CD14 Signaling Restrains Chronic Inflammation through Induction of p38-MAPK/SOCS-Dependent Tolerance

Current thinking emphasizes the primacy of CD14 in facilitating recognition of microbes by certain TLRs to initiate pro-inflammatory signaling events and the importance of p38-MAPK in augmenting such responses. Herein, this paradigm is challenged by demonstrating that recognition of live Borrelia burgdorferi not only triggers an inflammatory response in the absence of CD14, but one that is, in part, a consequence of altered PI3K/AKT/p38-MAPK signaling and impaired negative regulation of TLR2. CD14 deficiency results in increased localization of PI3K to lipid rafts, hyperphosphorylation of AKT, and reduced activation of p38. Such aberrant signaling leads to decreased negative regulation by SOCS1, SOCS3, and CIS, thereby compromising the induction of tolerance in macrophages and engendering more severe and persistent inflammatory responses to B. burgdorferi. Importantly, these altered signaling events and the higher cytokine production observed can be mimicked through shRNA and pharmacological inhibition of p38 activity in CD14-expressing macrophages. Perturbation of this CD14/p38-MAPK-dependent immune regulation may underlie development of infectious chronic inflammatory syndromes

A GATA4-regulated secretory program suppresses tumors through recruitment of cytotoxic CD8 T cells

AbstractThe GATA4 transcription factor acts as a master regulator of development of multiple tissues. GATA4 also acts in a distinct capacity to control a stress-inducible pro-inflammatory secretory program that is associated with senescence, a potent tumor suppression mechanism, but also operates in non-senescent contexts such as tumorigenesis. This secretory pathway is composed of chemokines, cytokines, growth factors, and proteases. Since GATA4 is deleted or epigenetically silenced in cancer, here we examine the role of GATA4 in tumorigenesis in mouse models through both loss-of-function and overexpression experiments. We find that GATA4 promotes non-cell autonomous tumor suppression in multiple model systems. Mechanistically, we show that Gata4-dependent tumor suppression requires cytotoxic CD8 T cells and partially requires the secreted chemokine CCL2. Analysis of transcriptome data in human tumors reveals reduced lymphocyte infiltration in GATA4-deficient tumors, consistent with our murine data. Notably, activation of the GATA4-dependent secretory program combined with an anti-PD-1 antibody robustly abrogates tumor growth in vivo.</jats:p

Participation in and gains from traditional vegetable value chains: A gendered analysis of perceptions of labour, income and expenditure in producers’ and traders’ households

Horticulture is one of the fastest growing subsectors of agriculture in Tanzania. Gender relations in vegetable-producing and vegetable-trading households need to be understood to make value chain development equitable. This study, carried out in northern and central Tanzania, is based on data from surveys, focus group discussions and semi-structured interviews. The perceptions of men and women traders and producers are investigated with regard to labour participation in traditional vegetable value chains and gains (income and expenditure) from it. Farmers were found to report more balanced intra-household labour arrangements paired with less-balanced income and expenditure shares, while traders indicated less-balanced labour contributions that went hand in hand with more-balanced shares of benefits. Farmers related limited household development not only to imbalances in benefits but also to a lack of trust and cooperation between spouses. The importance of gender-transformative approaches in agricultural value chains is emphasized herein