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Cancer cachexia is a highly prevalent condition associated with poor quality of life and reduced survival 1 . Tumor-induced perturbations in the endocrine, immune and nervous systems drive anorexia and catabolic changes in adipose tissue and skeletal muscle, hallmarks of cancer cachexia 2 – 4 . However, the molecular mechanisms driving cachexia remain poorly defined, and there are currently no approved drugs for the condition. Elevation in circulating growth differentiation factor 15 (GDF15) correlates with cachexia and reduced survival in patients with cancer 5 – 8 , and a GDNF family receptor alpha like (GFRAL)–Ret proto-oncogene (RET) signaling complex in brainstem neurons that mediates GDF15-induced weight loss in mice has recently been described 9 – 12 . Here we report a therapeutic antagonistic monoclonal antibody, 3P10, that targets GFRAL and inhibits RET signaling by preventing the GDF15-driven interaction of RET with GFRAL on the cell surface. Treatment with 3P10 reverses excessive lipid oxidation in tumor-bearing mice and prevents cancer cachexia, even under calorie-restricted conditions. Mechanistically, activation of the GFRAL–RET pathway induces expression of genes involved in lipid metabolism in adipose tissues, and both peripheral chemical sympathectomy and loss of adipose triglyceride lipase protect mice from GDF15-induced weight loss. These data uncover a peripheral sympathetic axis by which GDF15 elicits a lipolytic response in adipose tissue independently of anorexia, leading to reduced adipose and muscle mass and function in tumor-bearing mice. Pharmacological inhibition of GFRAL–RET signaling in preclinical tumor models supports the therapeutic potential for reversing GDF15-dependent cachexia in people with cancer.

GDNF receptor alpha-like is a brainstem-restricted receptor for growth and differentiation factor 15, regulating appetite and body weight in non-homeostatic conditions by activating the emergency circuit response to disease and toxin stresses. Brainstem receptor regulates body mass loss Growth and differentiation factor 15 (GDF15) acts on feeding centres in the brain to cause anorexia, leading to loss of both lean and fat mass and eventually cachexia. GDF15 levels rise in response to tissue stress and injury, and higher levels are associated with weight loss in numerous chronic human diseases, including cancer. Bernard Allan and colleagues now show that glial cell-derived neurotrophic factor (GDNF) receptor alpha-like (GFRAL) is a GDF15 receptor in the brainstem. The structure of GDF15 and its interaction with GFRAL together with biochemical experiments and analysis of Gfral knockout mice demonstrate that regulation of body weight by GFRAL is independent of previously characterized pathways. Unlike hormones from gut and adipose tissue that activate receptors mostly in the hypothalamus, GDF15 increases in response to tissue damage and activates GFRAL-expressing neurons in the brainstem. Gfral knockout mice overate under stressed conditions and were resistant to chemotherapy-induced anorexia and weight loss. These findings provide therapeutic opportunities for disorders with altered energy demands. Under homeostatic conditions, animals use well-defined hypothalamic neural circuits to help maintain stable body weight, by integrating metabolic and hormonal signals from the periphery to balance food consumption and energy expenditure 1 , 2 . In stressed or disease conditions, however, animals use alternative neuronal pathways to adapt to the metabolic challenges of altered energy demand 3 . Recent studies have identified brain areas outside the hypothalamus that are activated under these ‘non-homeostatic’ conditions 4 , 5 , 6 , but the molecular nature of the peripheral signals and brain-localized receptors that activate these circuits remains elusive. Here we identify glial cell-derived neurotrophic factor (GDNF) receptor alpha-like (GFRAL) as a brainstem-restricted receptor for growth and differentiation factor 15 (GDF15). GDF15 regulates food intake, energy expenditure and body weight in response to metabolic and toxin-induced stresses; we show that Gfral knockout mice are hyperphagic under stressed conditions and are resistant to chemotherapy-induced anorexia and body weight loss. GDF15 activates GFRAL-expressing neurons localized exclusively in the area postrema and nucleus tractus solitarius of the mouse brainstem. It then triggers the activation of neurons localized within the parabrachial nucleus and central amygdala, which constitute part of the ‘emergency circuit’ that shapes feeding responses to stressful conditions 7 . GDF15 levels increase in response to tissue stress and injury, and elevated levels are associated with body weight loss in numerous chronic human diseases 8 , 9 . By isolating GFRAL as the receptor for GDF15-induced anorexia and weight loss, we identify a mechanistic basis for the non-homeostatic regulation of neural circuitry by a peripheral signal associated with tissue damage and stress. These findings provide opportunities to develop therapeutic agents for the treatment of disorders with altered energy demand.

Background Colony stimulating factor 1 receptor (CSF1R) signaling is crucial for the maintenance and function of various myeloid subsets. CSF1R antagonism was previously shown to mitigate clinical severity in experimental autoimmune encephalomyelitis (EAE). The associated mechanisms are still not well delineated. Methods To assess the effect of CSF1R signaling, we employed the CSF1R antagonist PLX5622 formulated in chow (PLX5622 diet, PD) and its control chow (control diet, CD). We examined the effect of PD in steady state and EAE by analyzing cells isolated from peripheral immune organs and from the CNS via flow cytometry. We determined CNS infiltration sites and assessed the extent of demyelination using immunohistochemistry of cerebella and spinal cords. Transcripts of genes associated with neuroinflammation were also analyzed in these tissues. Results In addition to microglial depletion, PD treatment reduced dendritic cells and macrophages in peripheral immune organs, both during steady state and during EAE. Furthermore, CSF1R antagonism modulated numbers and relative frequencies of T effector cells both in the periphery and in the CNS during the early stages of the disease. Classical neurological symptoms were milder in PD compared to CD mice. Interestingly, a subset of PD mice developed atypical EAE symptoms. Unlike previous studies, we observed that the CNS of PD mice was infiltrated by increased numbers of peripheral immune cells compared to that of CD mice. Immunohistochemical analysis showed that CNS infiltrates in PD mice were mainly localized in the cerebellum while in CD mice infiltrates were primarily localized in the spinal cords during the onset of neurological deficits. Accordingly, during the same timepoint, cerebella of PD but not of CD mice had extensive demyelinating lesions, while spinal cords of CD but not of PD mice were heavily demyelinated. Conclusions Our findings suggest that CSF1R activity modulates the cellular composition of immune cells both in the periphery and within the CNS, and affects lesion localization during the early EAE stages.

Despite obesity reaching pandemic proportions, its impact on antigen-specific T cell responses is still unclear. We have recently demonstrated that obesity results in increased expression of PD-1 on T cells, and checkpoint blockade targeting PD-1/PD-L1 surprisingly resulted in greater clinical efficacy in cancer therapy. Adverse events associated with this therapy center around autoimmune reactions. In this study, we examined the impact of obesity on T cell priming and on autoimmune pathogenesis using the mouse model experimental autoimmune encephalomyelitis (EAE), which is mediated by autoreactive myelin-specific T cells generated after immunization. We observed that diet-induced obese (DIO) mice had a markedly delayed EAE onset and developed milder clinical symptoms compared to mice on control diet (CD). This delay was associated with impaired generation of myelin-specific T cell numbers and concurrently correlated with increased PD-L1 upregulation on antigen-presenting cells in secondary lymphoid organs. PD-1 blockade during the priming stage of EAE restored disease onset and severity and increased numbers of pathogenic CD4+ T cells in the central nervous system (CNS) of DIO mice to similar levels to those of CD mice. Administration of anti-PD-1 after onset of clinical symptoms did not increase EAE pathogenesis demonstrating that initial priming is the critical juncture affected by obesity. These findings demonstrate that obesity impairs antigen-specific T cell priming, but this can be reversed with PD-1 blockade. Our results further suggest that PD-1 blockade may increase the risk of autoimmune toxicities, particularly in obesity.

IntroductionIn response to the burden of chronic disease among older adults, different chronic disease self-management tools have been created to optimise disease management. However, these seldom consider all aspects of disease management are not usually developed specifically for seniors or created for sustained use and are primarily focused on a single disease. We created an eHealth self-management application called ‘KeepWell’ that supports seniors with complex care needs in their homes. It incorporates the care for two or more chronic conditions from among the most prevalent high-burden chronic diseases.Methods and analysisWe will evaluate the effectiveness, cost and uptake of KeepWell in a 6-month, pragmatic, hybrid effectiveness–implementation randomised controlled trial. Older adults age ≥65 years with one or more chronic conditions who are English speaking are able to consent and have access to a computer or tablet device, internet and an email address will be eligible. All consenting participants will be randomly assigned to KeepWell or control. The allocation sequence will be determined using a random number generator.Primary outcome is perceived self-efficacy at 6 months. Secondary outcomes include quality of life, health background/status, lifestyle (nutrition, physical activity, caffeine, alcohol, smoking and bladder health), social engagement and connections, eHealth literacy; all collected via a Health Risk Questionnaire embedded within KeepWell (intervention) or a survey platform (control). Implementation outcomes will include reach, effectiveness, adoption, fidelity, implementation cost and sustainability.Ethics and disseminationEthics approval has been received from the North York General Hospital Research and Ethics Board. The study is funded by the Canadian Institutes of Health Research and the Ontario Ministry of Health. We will work with our team to develop a dissemination strategy which will include publications, presentations, plain language summaries and an end-of-grant meeting.Trial registration numberNCT04437238.

Multiple sclerosis (MS) is an autoimmune, demyelinating disease of the central nervous system. Importantly, it is an illness with unmet medical need. Although current therapeutics mitigate relapses, there is no treatment that halts the progression of MS. In order to develop improved medicines, we must better understand the disease and factors that drive it. Hence, the mouse model of MS, experimental autoimmune encephalomyelitis (EAE) has been employed in the field of neuroimmunology. In my thesis, I elucidate the roles of two myeloid cell-associated proteins in affecting EAE pathogenesis.In chapter 1, I review the current understanding of the role of myeloid cells in MS. In the healthy CNS, dendritic cells, granulocytes, tissue resident macrophages are present in small quantities. Importantly, microglia reside in the healthy CNS and continuously monitor the milieu. During inflammatory conditions, microglia become activated, and a host of other myeloid cells and lymphocytes infiltrate into the CNS and cause demyelination. Although lymphocytes are important, myeloid cells are an underappreciated component of MS disease which initiate and perpetuate the disease. Additionally, I review a few of the current MS therapeutics on the market, their targets, and their impact on myeloid cells. One target that has been studied for its therapeutic potential in MS treatment is CSF1R. PLX5622, a CSF1R antagonist, is known to deplete microglia. Microglial depletion has been previously proposed to be the cause of reduced EAE clinical symptoms that are detected in CSF1R-antagonized mice. In chapter 2, I show that PLX5622 formulated into rodent chow (PLX5622 diet; PD), in addition to ameliorating EAE clinical score, also increases infiltration into the CNS of PD mice. I determined that this was not due to changes in peripheral priming. Furthermore, although spinal cords were largely devoid of infiltration, cerebella showed increased infiltration in PD compared to CD mice. I propose that decreased incidence of ascending paralysis, a symptom associated with spinal cord demyelinating damage, is due to immune cell relocation to the cerebellum. Lastly, I explore possible mechanisms causing the observed relocation.An area of unmet therapeutic need is in developmental and adult myelination. In chapter 3, I explore the function of 5 lipoxygenase (5LO) in the healthy central nervous system (CNS). First, I show that 5LO, 5LO pathway, and 5LO’s enzymatic products, leukotrienes (LTs), are detected in development and adulthood in the CNS; this suggests that the 5LO pathway is present and active in healthy conditions. Due to the detection of the highest levels of 5LO pathway components being detected during developmental myelination, we investigate the connection between 5LO and the most dynamic cell type in the CNS, oligodendrocyte lineage cells (OLCs). Addition of leukotrienes onto differentiating oligodendrocyte progenitor cells in vitro promotes oligodendrocyte differentiation in my experiments, providing initial evidence of the link between LTs and OLCs. Next, in vivo experiments involving fate mapping of cells in the corpus callosum of 5LO global knockout mice and their littermate controls confirms that 5LO and LTs promote OLC differentiation. Lastly, pharmacological and genetic methods reveal that microglia are the primary expressors of 5LO and ostensibly, LTs.

Nature 550, 255–259 (2017); doi:10.1038/nature24042 Owing to an error during the production process, in Fig. 2c of this Letter, all four groups of mice were incorrectly labelled as ‘WT’ (wild type), but the two groups on the left (filled and open blue boxes) should have been labelled ‘WT’, whereas the two groups on the right (filled and open yellow boxes) should have been labelled ‘KO’ (knockout), as in the key for Fig. 2b. The original Letter has been corrected online.

The hypothesis that comprehensibility is a function of syntactic complexity was investigated. Seventy-five sentences, ranging in length from 5 to 29 words, each with a different syntactic structure, were tape-recorded and were then judged for comprehensibility by 40 Ss. The predictive validities of eight measures of surface structure complexity were evaluated by means of a stepwise multiple regression analysis of the comprehensibility ratings. Only three measures contributed significantly to the prediction of comprehensibility: mean linguistic depth, the number of self-embedded structures in the sentence, and the number of conjoining transformations in the derivational history of the sentence.