Nucleotide-binding oligomerization domain 1 (NOD1), a pattern recognition receptor (PRR) that detects bacterial peptidoglycan fragments and other danger signals, has been linked to inflammatory pathologies. NOD1, which is expressed by immune and non-immune cells, is activated after recognizing microbe-associated molecular patterns (MAMPs). This recognition triggers host defense responses and both immune memory and tolerance can also be achieved during these processes. Since the gut microbiota is currently considered a master regulator of human physiology central in health and disease and the intestine metabolizes a wide range of nutrients, drugs and hormones, it is a fact that dysbiosis can alter tissues and organs homeostasis. These systemic alterations occur in response to gastrointestinal immune adaptations that are not yet fully understood. Even if previous evidence confirms the connection between the microbiota, the immune system and metabolic disorders, much remains to be discovered about the contribution of NOD1 to low-grade inflammatory pathologies such as obesity, diabetes and cardiovascular diseases. This review compiles the most recent findings in this area, while providing a dynamic and practical framework with future approaches for research and clinical applications on targeting NOD1. This knowledge can help to rate the consequences of the disease and to stratify the patients for therapeutic interventions.

Atherosclerosis is a chronic disease characterized by vascular lipid retention and inflammation, and pattern recognition receptors (PRRs) are important contributors in early stages of the disease. Given the implication of the intracellular PRR nucleotide‐binding oligomerization domain 1 (NOD1) in cardiovascular diseases, we investigated its contribution to early atherosclerosis. We evidenced NOD1 induction in atherosclerotic human and mouse tissues, predominantly in vascular endothelial cells. Accordingly, NOD1 genetic inactivation in Apoe ^−/− mice reduced not only atherosclerosis burden, but also monocyte and neutrophil accumulation in atheromata. Of note, in the presence of either peptidoglycan or oxidized LDLs, endothelial NOD1 triggered VCAM‐1 up‐regulation through the RIP2‐NF‐κB axis in an autocrine manner, enhancing firm adhesion of both sets of myeloid cells to the inflamed micro‐ and macro vasculature in vivo . Our data define a major proatherogenic role for endothelial NOD1 in early leukocyte recruitment to the athero‐prone vasculature, thus introducing NOD1 as an innovative therapeutic target and potential prognostic molecule.—González‐Ramos, S., Paz‐García, M., Rius, C., del Monte‐Monge, A., Rodríguez, C., Fernández‐García, V., Andrés, V., Martínez‐González, J., Lasunción, M. A., Martín‐Sanz, P., Soehnlein, O., Boscá, L. Endothelial NOD1 directs myeloid cell recruitment in atherosclerosis through VCAM‐1. FASEB J. 33, 3912–3921 (2019). www.fasebj.org

It has long been known that thyroid hormones have implications for multiple physiological processes and can lead to serious illness when there is an imbalance in its metabolism. The connections between thyroid hormone metabolism and the immune system have been extensively described, as they can participate in inflammation, autoimmunity, or cancer progression. In addition, changes in the normal intestinal microbiota involve the activation of the immune system while triggering different pathophysiological disorders. Recent studies have linked the microbiota and certain bacterial fragments or metabolites to the regulation of thyroid hormones and the general response in the endocrine system. Even if the biology and function of the thyroid gland has attracted more attention due to its pathophysiological importance, there are essential mechanisms and issues related to it that are related to the interplay between the intestinal microbiota and the immune system and must be further investigated. Here we summarize additional information to uncover these relationships, the knowledge of which would help establish new personalized medical strategies.

Atherothrombosis, the main cause of acute coronary syndromes (ACS), is characterized by the rupture of the atherosclerotic plaque followed by the formation of thrombi. Fatal plaque rupture sites show large necrotic cores combined with high levels of inflammation and thin layers of collagen. Plaque necrosis due to the death of macrophages and smooth muscle cells (SMCs) remains critical in the process. To determine the contribution of the innate immunity receptor NOD1 to the stability of atherosclerotic plaque, Apoe^−/− and Apoe^−/− Nod1^−/− atherosclerosis prone mice were placed on a high-fat diet for 16 weeks to assess post-mortem advanced atherosclerosis in the aortic sinus. The proliferation and apoptosis activity were analyzed, as well as the foam cell formation capacity in these lesions and in primary cultures of macrophages and vascular SMCs obtained from both groups of mice. Our results reinforce the preeminent role for NOD1 in human atherosclerosis. Advanced plaque analysis in the Apoe^−/− atherosclerosis model suggests that NOD1 deficiency may decrease the risk of atherothrombosis by decreasing leukocyte infiltration and reducing macrophage apoptosis. Furthermore, Nod1^−/− SMCs exhibit higher proliferation rates and decreased apoptotic activity, contributing to thicker fibrous caps with reduced content of pro-thrombotic collagen. These findings demonstrate a direct link between NOD1 and plaque vulnerability through effects on both macrophages and SMCs, suggesting promising insights for early detection of biomarkers for treating patients before ACS occurs.

The contribution of the nucleotide-binding oligomerization domain protein NOD1 to obesity has been investigated in mice fed a high fat diet (HFD). Absence of NOD1 accelerates obesity as early as 2 weeks after feeding a HFD. The obesity was due to increases in abdominal and inguinal adipose tissues. Analysis of the resting energy expenditure showed an impaired function in NOD1-deficient animals, compatible with an alteration in thyroid hormone homeostasis. Interestingly, free thyroidal T4 increased in NOD1-deficient mice fed a HFD and the expression levels of UCP1 in brown adipose tissue were significantly lower in NOD1-deficient mice than in the wild type animals eating a HFD, thus contributing to the observed adiposity in NOD1-deficient mice. Feeding a HFD resulted in an alteration of the proinflammatory profile of these animals, with an increase in the infiltration of inflammatory cells in the liver and in the white adipose tissue, and an elevation of the circulating levels of TNF-α. In addition, alterations in the gut microbiota in NOD1-deficient mice correlate with increased vulnerability of their ecosystem to the HFD challenge and affect the immune-metabolic phenotype of obese mice. Together, the data are compatible with a protective function of NOD1 against low-grade inflammation and obesity under nutritional conditions enriched in saturated lipids. Moreover, one of the key players of this early obesity onset is a dysregulation in the metabolism and release of thyroid hormones leading to reduced energy expenditure, which represents a new role for these hormones in the metabolic actions controlled by NOD1.

Background: Tumor-associated macrophages (TAMs) play a crucial role in suppressing the immunosurveillance function of the immune system that prevents tumor growth. Indeed, macrophages can also be targeted by different chemotherapeutic agents improving the action over immune checkpoints to fight cancer. Here we describe the effect of trabectedin and lurbinectedin on human macrophage cell viability and function. Methods: Blood monocytes from healthy donors were differentiated into macrophages and exposed to different stimuli promoting functional polarization and differentiation into tumor-associated macrophages. Cells were challenged with the chemotherapeutic drugs and the effects on cell viability and function were analyzed. Results: Human macrophages exhibit at least two different profiles in response to these drugs. One-fourth of the blood donors assayed (164 individuals) were extremely sensitive to trabectedin and lurbinectedin, which promoted apoptotic cell death. Macrophages from other individuals retained viability but responded to the drugs increasing reactive oxygen production and showing a rapid intracellular calcium rise and a loss of mitochondrial oxygen consumption. Cell-membrane exposure of programmed-death ligand 1 (PD-L1) significantly decreased after treatment with therapeutic doses of these drugs, including changes in the gene expression profile of hypoxia-inducible factor 1 alpha (HIF-1α)-dependent genes, among other. Conclusions: The results provide evidence of additional onco-therapeutic actions for these drugs.