IL-1 and IL-23 Mediate Early IL-17A Production in Pulmonary Inflammation Leading to Late Fibrosis

BACKGROUND: Idiopathic pulmonary fibrosis is a devastating as yet untreatable disease. We demonstrated recently the predominant role of the NLRP3 inflammasome activation and IL-1β expression in the establishment of pulmonary inflammation and fibrosis in mice. METHODS: The contribution of IL-23 or IL-17 in pulmonary inflammation and fibrosis was assessed using the bleomycin model in deficient mice. RESULTS: We show that bleomycin or IL-1β-induced lung injury leads to increased expression of early IL-23p19, and IL-17A or IL-17F expression. Early IL-23p19 and IL-17A, but not IL-17F, and IL-17RA signaling are required for inflammatory response to BLM as shown with gene deficient mice or mice treated with neutralizing antibodies. Using FACS analysis, we show a very early IL-17A and IL-17F expression by RORγt(+) γδ T cells and to a lesser extent by CD4αβ(+) T cells, but not by iNKT cells, 24 hrs after BLM administration. Moreover, IL-23p19 and IL-17A expressions or IL-17RA signaling are necessary to pulmonary TGF-β1 production, collagen deposition and evolution to fibrosis. CONCLUSIONS: Our findings demonstrate the existence of an early IL-1β-IL-23-IL-17A axis leading to pulmonary inflammation and fibrosis and identify innate IL-23 and IL-17A as interesting drug targets for IL-1β driven lung pathology

TNF in host resistance to tuberculosis infection

TNF is essential to control Mycobacterium tuberculosis infection and cannot be replaced by other proinflammatory cytokines. Overproduction of TNF may cause immunopathology, while defective TNF production results in uncontrolled infection. The critical role of TNF in the control of tuberculosis has been illustrated recently by primary and reactivation of latent infection in some patients under pharmacological anti-TNF therapy for rheumatoid arthritis or Crohn's disease. In this review, we discuss results of recent studies aimed at better understanding of molecular, cellular and kinetic aspects of TNF-mediated regulation of host-mycobacteria interactions. In particular, recent data using either mutant mice expressing solely membrane TNF or specific inhibitor sparing membrane TNF demonstrated that membrane TNF is sufficient to control acute M. tuberculosis infection. This is opening the way to selective TNF neutralization that might retain the desired anti-inflammatory effect but reduce the infectious risk

Limited role for lymphotoxin alpha in the host immune response to Mycobacterium tuberculosis

The contribution of lymphotoxin (LT)alpha in the host immune response to virulent Mycobacterium tuberculosis and Mycobacterium bovis bacillus Calmette-Guerin infections was investigated. Despite their ability to induce Th1 cytokine, IFN-gamma, and IL-12 pulmonary response, "conventional" LTalpha(-/-) mice succumb rapidly to virulent M. tuberculosis aerosol infection, with uncontrolled bacilli growth, defective granuloma formation, necrosis, and reduced pulmonary inducible NO synthase expression, similar to TNF(-/-) mice. Contributions from developmental lymphoid abnormalities in LTalpha(-/-) mice were excluded because hematopoietic reconstitution with conventional LTalpha(-/-) bone marrow conferred enhanced susceptibility to wild-type mice, comparable to conventional LTalpha(-/-) control mice. However, conventional LTalpha(-/-) mice produced reduced levels of TNF after M. bovis bacillus Calmette-Guerin infection, and their lack of control of mycobacterial infection could be due to a defective contribution of either LTalpha or TNF, or both, to the host immune response. To address this point, the response of "neo-free" LTalpha(-/-) mice with unperturbed intrinsic TNF expression to M. tuberculosis infection was investigated in a direct comparative study with conventional LTalpha(-/-) mice. Strikingly, although conventional LTalpha(-/-) mice were highly sensitive, similar to TNF(-/-) mice, neo-free LTalpha(-/-) mice controlled acute M. tuberculosis infection essentially as wild-type mice. Pulmonary bacterial burden and inflammation was, however, slightly increased in neo-free LTalpha(-/-) mice 4-5 mo postinfection, but importantly, they did not succumb to infection. Our findings revise the notion that LTalpha might have a critical role in host defense to acute mycobacterial infection, independent of TNF, but suggest a contribution of LTalpha in the control of chronic M. tuberculosis infection

10 years later: revisiting priorities for science and society a decade after the millennium ecosystem assessment

The study of ecological services (ESs) is fast becoming a cornerstone of mainstream ecology, largely because they provide a useful means of linking functioning to societal benefits in complex systems by connecting different organizational levels. In order to identify the main challenges facing current and future ES research, we analyzed the effects of the publication of the Millennium Ecosystem Assessment (MEA, 2005) on different disciplines. Within a set of topics framed around concepts embedded within the MEA, each co-author identified five key research challenges and, where feasible, suggested possible solutions. Concepts included those related to specific service types (i.e. provisioning, supporting, regulating, cultural, aesthetic services) as well as more synthetic issues spanning the natural and social sciences, which often linked a wide range of disciplines, as was the case for the application of network theory. By merging similar responses, and removing some of the narrower suggestions from our sample pool, we distilled the key challenges into a smaller subset. We review some of the historical context to the MEA and identify some of the broader scientific and philosophical issues that still permeate discourse in this field. Finally, we consider where the greatest advances are most likely to be made in the next decade and beyond