/100 mL) in whey powder (5 % w/v) solution at 180-min incubation, pH 6.5 and 30°C. Further, the hydrolyzed whey was evaluated for amelioration of growth of non-lactose-consuming yeast Saccharomyces cerevisiae. S. cerevisiae was able to grow in hydrolyzed whey simultaneously with K. marxianus. The study confirmed that N-LS could be used to permeabilize K. marxianus cells to make available the enzyme activity

On the restoration of the last relict population of a dragonfly Urothemis edwardsii Selys (Libellulidae: Odonata) in the Mediterranean

The restoration of endangered relict populations is challenging in conservation biology because they require specific environmental conditions within an inhospitable regional climate. Urothemis edwardsii Selys is the most endangered dragonfly in the Mediterranean with only one known relict small population (Lac Bleu) left in Northeast Algeria. With the absence of successful (re-) colonization over the last two decades, the restoration of the species became a top priority. To improve the status of the species in Northeast Algeria, we carried out a reintroduction and translocation scheme during 2011–2015 and assessed the changes in distribution and population size. Our restoration plan led to the emergence of three populations of which one was restored (Lac Noir), one resulted from successful translocation (Lac Tonga Northeast), and one established after successful colonization (Lac Tonga Southwest). In three localities (Lac Noir, Lac Tonga Northeast, and Lac Tonga Southwest), signs of population growth were observed, whereas no significant trend in the source population (Lac Bleu) was detected. A new population (El Graeate) was also recorded in 2015, but its origin is uncertain. Capture-mark-recapture on adults conducted recapture rates and no sign of dispersal between the two sites. Dispersal capacity of the species and conservation implications of adult distribution are discussed. This study highlights the importance of using biological indicators in selecting host habitats for the restoration of critically threatened populations