Journal Article

Emerging inflammasome effector mechanisms

Lamkanfi, Mohamed

2011

Overview

Key Points In addition to mediating the maturation and secretion of the cytokines interleukin-1β (IL-1β) and IL-18, caspase 1 activation by inflammasome complexes controls a set of non-canonical effectors that might contribute to the immune response during infection and autoimmunity. These mechanisms include unconventional protein secretion, pyroptosis, regulation of metabolic pathways and restriction of bacterial replication. Caspase 1 activation in macrophages, epithelial cells and keratinocytes drives unconventional protein secretion of leaderless cytokines such as IL-1α, IL-1β and IL-18, growth factors such as fibroblast growth factor 2 and possibly damage-associated molecular patterns such as high mobility group box 1. After their release into the extracellular environment, these factors can enhance inflammatory and healing responses. Infected myeloid cells can remove intracellular replication niches for pathogens by inducing pyroptosis, a specialized caspase 1-dependent cell death programme. Pyroptosis is accompanied by osmotic lysis and the release of the intracellular content into the extracellular milieu, and this is thought (together with other inflammasome functions) to render it an inherently pro-inflammatory cell death mode. Pyroptosis is thought to confer resistance to infection with intracellular pathogens in vivo , illustrating the importance of this cell death mode for host defence. Caspase 1 can cleave poly(ADP-ribose) polymerase 1 (PARP1) and glycolysis enzymes (such as glyceraldehyde-3-phosphate dehydrogenase) to preserve ATP energy stores and to decrease the metabolic rate of infected cells. As such, caspase 1-mediated targeting of bioenergetic pathways might help to preserve cellular energy stores during infection. Caspase 1 activates lipid metabolic pathways in fibroblasts intoxicated with pore-forming toxins or infected with bacteria that produce these toxins. This leads to the repair of toxin-induced damage to the plasma membrane and promotes cell survival. In a process that proceeds independently of IL-1β and IL-18, caspase 1-mediated activation of caspase 7, an executioner caspase, contributes to the restriction of Legionella pneumophila replication in infected macrophages. In vivo studies have shown the importance of this inflammasome pathway for host defence against L. pneumophila infection in the lungs. Recent studies have shown that caspase 1 activation by inflammasomes controls a set of non-canonical effector mechanisms that might contribute to the immune response during infection and autoimmunity. These mechanisms include unconventional protein secretion, pyroptosis, regulation of metabolic pathways and restriction of bacterial replication. Caspase 1 activation by inflammasome complexes in response to pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) induces the maturation and secretion of the pro-inflammatory cytokines interleukin-1β (IL-1β) and IL-18. Recent reports have begun to identify additional inflammasome effector mechanisms that proceed independently of IL-1β and IL-18. These include the induction of pyroptotic cell death, the restriction of bacterial replication, the activation of lipid metabolic pathways for cell repair and the secretion of DAMPs and leaderless cytokines. These non-canonical functions of caspase 1 illustrate the diverse mechanisms by which inflammasomes might contribute to innate immunity, repair responses and host defence.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/250/1932 / 631/250/256/2177 / 631/250/516 / Adenosine diphosphate / Animals / Apoptosis / Autoimmunity / Bacteria - immunology / Bacteria - metabolism / Bioenergetics / Biomedical and Life Sciences / Biomedicine / Caspase 1 - physiology / Caspase 7 - metabolism / Caspase-1 / Caspase-7 / Cell activation / Cell Death / Cell Membrane Permeability / Cell survival / Communicable Diseases - immunology / Cysteine proteinases / Cytokines / Cytokines - biosynthesis / Cytokines - secretion / Enzyme Activation / Epithelial cells / Fibroblast growth factor 2 / Fibroblasts / Glyceraldehyde-3-phosphate dehydrogenase / Glycolysis / Growth factors / Health aspects / Host-Pathogen Interactions - immunology / Humans / Immune response / Immunity / Immunity, Innate - physiology / Immunology / Infections / Inflammasomes - physiology / Inflammation / Inflammation - immunology / Interleukin 18 / Intracellular / Keratinocytes / Lysis / Macrophages / Macrophages - immunology / Macrophages - microbiology / Metabolic pathways / Metabolic rate / Metabolism / Mice / Models, Immunological / Mortality / Nod Signaling Adaptor Proteins - immunology / Nuclear Proteins - immunology / Oligomers / Pathogens / Physiological aspects / Poly(ADP-ribose) polymerase / Proteins / Pyroptosis / Replication / review-article / Toxins / Wounds and Injuries - immunology