Dimensions of inflammation in host defense and diseases.

Inflammation is the body’s natural response to injury or biotic and abiotic challenges to the host. Controlled inflammation is required in order to maintain tissue homeostasis and physiological processes under various intrinsic and extrinsic perturbations. However, uncontrolled inflammation leads to various degrees of immune-pathologies such as susceptibility to infection or autoimmune diseases. Various biotic and abiotic factors induce inflammation, including, pathogenic invasion, physical injury, stress, obesity, and chemical or radiation insult to the host. At the cellular or molecular level, inflammation is induced by complex signaling through innate immune sensors expressed on immune and non-immune cells, and through specialized adaptive immune cells. Inflammatory mediators can be amines (e.g. histamine), lipid derivatives (e.g. prostaglandins), the peptide, bradykinin or proteins (small fragments of complements and inflammatory cytokines). These inflammatory mediators can cause cell damage, can result in a cytokine storm, and can lead to damage to the vital organs. This special issue of International Reviews of Immunology focuses on inducers of inflammation and how inflammation shapes immunity and its dysregulation results in the development of diseases and disorders (Figure 1). In mammals, lactate is a metabolic by-product of anaerobic respiration, a glycolytic pathway that ensures quick energy replenishment in the form of adenosine triphosphate (ATP) for the cells and prevention of muscle fatigue. Lactate acts as a circulating fuel in the blood that goes to the liver and is converted into pyruvate by the enzyme lactate dehydrogenase. Pyruvate is then converted into glucose via a metabolic pathway known as gluconeogenesis in the liver. Notably, lactate production increases when demand for ATP increases. In the past three decades, lactate has also been proved to be a very important signaling molecule that regulates various signaling pathways including inflammation-associated immune pathways. In this special issue, Zhou et al. [1] and Luo et al. [2] shed light on how endogenous lactate regulates inflammation in various immunological events, such as via macrophage polarization, T-cell immune dysfunction and its link with infectious and noninfectious diseases such as tumors. These two articles will be of interest to a broad readership in the field of immunology, as well as researchers investigating metaflammation and immunometabolic disorders and those in associated fields (Figure 1). Extracellular vesicles (EVs) are cell-derived membranous structures generated from broad cell-types including hematopoetic and non-hematopoetic cells. They range in size from the smallest exosomes and medium-sized micro-vesicles to apoptotic bodies and large-sized macrolets. Extracellular vesicles carry several biomolecules such as proteins (enzymes, receptors, cytokines etc.), lipids, genetic materials (miRNA, RNA, DNA) in them. Hence, by virtue of carrying a variety of biomolecules, EVs qualify to participate in several cellular processes, namely, signaling pathways that regulate cell growth, metabolism, immunity and inflammation, and thereby help in intercellular communication. Depending on what biomolecules they carry, EVs either induce or suppress physiological processes. In this special issue, Kumar et al. [3] discuss how EVs secreted from adipose tissue initiate inflammation at target cells by carrying several adipokines (pro-inflammatory cytokines) in obese people. Obesity is the manifestation of an unwanted accumulation of fat (lipids) and a slow metabolic rate. Obesity predisposes individuals to many diseases such as cardiovascular diseases, diabetes mellitus, hypertension,