PTX3 is an extrinsic oncosuppressor regulating complement-dependent inflammation in cancer.

PTX3 is an essential component of the humoral arm of innate immunity, playing a nonredundant role in resistance against selected microbes and in the regulation of inflammation. PTX3 activates and regulates the Complement cascade by interacting with C1q and with Factor H. PTX3 deficiency was associated with increased susceptibility to mesenchymal and epithelial carcinogenesis. Increased susceptibility of Ptx3(-/-) mice was associated with enhanced macrophage infiltration, cytokine production, angiogenesis, and Trp53 mutations. Correlative evidence, gene-targeted mice, and pharmacological blocking experiments indicated that PTX3 deficiency resulted in amplification of Complement activation, CCL2 production, and tumor-promoting macrophage recruitment. PTX3 expression was epigenetically regulated in selected human tumors (e.g., leiomyosarcomas and colorectal cancer) by methylation of the promoter region and of a putative enhancer. Thus, PTX3, an effector molecule belonging to the humoral arm of innate immunity, acts as an extrinsic oncosuppressor gene in mouse and man by regulating Complement-dependent, macrophage-sustained, tumor-promoting inflammation.

The challenges of institutionalizing community-level social accountability mechanisms for health and nutrition: a qualitative study in Odisha, India.

BACKGROUND: India has been at the forefront of innovations around social accountability mechanisms in improving the delivery of public services, including health and nutrition. Yet little is known about how such initiatives are faring now that they are incorporated formally into government programmes and implemented at scale. This brings greater impetus to understand their effectiveness. This formative qualitative study focuses on how such mechanisms have sought to strengthen community-level nutrition and health services (the Integrated Child Development Services and the National Rural Health Mission) in the state of Odisha. It fills a gap in the literature on considering how such initiatives are running when institutionalised at scale. The primary research questions were 'what kinds of community level mechanisms are functioning in randomly selected villages in 3 districts of state of Odisha' and 'how are they perceived to function by their members and frontline workers'. METHODS: The study is based on focus group discussions with pregnant women and mothers of children below the age of 2 (n = 12) and with women's self-help groups (n = 12); interviews with frontline health workers (n = 24) and with members of community committees (n = 36). Interviews were analysed thematically using a priori coding derived from wider literature on key accountability themes. RESULTS: Four main types of community-based mechanisms were examined - Mothers committees, Jaanch committees, Village Health and Sanitation Committees and Self-Help Groups. The degree of their effectiveness varied depending on their ability to offer meaningful avenues for participation of their members and empower women for autonomous action. Notably, in most of these mechanisms community participation is very weak, with committees largely controlled by the frontline workers who are supposed to be held to account. However, self-help groups showed real levels of autonomy and collective power. Despite not having an explicit accountability role, these groups were nevertheless effective in advocating for better service delivery and the broader needs of their members to a level not seen in institutional committees. CONCLUSIONS: The study points to the need for community-level mechanisms in India to adequately address issues of participation and empowerment of community members to be successful in contributing to service improvements in health and nutrition.

Expression and function of IL-1R8 (TIR8/SIGIRR): a regulatory member of the IL-1 receptor family in platelets.

AIMS: Platelets express functional interleukin-1 receptor-1 (IL-1R1) as well as a repertoire of toll-like receptors (TLRs) involved in platelet activation, platelet-leucocyte reciprocal activation, and immunopathology. IL-1R8, also known as single Ig IL-1-related receptor (SIGIRR) or TIR8, is a member of the IL-1R family that negatively regulates responses to IL-1R family members and TLRs. In the present study, we addressed the expression of IL-1R8 in platelets and megakaryocytes and its role in the control of platelet activation during inflammatory conditions and thromboembolism. METHODS AND RESULTS: Here, we show by flow cytometry analysis, western blot, confocal microscopy, and quantitative real-time polymerase chain reaction that IL-1R8 is expressed on human and mouse platelets at high levels and on megakaryocytes. IL-1R8-deficient mice show normal levels of circulating platelets. Homotypic and heterotypic (platelet-neutrophil) aggregation triggered by Adenosine DiPhosphate (ADP) and IL-1 or lipopolysaccharide (LPS) was increased in IL-1R8-deficient platelets. IL-1R8-deficient mice showed increased soluble P-selectin levels and increased platelet-neutrophil aggregates after systemic LPS administration. Commensal flora depletion and IL-1R1 deficiency abated platelet hyperactivity and the increased platelet/neutrophil aggregation observed in Il1r8(-/-) mice in vitro and in vivo, suggesting a key role of IL-1R8 in regulating platelet TLR and IL-1R1 function. In a mouse model of platelet-dependent pulmonary thromboembolism induced by ADP administration, IL-1R8-deficient mice showed an increased frequency of blood vessel complete obstruction. CONCLUSION: These results show that platelets, which have a large repertoire of TLRs and IL-1 receptors, express high levels of IL-1R8, which plays a non-redundant function as a regulator of thrombocyte activity in vitro and in vivo.