Adiposity, immunity, and inflammation: interrelationships in health and disease: a report from 24th Annual Harvard Nutrition Obesity Symposium, June 2023.

The rapidly evolving field of immunometabolism explores how changes in local immune environments may affect key metabolic and cellular processes, including that of adipose tissue. Importantly, these changes may contribute to low-grade systemic inflammation. In turn, chronic low-grade inflammation affecting adipose tissue may exacerbate the outcome of metabolic diseases.

β-glucans from mushroom products drive Trained Immunity.

Introduction: Macrofungi, such as edible mushrooms, have been used as a valuable medical resource for millennia as a result of their antibacterial and immuno-modulatory components. Mushrooms contain dietary fibers known as β-glucans, a class of polysaccharides previously linked to the induction of Trained Immunity. However, little is known about the ability of mushroom-derived β-glucans to induce Trained Immunity.

Recognition of yeast β-glucan particles triggers immunometabolic signaling required for trained immunity.

Fungal β-glucans are major drivers of trained immunity which increases long-term protection against secondary infections. Heterogeneity in β-glucan source, structure, and solubility alters interaction with the phagocytic receptor Dectin-1 and could impact strategies to improve trained immunity in humans. Using a panel of diverse β-glucans, we describe the ability of a specific yeast-derived whole-glucan particle (WGP) to reprogram metabolism and thereby drive trained immunity in human monocyte-derived macrophages and mice bone marrow .

Negative Regulation of Innate Immune Signaling by Components of the Button Mushroom Agaricus bisporus.

Scope: Mushrooms are valued as an edible and medical resource for millennia. As macrofungi, they possess conserved molecular components recognized by innate immune cells like macrophages, yet unlike pathogenic fungi, they do not trigger the immune system in the same way. That these well-tolerated foods both avoid immuno-surveillance and have positive health benefits, highlights the dearth of information on the interactions of mushroom-derived products with the immune system.

von Willebrand factor links primary hemostasis to innate immunity.

The plasma multimeric glycoprotein von Willebrand factor (VWF) plays a critical role in primary hemostasis by tethering platelets to exposed collagen at sites of vascular injury. Recent studies have identified additional biological roles for VWF, and in particular suggest that VWF may play an important role in regulating inflammatory responses. However, the molecular mechanisms through which VWF exerts its immuno-modulatory effects remain poorly understood.

Macrophage innate training induced by IL-4 and IL-13 activation enhances OXPHOS driven anti-mycobacterial responses.

Macrophages are a highly adaptive population of innate immune cells. Polarization with IFNγ and LPS into the 'classically activated' M1 macrophage enhances pro-inflammatory and microbicidal responses, important for eradicating bacteria such as . By contrast, 'alternatively activated' M2 macrophages, polarized with IL-4, oppose bactericidal mechanisms and allow mycobacterial growth.

Respiratory Tract Infections in Diabetes - Lessons From Tuberculosis and Influenza to Guide Understanding of COVID-19 Severity.

Patients with type-2 diabetes (T2D) are more likely to develop severe respiratory tract infections. Such susceptibility has gained increasing attention since the global spread of Coronavirus Disease 2019 (COVID-19) in early 2020. The earliest reports marked T2D as an important risk-factor for severe forms of disease and mortality across all adult age groups.

Phagocyte metabolism: neutrophils have their cake but don't eat it.

Selectively targeting facets of neutrophil function could benefit infectious and inflammatory diseases. Amara et al. report on a compound which blocks human neutrophil activation by activating the glycolytic enzyme phosphofructokinase, liver-type (PFKL).

Targeting immunometabolism in host defence against Mycobacterium tuberculosis.

In the face of ineffective vaccines, increasing antibiotic resistance and the decline in new antibacterial drugs in the pipeline, tuberculosis (TB) still remains pandemic. Exposure to Mycobacterium tuberculosis (Mtb), which causes TB, results in either direct elimination of the pathogen, most likely by the innate immune system, or infection and containment that requires both innate and adaptive immunity to form the granuloma. Host defence strategies against infectious diseases are comprised of both host resistance, which is the ability of the host to prevent invasion or to eliminate the pathogen, and disease tolerance, which is defined by limiting the collateral tissue damage.

An Army Marches on Its Stomach: Metabolic Intermediates as Antimicrobial Mediators in Infection.

The cells of the immune system are reliant on their metabolic state to launch effective responses to combat mycobacterial infections. The bioenergetic profile of the cell determines the molecular fuels and metabolites available to the host, as well as to the bacterial invader. How cells utilize the nutrients in their microenvironment-including glucose, lipids and amino acids-to sustain their functions and produce antimicrobial metabolites, and how mycobacteria exploit this to evade the immune system is of great interest.

Obesity, COVID-19 and innate immunometabolism.

As COVID-19 continues to spread worldwide, severe disease and mortality have been observed in obese patients. We discuss how obesity and obesity-associated factors such as ‘meta-flammation’, dietary fat intake and paradoxical suppression of the innate immune response within the pulmonary compartment may be crucial determinants in the host response to a novel viral pathogen. Modulation of immune cell bioenergetics and metabolic potential plays a central role in the innate immune response to infection, and as we strive to combat this new global health threat, immunometabolism of the innate immune system warrants attention.

Train to Lose: Innate Immune Memory in Metaflammation.

Westernized diets and lifestyle are linked to the development of metabolic syndrome, characterized by obesity, type 2 diabetes, and increased cardiovascular disease risk. Systemic low-grade inflammation is a common feature of chronic metabolic disorders and is believed to promote disease progression. Therefore, modulating inflammation is a commonly explored strategy to prevent obesity-associated co-morbidities.

Mycobacterium tuberculosis Limits Host Glycolysis and IL-1β by Restriction of PFK-M via MicroRNA-21.

Increased glycolytic metabolism recently emerged as an essential process driving host defense against Mycobacterium tuberculosis (Mtb), but little is known about how this process is regulated during infection. Here, we observe repression of host glycolysis in Mtb-infected macrophages, which is dependent on sustained upregulation of anti-inflammatory microRNA-21 (miR-21) by proliferating mycobacteria. The dampening of glycolysis by miR-21 is mediated through targeting of phosphofructokinase muscle (PFK-M) isoform at the committed step of glycolysis, which facilitates bacterial growth by limiting pro-inflammatory mediators, chiefly interleukin-1β (IL-1β).

Cigarette Smoking Impairs the Bioenergetic Immune Response to Mycobacterium tuberculosis Infection.

Smoking is a major risk factor driving the tuberculosis epidemic, and smokers' alveolar macrophages (AM) demonstrate significant immune defects after infection. Recently, macrophage glycolytic reprogramming has emerged as crucial in the early host immune response to Mycobacterium tuberculosis (Mtb) infection. In the present study, we sought to compare baseline metabolic characteristics and the glycolytic response to infection of human AM from smokers and nonsmokers.

Metabolic reprogramming & inflammation: Fuelling the host response to pathogens.

Successful immune responses to pathogens rely on efficient host innate processes to contain and limit bacterial growth, induce inflammatory response and promote antigen presentation for the development of adaptive immunity. This energy intensive process is regulated through multiple mechanisms including receptor-mediated signaling, control of phago-lysomal fusion events and promotion of bactericidal activities. Inherent macrophage activities therefore are dynamic and are modulated by signals and changes in the environment during infection.

Mycobacterium tuberculosis induces the miR-33 locus to reprogram autophagy and host lipid metabolism.

Mycobacterium tuberculosis (Mtb) survives in macrophages by evading delivery to the lysosome and promoting the accumulation of lipid bodies, which serve as a bacterial source of nutrients. We found that by inducing the microRNA (miRNA) miR-33 and its passenger strand miR-33*, Mtb inhibited integrated pathways involved in autophagy, lysosomal function and fatty acid oxidation to support bacterial replication. Silencing of miR-33 and miR-33* by genetic or pharmacological means promoted autophagy flux through derepression of key autophagy effectors (such as ATG5, ATG12, LC3B and LAMP1) and AMPK-dependent activation of the transcription factors FOXO3 and TFEB, which enhanced lipid catabolism and Mtb xenophagy.

A Common Variant in the Adaptor Mal Regulates Interferon Gamma Signaling.

Humans that are heterozygous for the common S180L polymorphism in the Toll-like receptor (TLR) adaptor Mal (encoded by TIRAP) are protected from a number of infectious diseases, including tuberculosis (TB), whereas those homozygous for the allele are at increased risk. The reason for this difference in susceptibility is not clear. We report that Mal has a TLR-independent role in interferon-gamma (IFN-γ) receptor signaling.

Cutting Edge: Mycobacterium tuberculosis Induces Aerobic Glycolysis in Human Alveolar Macrophages That Is Required for Control of Intracellular Bacillary Replication.

Recent advances in immunometabolism link metabolic changes in stimulated macrophages to production of IL-1β, a crucial cytokine in the innate immune response to Mycobacterium tuberculosis. To investigate this pathway in the host response to M. tuberculosis, we performed metabolic and functional studies on human alveolar macrophages, human monocyte-derived macrophages, and murine bone marrow-derived macrophages following infection with the bacillus in vitro.

MicroRNA-33-dependent regulation of macrophage metabolism directs immune cell polarization in atherosclerosis.

Cellular metabolism is increasingly recognized as a controller of immune cell fate and function. MicroRNA-33 (miR-33) regulates cellular lipid metabolism and represses genes involved in cholesterol efflux, HDL biogenesis, and fatty acid oxidation. Here, we determined that miR-33-mediated disruption of the balance of aerobic glycolysis and mitochondrial oxidative phosphorylation instructs macrophage inflammatory polarization and shapes innate and adaptive immune responses.

Turning 21: Induction of miR-21 as a Key Switch in the Inflammatory Response.

miR-21 is one of the most highly expressed members of the small non-coding microRNA family in many mammalian cell types. Its expression is further enhanced in many diseased states including solid tumors, cardiac injury, and inflamed tissue. While the induction of miR-21 by inflammatory stimuli cells has been well documented in both hematopoietic cells of the immune system (particularly monocytes/macrophages but also dendritic and T-cells) and non-hematopoietic tumorigenic cells, the exact functional outcome of this elevated miR-21 is less obvious.