Metabolomics Profiling Reveals Critical Roles of Indoxyl Sulfate in the Regulation of Innate Monocytes in COVID-19.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is intricately related to the reprogramming of host metabolism. However, existing studies have mainly focused on peripheral blood samples and barely identified specific metabolites that are critically involved in the pathology of coronavirus disease 2019 (COVID-19). In the current small-scale study, we performed metabolic profiling in plasma ( = 61) and paired bronchoalveolar lavage fluid (BALF) samples ( = 20) using parallel two-dimensional liquid chromatography-mass spectrometry (2DLC-MS).

Multifaceted roles of neutrophils in cardiac disease.

Neutrophils, the most abundant leukocytes in human blood, have long been recognized as critical first responders in the innate immune system's defense against pathogens. Some of the more notable innate anti-microbial properties of neutrophils include generation of superoxide free radicals like myeloperoxidase (MPO), production of proteases that reshape the extracellular matrix allowing for easier access to infected tissues, and release of neutrophil extracellular traps (NETs), extruded pieces of DNA that ensnare bacterial and fungi. These mechanisms developed to provide neutrophils with a vast array of specialized functions to provide the host defense against infection in an acute setting.

CXCL12 ameliorates neutrophilia and disease severity in SARS-CoV-2 infection.

Neutrophils, particularly low-density neutrophils (LDNs), are believed to contribute to acute COVID-19 severity. Here, we showed that neutrophilia can be detected acutely and even months after SARS-CoV-2 infection in patients and mice, while neutrophil depletion reduced disease severity in mice. A key factor in neutrophilia and severe disease in infected mice was traced to the chemokine CXCL12 secreted by bone marrow cells and unexpectedly, endothelial cells.

Lactate supports a metabolic-epigenetic link in macrophage polarization.

Lactate accumulation is a hallmark of solid cancers and is linked to the immune suppressive phenotypes of tumor-infiltrating immune cells. We report herein that interleukin-4 (IL-4)–induced M0 → M2 macrophage polarization is accompanied by interchangeable glucose- or lactate-dependent tricarboxylic acid (TCA) cycle metabolism that directly drives histone acetylation, M2 gene transcription, and functional immune suppression. Lactate-dependent M0 → M2 polarization requires both mitochondrial pyruvate uptake and adenosine triphosphate–citrate lyase (ACLY) enzymatic activity.

Tumor-derived exosomes drive immunosuppressive macrophages in a pre-metastatic niche through glycolytic dominant metabolic reprogramming.

One of the defining characteristics of a pre-metastatic niche, a fundamental requirement for primary tumor metastasis, is infiltration of immunosuppressive macrophages. How these macrophages acquire their phenotype remains largely unexplored. Here, we demonstrate that tumor-derived exosomes (TDEs) polarize macrophages toward an immunosuppressive phenotype characterized by increased PD-L1 expression through NF-kB-dependent, glycolytic-dominant metabolic reprogramming.

Exosomal PD-L1: Roles in Tumor Progression and Immunotherapy.

The use of immune checkpoint therapies targeting programmed death-1 (PD-1) and its ligand (PD-L1) continue to show limited durable success in clinical cases despite widespread application. While some patients achieve complete responses and disease remission, others are completely resistant to the therapy. Recent evidence in the field suggests that tumor-derived exosomes could be responsible for mediating systemic immunosuppression that antagonizes anti-PD-1 checkpoint therapy.

Novel Insight Into the Molecular and Metabolic Mechanisms Orchestrating IL-17 Production in γδ T Cells.

Increasing evidence has demonstrated that IL-17-producing γδ T cells (γδ T17) play a tumor-promoting role in a series of cancers via various mechanisms in mice and human cancers, though the relationship between γδ T17 and human tumors has yet to be extensively characterized and established. Molecular signals such as intrinsic cascade, environmental cues and cellular metabolic pathways including nutrient uptake and utilization in γδ T17 cells are significantly important for their activation, differentiation, and function. Understanding the molecular mechanisms and metabolic pathways of γδ T17 cells in both the physiological setting and tumor environment would contribute to the development of therapeutic approaches or drugs targeting γδ T17 for immunotherapy in cancers.

γδ T Cells: Unexpected Regulators of Cancer Development and Progression.

Accumulating evidence suggests a role for gamma delta (γδ) T cells as unexpected drivers of tumor development and progression. These protumoral γδ T cells are abundant in the tumor microenvironment in both mouse and human. They promote tumor progression by: (i) inducing an immunosuppressive tumor microenvironment and angiogenesis via cytokine production; (ii) functioning as regulatory T (Treg)/T helper 2 (Th2)-like cells; (iii) interfering with dendritic cell (DC) effector function; and (iv) inhibiting antitumor adaptive T cell immunity via the programmed death-1 (PD-1)-programmed death ligand-1 (PD-L1) pathway.

Microbiota-activated CD103 DCs stemming from microbiota adaptation specifically drive γδT17 proliferation and activation.

Background: IL-17-producing γδT cells (γδT17) promote autoinflammatory diseases and cancers. Yet, γδT17 peripheral regulation has not been thoroughly explored especially in the context of microbiota-host interaction. The potent antigen-presenting CD103 dendritic cell (DC) is a key immune player in close contact with both γδT17 cells and microbiota.

Exacerbated experimental colitis in TNFAIP8-deficient mice.

The TNF-α-induced protein 8 (TNFAIP8 or TIPE) is a risk factor for cancer and bacterial infection, and its expression is upregulated in a number of human cancers. However, its physiologic and pathologic functions are unclear. In this study, we describe the generation of TIPE-deficient mice and their increased sensitivity to colonic inflammation.

Critical roles of TIPE2 protein in murine experimental colitis.

Both commensal bacteria and infiltrating inflammatory cells play essential roles in the pathogenesis of inflammatory bowel disease. The molecular mechanisms whereby these pathogenic factors are regulated during the disease are not fully understood. We report in this article that a member of the TNF-α-induced protein 8 (TNFAIP8) family called TIPE2 (TNFAIP8-like 2) plays a crucial role in regulating commensal bacteria dissemination and inflammatory cell function in experimental colitis induced by dextran sodium sulfate (DSS).

Use of postexcision preirradiation mammography in patients with ductal carcinoma in situ of the breast treated with breast-conserving therapy.

Purpose: Postexcision preirradiation mammography (PPM) is frequently performed in patients with ductal carcinoma in situ (DCIS) treated with breast-conserving therapy (BCT) to evaluate for residual suspicious calcifications; but no clear evidence supports this practice. The current study was undertaken to investigate the value of PPM in the management of patients with DCIS.

Methods And Materials: We conducted a retrospective review of patients treated for DCIS with BCT at the University of Pennsylvania.