Resveratrol attenuates TLR-4 mediated inflammation and elicits therapeutic potential in models of sepsis.

Sepsis is a potentially fatal condition triggered by systemic inflammatory response to infection. Due to the heightened immune reactivity and multi-organ pathology, treatment options are limited and several clinical trials have not produced the desired outcome, hence the interest in the discovery of novel therapeutic strategies. The polyphenol resveratrol (RSV) has shown promise against several pathological states, including acute and chronic inflammation. In this study, we evaluated its therapeutic potential in a murine model of sepsis and in patients undergoing transrectal ultrasound biopsy. RSV was able to inhibit lipopolysaccharide (LPS) stimulated inflammatory responses through blocking Phospholipase D (PLD) and its downstream signaling molecules SphK1, ERK1/2 and NF-κB. In addition, RSV treatment resulted in the downregulation of MyD88, an adaptor molecule in the TLR4 signaling pathway, and this effect at least in part, involved RSV-induced autophagy. Notably, RSV protected mice against polymicrobial septic shock induced upon cecal ligation and puncture, and inhibited pro-inflammatory cytokine production by human monocytes from transrectal ultrasound (TRUS) biopsy patients. Together, these findings demonstrate the immune regulatory activity of RSV and highlight its therapeutic potential in the management of sepsis.

Gene expression profiling reveals the defining features of the classical, intermediate, and nonclassical human monocyte subsets.

New official nomenclature subdivides human monocytes into 3 subsets: the classical (CD14(++)CD16(-)), intermediate (CD14(++)CD16(+)), and nonclassical (CD14(+)CD16(++)) monocytes. This introduces new challenges, as monocyte heterogeneity is mostly understood based on 2 subsets, the CD16(-) and CD16(+) monocytes. Here, we comprehensively defined the 3 circulating human monocyte subsets using microarray, flow cytometry, and cytokine production analysis. We find that intermediate monocytes expressed a large majority (87%) of genes and surface proteins at levels between classical and nonclassical monocytes. This establishes their intermediary nature at the molecular level. We unveil the close relationship between the intermediate and nonclassic monocytes, along with features that separate them. Intermediate monocytes expressed highest levels of major histocompatibility complex class II, GFRα2 and CLEC10A, whereas nonclassic monocytes were distinguished by cytoskeleton rearrangement genes, inflammatory cytokine production, and CD294 and Siglec10 surface expression. In addition, we identify new features for classic monocytes, including AP-1 transcription factor genes, CLEC4D and IL-13Rα1 surface expression. We also find circumstantial evidence supporting the developmental relationship between the 3 subsets, including gradual changes in maturation genes and surface markers. By comprehensively defining the 3 monocyte subsets during healthy conditions, we facilitate target identification and detailed analyses of aberrations that may occur to monocyte subsets during diseases.

Impact of age on T cell signaling: a general defect or specific alterations?

Decreased immune responsiveness associated with aging is generally termed "immunosenescence". Several theories have been proposed to explain age-related declines in immune responses. Here, we will focus on and describe potential defects in T cell signal transduction from the membrane to the nucleus, leading to changes in the type, intensity and duration of the response as a major factor contributing to immunosenescence. We will first detail T cell signaling through the T cell receptor (TCR), CD28 and IL-2 receptor (IL-2R) and then discuss the observed age-related alterations to these signaling pathways. The role of membrane rafts in T cell signaling and T cell aging will be described. These factors will be considered in the context of the notion that age-related changes to T cell signaling may be attributed to changes in the functionality of the T cells due to shifts in T cell subpopulations with age. For this reason, we conclude by highlighting the application of multiparametric signaling analysis in leukocyte subsets using flow cytometry as a means to obtain a clearer picture with respect to age-related changes to immune signaling.