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Caspase-dependent apoptosis accounts for approximately 90% of homeostatic cell turnover in the body 1 , and regulates inflammation, cell proliferation, and tissue regeneration 2 – 4 . How apoptotic cells mediate such diverse effects is not fully understood. Here we profiled the apoptotic metabolite secretome and determined its effects on the tissue neighbourhood. We show that apoptotic lymphocytes and macrophages release specific metabolites, while retaining their membrane integrity. A subset of these metabolites is also shared across different primary cells and cell lines after the induction of apoptosis by different stimuli. Mechanistically, the apoptotic metabolite secretome is not simply due to passive emptying of cellular contents and instead is a regulated process. Caspase-mediated opening of pannexin 1 channels at the plasma membrane facilitated the release of a select subset of metabolites. In addition, certain metabolic pathways continued to remain active during apoptosis, with the release of only select metabolites from a given pathway. Functionally, the apoptotic metabolite secretome induced specific gene programs in healthy neighbouring cells, including suppression of inflammation, cell proliferation, and wound healing. Furthermore, a cocktail of apoptotic metabolites reduced disease severity in mouse models of inflammatory arthritis and lung-graft rejection. These data advance the concept that apoptotic cells are not inert cells waiting for removal, but instead release metabolites as ‘good-bye’ signals to actively modulate outcomes in tissues. Apoptotic cells communicate with neighbouring cells by the regulated release of specific metabolites, and a cocktail of select apoptotic metabolites reduces disease severity in mouse models of inflammatory arthritis and lung transplant rejection.

Development and routine tissue homeostasis require a high turnover of apoptotic cells. These cells are removed by professional and non-professional phagocytes via efferocytosis 1 . How a phagocyte maintains its homeostasis while coordinating corpse uptake, processing ingested materials and secreting anti-inflammatory mediators is incompletely understood 1 , 2 . Here, using RNA sequencing to characterize the transcriptional program of phagocytes actively engulfing apoptotic cells, we identify a genetic signature involving 33 members of the solute carrier (SLC) family of membrane transport proteins, in which expression is specifically modulated during efferocytosis, but not during antibody-mediated phagocytosis. We assessed the functional relevance of these SLCs in efferocytic phagocytes and observed a robust induction of an aerobic glycolysis program, initiated by SLC2A1-mediated glucose uptake, with concurrent suppression of the oxidative phosphorylation program. The different steps of phagocytosis 2 —that is, ‘smell’ (‘find-me’ signals or sensing factors released by apoptotic cells), ‘taste’ (phagocyte–apoptotic cell contact) and ‘ingestion’ (corpse internalization)—activated distinct and overlapping sets of genes, including several SLC genes, to promote glycolysis. SLC16A1 was upregulated after corpse uptake, increasing the release of lactate, a natural by-product of aerobic glycolysis 3 . Whereas glycolysis within phagocytes contributed to actin polymerization and the continued uptake of corpses, lactate released via SLC16A1 promoted the establishment of an anti-inflammatory tissue environment. Collectively, these data reveal a SLC program that is activated during efferocytosis, identify a previously unknown reliance on aerobic glycolysis during apoptotic cell uptake and show that glycolytic by-products of efferocytosis can influence surrounding cells. Distinct transcriptional programs are activated during different stages of apoptotic cell engulfment, including a unique program of genes coding for solute carrier proteins and enzymes in the glycolytic pathway.

Regulated cell death is an integral part of life, and has broad effects on organism development and homeostasis 1 . Malfunctions within the regulated cell death process, including the clearance of dying cells, can manifest in diverse pathologies throughout various tissues including the gastrointestinal tract 2 . A long appreciated, yet elusively defined relationship exists between cell death and gastrointestinal pathologies with an underlying microbial component 3 – 6 , but the direct effect of dying mammalian cells on bacterial growth is unclear. Here we advance a concept that several Enterobacteriaceae, including patient-derived clinical isolates, have an efficient growth strategy to exploit soluble factors that are released from dying gut epithelial cells. Mammalian nutrients released after caspase-3/7-dependent apoptosis boosts the growth of multiple Enterobacteriaceae and is observed using primary mouse colonic tissue, mouse and human cell lines, several apoptotic triggers, and in conventional as well as germ-free mice in vivo. The mammalian cell death nutrients induce a core transcriptional response in pathogenic Salmonella , and we identify the pyruvate formate-lyase-encoding pflB gene as a key driver of bacterial colonization in three contexts: a foodborne infection model, a TNF- and A20-dependent cell death model, and a chemotherapy-induced mucositis model. These findings introduce a new layer to the complex host–pathogen interaction, in which death-induced nutrient release acts as a source of fuel for intestinal bacteria, with implications for gut inflammation and cytotoxic chemotherapy treatment. Intestinal microorganisms exploit nutrients released by apoptotic gut epithelial cells for growth.

Phagocytosis is an intensely physical process that depends on the mechanical properties of both the phagocytic cell and its chosen target. Here, we employed differentially deformable hydrogel microparticles to examine the role of cargo rigidity in the regulation of phagocytosis by macrophages. Whereas stiff cargos elicited canonical phagocytic cup formation and rapid engulfment, soft cargos induced an architecturally distinct response, characterized by filamentous actin protrusions at the center of the contact site, slower cup advancement, and frequent phagocytic stalling. Using phosphoproteomics, we identified β2 integrins as critical mediators of this mechanically regulated phagocytic switch. Macrophages lacking β2 integrins or their downstream effectors, Talin1 and Vinculin, exhibited specific defects in phagocytic cup architecture and selective suppression of stiff cargo uptake. We conclude that integrin signaling serves as a mechanical checkpoint during phagocytosis to pair cargo rigidity to the appropriate mode of engulfment. Phagocytosis is regulated by the mechanical properties of both the phagocyte and its cargo. Here, the authors show that macrophages employ β2 integrins to sense the rigidity of phagocytic cargo and then mount the appropriate form of engulfment.

Apoptotic cell clearance (efferocytosis) elicits an anti-inflammatory response by phagocytes, but the mechanisms that underlie this response are still being defined. Here, we uncover a chloride-sensing signalling pathway that controls both the phagocyte ‘appetite’ and its anti-inflammatory response. Efferocytosis transcriptionally altered the genes that encode the solute carrier (SLC) proteins SLC12A2 and SLC12A4. Interfering with SLC12A2 expression or function resulted in a significant increase in apoptotic corpse uptake per phagocyte, whereas the loss of SLC12A4 inhibited corpse uptake. In SLC12A2-deficient phagocytes, the canonical anti-inflammatory program was replaced by pro-inflammatory and oxidative-stress-associated gene programs. This ‘switch’ to pro-inflammatory sensing of apoptotic cells resulted from the disruption of the chloride-sensing pathway (and not due to corpse overload or poor degradation), including the chloride-sensing kinases WNK1, OSR1 and SPAK—which function upstream of SLC12A2—had a similar effect on efferocytosis. Collectively, the WNK1–OSR1–SPAK–SLC12A2/SLC12A4 chloride-sensing pathway and chloride flux in phagocytes are key modifiers of the manner in which phagocytes interpret the engulfed apoptotic corpse. Perry and Morioka et al. show that the chloride transporter SLC12A2 regulates apoptotic cell uptake by phagocytes and, together with SLC12 kinases WNK1, OSR1 and SPAK, this pathway maintains an anti-inflammatory gene signature.

Rheumatoid arthritis is characterized by progressive joint inflammation and affects ~1% of the human population. We noted single-nucleotide polymorphisms (SNPs) in the apoptotic cell–engulfment genes ELMO1, DOCK2 , and RAC1 linked to rheumatoid arthritis. As ELMO1 promotes cytoskeletal reorganization during engulfment, we hypothesized that ELMO1 loss would worsen inflammatory arthritis. Surprisingly, Elmo1 -deficient mice showed reduced joint inflammation in acute and chronic arthritis models. Genetic and cell-biology studies revealed that ELMO1 associates with receptors linked to neutrophil function in arthritis and regulates activation and early neutrophil recruitment to the joints, without general inhibition of inflammatory responses. Further, neutrophils from the peripheral blood of human donors that carry the SNP in ELMO1 associated with arthritis display increased migratory capacity, whereas ELMO1 knockdown reduces human neutrophil migration to chemokines linked to arthritis. These data identify ‘noncanonical’ roles for ELMO1 as an important cytoplasmic regulator of specific neutrophil receptors and promoter of arthritis. ELMO1 is a protein centrally involved in controlling the engulfment of apoptotic cells. Ravichandran and colleagues demonstrate a noncanonical role for ELMO1 in the promotion of neutrophil migration and inflammatory arthritis.

Osteoporosis affects millions worldwide and is often caused by osteoclast induced bone loss. Here, we identify the cytoplasmic protein ELMO1 as an important ‘signaling node’ in osteoclasts. We note that ELMO1 SNPs associate with bone abnormalities in humans, and that ELMO1 deletion in mice reduces bone loss in four in vivo models: osteoprotegerin deficiency, ovariectomy, and two types of inflammatory arthritis. Our transcriptomic analyses coupled with CRISPR/Cas9 genetic deletion identify Elmo1 associated regulators of osteoclast function, including cathepsin G and myeloperoxidase. Further, we define the ‘ELMO1 interactome’ in osteoclasts via proteomics and reveal proteins required for bone degradation. ELMO1 also contributes to osteoclast sealing zone on bone-like surfaces and distribution of osteoclast-specific proteases. Finally, a 3D structure-based ELMO1 inhibitory peptide reduces bone resorption in wild type osteoclasts. Collectively, we identify ELMO1 as a signaling hub that regulates osteoclast function and bone loss, with relevance to osteoporosis and arthritis. Osteoporosis and bone fractures affect millions of patients worldwide and are often due to increased bone resorption. Here the authors identify the cytoplasmic protein ELMO1 as an important ‘signaling node’ promoting the bone resorption function of osteoclasts.

Dendritic cells produce interleukin-2 (IL-2) and express the IL-2 receptor subunit CD25. Bibiana Bielekova and her colleagues show that dendritic cells, upon interacting with cognate T cells, secrete IL-2 into the immune synapse and use their CD25 to trans -present IL-2 to T cells, facilitating early IL-2 signaling in T cells. Inhibition of CD25 by the monoclonal antibody daclizumab prevents T cell activation and may partly account for the therapeutic effects of daclizumab in patients with multiple sclerosis. Although previous studies have described CD25 expression and production of interleukin-2 (IL-2) by mature dendritic cells (mDCs), it remains unclear how these molecules participate in the activation of T cells. In search of the mechanisms by which daclizumab, a humanized monoclonal antibody against CD25, inhibits brain inflammation in multiple sclerosis, we observed that although the drug has limited effects on polyclonal T cell activation, it potently inhibits activation of antigen-specific T cells by mDCs. We show that mDCs (and antigen-experienced T cells) secrete IL-2 toward the mDC-T cell interface in an antigen-specific manner, and mDCs 'lend' their CD25 to primed T cells in trans to facilitate early high-affinity IL-2 signaling, which is crucial for subsequent T cell expansion and development of antigen-specific effectors. Our data reveal a previously unknown mechanism for the IL-2 receptor system in DC-mediated activation of T cells.

The flowering stage of oilseed rape ( Brassica napus L.) is of vital interest in precision agriculture. It has been shown that data describing the flower production of oilseed rape (OSR), at stage 3, in spring can be used to predict seed yield at harvest. Traditional field-based techniques for assessing OSR flowers are based on a visual assessment which is subjective and time consuming. However, a high throughput phenotyping technique, using an unmanned aerial vehicle (UAV) with multispectral image (MSI) camera, was used to investigate the growth stages of OSR (in terms of crop height) and to quantify its flower production. A simplified approach using a normalised difference yellowness index (NDYI) was coupled with an iso-cluster classification method to quantify the number of OSR flower pixels and incorporate the data into an OSR seed yield estimation. The estimated OSR seed yield showed strong correlation with the actual OSR seed yield (R 2 = 0.86), as determined using in-situ sensors mounted on the combine harvester. Also, using our approach allowed the variation in crop height to be assessed across all growing stages; the maximum crop height of 1.35 m OSR was observed at the flowering stage. This methodology is proposed for effectively predicting seed yield 3 months prior to harvesting.

Species are largely predicted to shift polewards as global temperatures increase. Now research—based on historical changes in the distribution of Australian birds—shows that if only poleward shifts in distribution are considered, the fingerprint of climate change is underestimated by an average of 26% in temperate regions and 95% in tropical regions. Species are largely predicted to shift poleward as global temperatures increase, with this fingerprint of climate change being already observed across a range of taxonomic groups and, mostly temperate, geographic locations 1 , 2 , 3 , 4 , 5 . However, the assumption of uni-directional distribution shifts does not account for complex interactions among temperature, precipitation and species-specific tolerances 6 , all of which shape the direction and magnitude of changes in a species’ climatic niche. We analysed 60 years of past climate change on the Australian continent, assessing the velocity of changes in temperature and precipitation, as well as changes in climatic niche space for 464 Australian birds. We show large magnitude and rapid rates of change in Australian climate over the past 60 years resulting in high-velocity and multi-directional, including equatorial, shifts in suitable climatic space for birds (ranging from 0.1 to 7.6 km yr −1 , mean 1.27 km yr −1 ). Overall, if measured only in terms of poleward distribution shifts, the fingerprint of climate change is underestimated by an average of 26% in temperate regions of the continent and by an average of 95% in tropical regions. We suggest that the velocity of movement required by Australian species to track their climatic niche may be much faster than previously thought and that the interaction between temperature and precipitation changes will result in multi-directional distribution shifts globally.