Search

The activation of immune cells in response to stimuli present in their microenvironment is regulated by their metabolic profile. Unlike the signal transduction events, which overlap to a huge degree in diverse cellular processes, the metabolome of a cell reflects a more precise picture of cell physiology and function. Different factors governing the cellular metabolome include receptor signaling, macro and micronutrients, normoxic and hypoxic conditions, energy needs, and biomass demand. Macrophages have enormous plasticity and can perform diverse functions depending upon their phenotypic state. This review presents recent updates on the cellular metabolome and molecular patterns associated with M1 and M2 macrophages, also termed "classically activated macrophages" and "alternatively activated macrophages," respectively. M1 macrophages are proinflammatory in nature and predominantly Th1-specific immune responses induce their polarization. On the contrary, M2 macrophages are anti-inflammatory in nature and primarily participate in Th2-specific responses. Interestingly, the same macrophage cell can adapt to the M1 or M2 phenotype depending upon the clues from its microenvironment. We elaborate on the various tissue niche-specific factors, which govern macrophage metabolism and heterogeneity. Furthermore, the current review provides an in-depth account of deregulated macrophage metabolism associated with pathological disorders such as cancer, obesity, and atherosclerosis. We further highlight significant differences in various metabolic pathways governing the cellular bioenergetics and their impact on macrophage effector functions and associated disorders., (© 2022 International Federation for Cell Biology.)

Acetaminophen (APAP) is a widely used drug known for its analgesic and antipyretic properties. However, its exact mechanism of action is still unclear and has been primarily associated with its effects on COX enzymes and serotonergic pathways. Till date, the immunological mechanisms affected by APAP has gained only inadequate attention. A distinct group of immune cells called Group 2 Innate Lymphoid Cells (ILC2s) are known to play an important role in type 2 cytokine-mediated immunity and their regulatory dysfunction is associated with numerous type 2 pathologies, such as allergy. Conversely, another class of recently characterized Innate Lymphoid Cells called Innate Regulatory Cells (ILCregs) suppress the activation of ILC2s. Maintaining a balance between ILC2s and ILCregs is vital for achieving a well-controlled immune response and tissue homeostasis. Recent studies have highlighted the critical role of prostaglandin D2 (PGD2) in the maturation and development of ILC2 functions. Since APAP also suppresses PGD2 synthesis, it was speculated that APAP treatment could reduce the number of ILC2s while potentially increasing the number of ILCregs. To investigate this hypothesis, here, we administered therapeutic doses of APAP to OVA-sensitized mice, a well-established model of type 2 pathological inflammation. The mice received oral doses of 200 mg/kg body wt. of APAP twice weekly, along with weekly OVA sensitizations for six weeks. The mice were sacrificed at different time points (days 14, 28 and 42) to assess the kinetics of ILC2s, ILCregs and immunoglobulins (IgE and IgG1). The results demonstrated that APAP treatment effectively suppressed OVA-induced ILC2s while significantly increasing the number of IL-10+ ILCregs. APAP exposure also led to decreased levels of serum PGD2, OVA-specific IgE and IgG1, and enhanced the level of IL-10 in OVA sensitized mice. Moreover, OVA sensitized mice treated with APAP did not develop pathological changes in spleen, when compared to OVA sensitized mice. Additionally, APAP treatment did not cause any adverse effects on mice liver in treatment groups. These preliminary findings suggest that APAP exhibits the capacity to modulate type 2 immune responses by suppressing ILC2s and inducing the expansion of IL-10+ ILCregs. [ABSTRACT FROM AUTHOR]

Dietary fibers are a major source of short-chain fatty acids (SCFAs) in the body, and the fermentation products of SCFAs induced by intestinal microbiota affect energy metabolism. Apart from serving as an energy source in the intestines, SCFAs also inhibit autophagy, nucleotide-binding oligomerization domain-containing protein, LRR, and pyrin domain-containing protein 3 inflammasome. SCFAs provide numerous therapeutic benefits through their influence on cognitive functioning and neurodegenerative diseases (NDD) pathophysiology. Additionally, NDDs are associated with abnormalities in the gut microbiota, including an increased load of pathogens and opportunistic microbes. SCFAs maintain the healthy mitochondrial function and stimulate the maturation of microglia, which consequently suppresses the progression of NDD and cognitive decline by regulating inflammation and oxidative stress. Basically, SCFAs function as cofactors for the host's mitochondrial enzymes and are being studied for their ability to reverse the alteration in the gut microbiota seen in many NDDs and cardiac diseases. In the present review, the focus is on the detrimental and beneficial roles of SCFAs in NDD, emphasizing the effects of SCFA on following phenomenon: (1) alteration in gut microbiota profile associated with NDD, (2) the molecular mechanism of metabolic regulation by SCFA's, and its co-relation with NDD, (3) use of mitochondrial antioxidants as a strategy for maintaining microbiota diversity in the gut, and (4) the future direction of metabolism and neurodegeneration in the gut–brain axis. In addition, the interplay between gut microbiota, SCFAs, epithelial barrier, and neuroimmune signaling in neurodegeneration has been reviewed. The current systematic review and meta-analysis indicate that dietary fermentation of nondigestible fibers leads to the production of short chain fatty acids (SCFAs) by gut microbiota. Moreover, they directly act on the central nervous system and inhibit the progression of different neurodegenerative diseases such as Parkinson disease, Alzheimer disease, and multiple sclerosis. SCFAs act by triggering cellular antioxidants and inhibiting inflammation. The properties of SCFAs depend on the G protein–coupled receptors, histone deacetylases and peroxisome proliferator-activated receptor gamma, and regulatory T-cell activation. [Display omitted] [ABSTRACT FROM AUTHOR]