Reprogramming of the LXRα Transcriptome Sustains Macrophage Secondary Inflammatory Responses.

Macrophages regulate essential aspects of innate immunity against pathogens. In response to microbial components, macrophages activate primary and secondary inflammatory gene programs crucial for host defense. The liver X receptors (LXRα, LXRß) are ligand-dependent nuclear receptors that direct gene expression important for cholesterol metabolism and inflammation, but little is known about the individual roles of LXRα and LXRß in antimicrobial responses. Here, the results demonstrate that induction of LXRα transcription by prolonged exposure to lipopolysaccharide (LPS) supports inflammatory gene expression in macrophages. LXRα transcription is induced by NF-κB and type-I interferon downstream of TLR4 activation. Moreover, LPS triggers a reprogramming of the LXRα cistrome that promotes cytokine and chemokine gene expression through direct LXRα binding to DNA consensus sequences within cis-regulatory regions including enhancers. LXRα-deficient macrophages present fewer binding of p65 NF-κB and reduced histone H3K27 acetylation at enhancers of secondary inflammatory response genes. Mice lacking LXRα in the hematopoietic compartment show impaired responses to bacterial endotoxin in peritonitis models, exhibiting reduced neutrophil infiltration and decreased expansion and inflammatory activation of recruited F4/80lo-MHC-IIhi peritoneal macrophages. Together, these results uncover a previously unrecognized function for LXRα-dependent transcriptional cis-activation of secondary inflammatory gene expression in macrophages and the host response to microbial ligands.

Contribution of Nucleotide-Binding Oligomerization Domain-like (NOD) Receptors to the Immune and Metabolic Health.

Nucleotide-binding oligomerization domain-like (NOD) receptors rely on the interface between immunity and metabolism. Dietary factors constitute critical players in the activation of innate immunity and modulation of the gut microbiota. The latter have been involved in worsening or improving the control and promotion of diseases such as obesity, type 2 diabetes, metabolic syndrome, diseases known as non-communicable metabolic diseases (NCDs), and the risk of developing cancer. Intracellular NODs play key coordinated actions with innate immune 'Toll-like' receptors leading to a diverse array of gene expressions that initiate inflammatory and immune responses. There has been an improvement in the understanding of the molecular and genetic implications of these receptors in, among others, such aspects as resting energy expenditure, insulin resistance, and cell proliferation. Genetic factors and polymorphisms of the receptors are determinants of the risk and severity of NCDs and cancer, and it is conceivable that dietary factors may have significant differential consequences depending on them. Host factors are difficult to influence, while environmental factors are predominant and approachable with a preventive and/or therapeutic intention in obesity, T2D, and cancer. However, beyond the recognition of the activation of NODs by peptidoglycan as its prototypical agonist, the underlying molecular response(s) and its consequences on these diseases remain ill-defined. Metabolic (re)programming is a hallmark of NCDs and cancer in which nutritional strategies might play a key role in preventing the unprecedented expansion of these diseases. A better understanding of the participation and effects of immunonutritional dietary ingredients can boost integrative knowledge fostering interdisciplinary science between nutritional precision and personalized medicine against cancer. This review summarizes the current evidence concerning the relationship(s) and consequences of NODs on immune and metabolic health.

Trabectedin and Lurbinectedin Modulate the Interplay between Cells in the Tumour Microenvironment-Progresses in Their Use in Combined Cancer Therapy.

Trabectedin (TRB) and Lurbinectedin (LUR) are alkaloid compounds originally isolated from Ecteinascidia turbinata with proven antitumoral activity. Both molecules are structural analogues that differ on the tetrahydroisoquinoline moiety of the C subunit in TRB, which is replaced by a tetrahydro-ß-carboline in LUR. TRB is indicated for patients with relapsed ovarian cancer in combination with pegylated liposomal doxorubicin, as well as for advanced soft tissue sarcoma in adults in monotherapy. LUR was approved by the FDA in 2020 to treat metastatic small cell lung cancer. Herein, we systematically summarise the origin and structure of TRB and LUR, as well as the molecular mechanisms that they trigger to induce cell death in tumoral cells and supporting stroma cells of the tumoral microenvironment, and how these compounds regulate immune cell function and fate. Finally, the novel therapeutic venues that are currently under exploration, in combination with a plethora of different immunotherapeutic strategies or specific molecular-targeted inhibitors, are reviewed, with particular emphasis on the usage of immune checkpoint inhibitors, or other bioactive molecules that have shown synergistic effects in terms of tumour regression and ablation. These approaches intend to tackle the complexity of managing cancer patients in the context of precision medicine and the application of tailor-made strategies aiming at the reduction of undesired side effects.