Single cell immune profiling reveals a developmentally distinct CD4+ GM-CSF+ T cell lineage that induces GI tract GVHD

Gastrointestinal (GI) tract involvement is a major determinant for subsequent morbidity and mortality arising during graft versus host disease (GVHD). CD4+ T cells that produce GM-CSF have emerged as central mediators of inflammation in this tissue site as GM-CSF serves as a critical cytokine link between the adaptive and innate arms of the immune system. However, cellular heterogeneity within the CD4+ GM-CSF+ T cell population due to the concurrent production of other inflammatory cytokines has raised questions as to whether these cells have a common ontology or if there exists a unique CD4+ GM-CSF+ subset that differs from other defined T helper (TH) subtypes. Using single cell RNA sequencing analysis, we identified two CD4+ GM-CSF+ T cell populations that arose during GVHD and were distinguishable by the presence or absence of IFN-γ co-expression. CD4+ GM-CSF+ IFN-γ- T cells which emerged preferentially in the colon had a distinct transcriptional profile, employed unique gene regulatory networks, and possessed a non-overlapping TCR repertoire when compared to CD4+ GM-CSF+ IFN-γ+ T cells as well as all other transcriptionally defined CD4+ T cell populations in the colon. Functionally, this CD4+ GM-CSF+ T cell population contributed to pathological damage in the GI tract which was critically dependent upon signaling through the IL-7 receptor but was independent of type 1 interferon signaling. Thus, these studies help to unravel heterogeneity within CD4+ GM-CSF+ T cells that arise during GVHD and define a developmentally distinct colitogenic TH GM-CSF+ subset that mediates immunopathology.

Molecular Basis of Selective Cytokine Signaling Inhibition by Antibodies Targeting a Shared Receptor

Interleukin-1 (IL-1) family cytokines are potent mediators of inflammation, acting to coordinate local and systemic immune responses to a wide range of stimuli. Aberrant signaling by IL-1 family cytokine members, however, is linked to myriad inflammatory syndromes, autoimmune conditions and cancers. As such, blocking the inflammatory signals inherent to IL-1 family signaling is an established and expanding therapeutic strategy. While several FDA-approved IL-1 inhibitors exist, including an Fc fusion protein, a neutralizing antibody, and an antagonist cytokine, none specifically targets the co-receptor IL-1 receptor accessory protein (IL-1RAcP). Most IL-1 family cytokines form productive signaling complexes by binding first to their cognate receptors – IL-1RI for IL-1α and IL-1β; ST2 for IL-33; and IL-36R for IL-36α, IL-36β and IL-36γ – after which they recruit the shared secondary receptor IL-1RAcP to form a ternary cytokine/receptor/co-receptor complex. Recently, IL-1RAcP was identified as a biomarker for both AML and CML. IL-1RAcP has also been implicated in tumor progression in solid tumors and an anti-IL1RAP antibody (nadunolimab, CAN04) is in phase II clinical studies in pancreatic cancer and non-small cell lung cancer (NCT03267316). As IL-1RAcP is common to all of the abovementioned IL-1 family cytokines, targeting this co-receptor raises the possibility of selective signaling inhibition for different IL-1 family cytokines. Indeed, previous studies of IL-1β and IL-33 signaling complexes have revealed that these cytokines employ distinct mechanisms of IL-1RAcP recruitment even though their overall cytokine/receptor/co-receptor complexes are structurally similar. Here, using functional, biophysical, and structural analyses, we show that antibodies specific for IL-1RAcP can differentially block signaling by IL-1 family cytokines depending on the distinct IL-1RAcP epitopes that they engage. Our results indicate that targeting a shared cytokine receptor is a viable therapeutic strategy for selective cytokine signaling inhibition.

Protective Effect of Eugenol against Acetaminophen-Induced Hepatotoxicity in Human Hepatocellular Carcinoma Cells via Antioxidant, Anti-Inflammatory, and Anti-Necrotic Potency

BACKGROUND: Overdoses acetaminophen (APAP) could cause acute liver failure, even though it used is for analgesics. APAP could cause hepatotoxicity due to multiple mediators of inflammation and oxidative stress. Eugenol has been reported to have anti-inflammatory and antioxidant activity but its hepatoprotective effect has not been widely reported. AIM: The purpose of this research is to know if eugenol could protect HepG2 cells from APAP. METHODS: HepG2 that induced by APAP as hepatotoxicity cells model was treated by using eugenol at 6.25 and 25 μg/mL. The protective effects of eugenol toward hepatotoxicity were evaluated by determine tumor necrosis factor-α (TNF-α) concentration, apoptotic activity, reactive oxygen species (ROS) level, also cytochrome (CYP)2E1 and GPX gene expression. RESULTS: Eugenol at 6.25 and 25 μg/mL concentration can reduce TNF-α concentration, the apoptotic, necrotic, dead cells, and ROS level. Besides it can increase the gene expression (GPX and CYP2E1). The best hepatoprotective effect was found when using the eugenol at 25 μg/mL. CONCLUSION: Therefore, eugenol can be used to protect HepG2 cells against APAP.

On the Question of the Reflexotherapy Action Mechanisms in the Ischemic Stroke Acute Period (Literature Review)

A high degree of disability in stroke patients, along with severe social and economic losses, determine the enduring urgency of the problem of early rehabilitation for post-stroke patients. Despite the proven effectiveness of the various reflexotherapy techniques in rehabilitation of patients with ischemic stroke, the underlying mechanisms remain unclear. The aim of the review was to analyze the mechanisms of the acupuncture intervention effect on the main links of the ischemic stroke pathogenesis, on neurological deficit and the volume of cerebral infarction (based on publications in international databases). The use of acupuncture in the acute period of ischemic stroke can improve the ability to cerebrovascular reserve, reduce the severity of arterial stiffness and endothelial dysfunction, induce neuroprotection, inhibit cell apoptosis and stimulate neuroplasticity, alleviate the inflammatory response in acute cerebral ischemia, regulate mediators of inflammation and oxidative stress etc., thus improving cerebral blood flow. The analysis of literature data has shown that acupuncture induces multilevel regulation through complex mechanisms, and one factor may not be enough to explain the positive effect against cerebral ischemia.

Immune Modulation as a Key Mechanism for the Protective Effects of Remote Ischemic Conditioning After Stroke

Remote ischemic conditioning (RIC), which involves a series of short cycles of ischemia in an organ remote to the brain (typically the limbs), has been shown to protect the ischemic penumbra after stroke and reduce ischemia/reperfusion (IR) injury. Although the exact mechanism by which this protective signal is transferred from the remote site to the brain remains unclear, preclinical studies suggest that the mechanisms of RIC involve a combination of circulating humoral factors and neuronal signals. An improved understanding of these mechanisms will facilitate translation to more effective treatment strategies in clinical settings. In this review, we will discuss potential protective mechanisms in the brain and cerebral vasculature associated with RIC. We will discuss a putative role of the immune system and circulating mediators of inflammation in these protective processes, including the expression of pro-and anti-inflammatory genes in peripheral immune cells that may influence the outcome. We will also review the potential role of extracellular vesicles (EVs), biological vectors capable of delivering cell-specific cargo such as proteins and miRNAs to cells, in modulating the protective effects of RIC in the brain and vasculature.

Cells and Mediators of Inflammation as Effectors of Epithelial Repair in the Inflamed Intestine

Mucosal and histological healing have become the gold standards for assessing the efficacy of therapy in patients living with inflammatory bowel diseases (IBD). Despite these being the accepted goals in therapy, the mechanisms that underlie the healing of the mucosa after an inflammatory insult are not well understood, and many patients fail to meet this therapeutic endpoint. Here we review the emerging evidence that mediators (e.g. prostaglandins, cytokines, proteases, reactive oxygen and nitrogen species) and innate immune cells (e.g. neutrophils and monocytes/macrophages), that are involved in the initiation of the inflammatory response, are also key players in the mechanisms underlying mucosal healing to resolve chronic inflammation in the colon. The dual function mediators comprise an inflammation/repair program that returns damaged tissue to homeostasis. Understanding details of the dual mechanisms of these mediators and cells may provide the basis for the development of drugs that can help to stimulate epithelial repair in patients affected by IBD.

Targeting Mediators of Inflammation in Heart Failure: A Short Synthesis of Experimental and Clinical Results

Inflammation has emerged as an important contributor to heart failure (HF) development and progression. Current research data highlight the diversity of immune cells, proteins, and signaling pathways involved in the pathogenesis and perpetuation of heart failure. Chronic inflammation is a major cardiovascular risk factor. Proinflammatory signaling molecules in HF initiate vicious cycles altering mitochondrial function and perturbing calcium homeostasis, therefore affecting myocardial contractility. Specific anti-inflammatory treatment represents a novel approach to prevent and slow HF progression. This review provides an update on the putative roles of inflammatory mediators involved in heart failure (tumor necrosis factor-alpha; interleukin 1, 6, 17, 18, 33) and currently available biological and non-biological therapy options targeting the aforementioned mediators and signaling pathways. We also highlight new treatment approaches based on the latest clinical and experimental research.

PCSK9 Imperceptibly Affects Chemokine Receptor Expression In Vitro and In Vivo

Proprotein convertase subtilin/kexin type 9 (PCSK9) is a protease secreted mainly by hepatocytes and in lesser quantities by intestines, pancreas, and vascular cells. Over the years, this protease has gained importance in the field of cardiovascular biology due to its regulatory action on the low-density lipoprotein receptor (LDLR). However, recently, it has also been shown that PCSK9 acts independent of LDLR to cause vascular inflammation and increase the severity of several cardiovascular disorders. We hypothesized that PCSK9 affects the expression of chemokine receptors, major mediators of inflammation, to influence cardiovascular health. However, using overexpression of PCSK9 in murine models in vivo and PCSK9 stimulation of myeloid and vascular cells in vitro did not reveal influences of PCSK9 on the expression of certain chemokine receptors that are known to be involved in the development and progression of atherosclerosis and vascular inflammation. Hence, we conclude that the inflammatory effects of PCSK9 are not associated with the here investigated chemokine receptors and additional research is required to elucidate which mechanisms mediate PCSK9 effects independent of LDLR.

Anti-Inflammatory Function of Fatty Acids and Involvement of Their Metabolites in the Resolution of Inflammation in Chronic Obstructive Pulmonary Disease

Lipid metabolism plays an important role in many lung functions. Disorders of lipid metabolism are part of the pathogenesis of chronic obstructive pulmonary disease (COPD). Lipids are involved in numerous cross-linkages with inflammation. Recent studies strongly support the involvement of fatty acids as participants in inflammation. They are involved in the initiation and resolution of inflammation, including acting as a substrate for the formation of lipid mediators of inflammation resolution. Specialized pro-inflammatory mediators (SPMs) belonging to the classes of lipoxins, resolvins, maresins, and protectins, which are formed enzymatically from unsaturated fatty acids, are now described. Disorders of their production and function are part of the pathogenesis of COPD. SPMs are currently the subject of active research in order to find new drugs. Short-chain fatty acids are another important participant in metabolic and immune processes, and their role in the pathogenesis of COPD is of great clinical interest.