Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field.

nflammation is a reflexive response to infection, the binding of antibodies to antigens within the body, mechanical irritation, or injury. 1 Microbes that breach epithelial barriers, for instance, directly activate complement and toll-like receptors, two principal components of the innate immune system. The activation of these sentinels triggers the synthesis and release of inflammatory mediators with acute effects on the vasculature. Localized vasodilation, increased vascular permeability, extravasation of plasma (and humoral) proteins, and migration of leukocytes into the affected tissue produce the classic signs of inflammation: calor, dolor, rubor, tumor, and functio laesa. A positive feedback loop initiates the production of additional inflammatory cytokines once infiltrating leukocytes become activated. Antiinflammatory homeostatic mechanisms reverse these processes as the infectious agent is cleared by the innate and adaptive immune systems. The hypothalamic-pituitaryadrenal axis and glucocorticoids in particular are essential in limiting and resolving the inflammatory process. 2 Whereas restricted inflammation is beneficial, excessive or persistent inflammation incites tissue destruction and disease. Together, inflammatory disorders such as allergies, asthma, autoimmune diseases, and sepsis are a major cause of illness and death. Asthma affects approximately 21.9 million adults and 8.9 million children in the United States alone. The prevalence of autoimmune diseases, which affect 8.5 million Americans, 3,4 is also noteworthy. Rheumatoid arthritis, Graves' disease, glomerulonephritis, type 1 diabetes mellitus, multiple sclerosis, thyroiditis, pernicious anemia, systemic lupus erythematosus, psoriasis, and vitiligo account for most of these autoimmune diseases. Sepsis is fatal for roughly 30 percent of the 700,000 patients affected annually in the United States. 5-7 Glucocorticoids are indicated for the treatment of many of these diverse conditions. The efficacy of glucocorticoids in alleviating inflammatory disorders results from the pleiotropic effects of the glucocorticoid receptor on multiple signaling pathways. Pleiotropy can, however, also have adverse effects: growth retardation in children, immunosuppression, hypertension, inhibition of wound repair, osteoporosis, and metabolic disturbances. All these harmful properties contraindicate prolonged glucocorticoid therapy. Here, we review mechanisms whereby glucocorticoids inhibit inflammation and the therapeutic limitations of these hormones. We then provide a prospectus for research on drugs that dissociate the beneficial and detrimental effects of glucocorticoids. The hypothalamic-pituitary-adrenal axis plays a central role in regulating signaling by the glucocorticoid receptor, which is expressed in virtually all cells. In brief, neural, endocrine, and cytokine signals converge at the level of the periventricular nucleus of the i basic actions of endogenous glucocorticoids

Endogenous glucocorticoids are crucial to various physiological processes, including metabolism, development and inflammation. Since 1948, synthetic glucocorticoids have been used to treat various immune-related disorders. The mechanisms that underlie the immunosuppressive properties of these hormones have been intensely scrutinized, and it is widely appreciated that glucocorticoids have pleiotropic effects on the immune system. However, a clear picture of the cellular and molecular basis of glucocorticoid action has remained elusive. In this Review, we distil several decades of intense (and often conflicting) research that defines the interface between the endocrine stress response and the immune system.