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Early-stage detection of chronic kidney diseases (CKD) is important to treatment that may slow and occasionally halt CKD progression. CKD of diverse etiologies share similar histologic patterns of glomerulosclerosis, tubular atrophy, and interstitial fibrosis. Macro-vascular disease and micro-vascular disease promote tissue ischemia, contributing to injury. Tissue ischemia promotes hypoxia, and this in turn activates the hypoxia-inducible transcription factors (HIFs). HIF-1α and HIF-2α, share a dimer partner, HIF-1β, with the aryl hydrocarbon receptor (AHR) and are each activated in CKD and associated with kidney cellular nicotinamide adenine dinucleotide (NAD) depletion. The Preiss-Handler, salvage, and de novo pathways regulate NAD biosynthesis and gap-junctions regulate NAD cellular retention. In the Preiss-Handler pathway, niacin forms NAD. Niacin also exhibits crosstalk with HIF and AHR cell signals in the regulation of insulin sensitivity, which is a complication in CKD. Dysregulated enzyme activity in the NAD de novo pathway increases the levels of circulating tryptophan metabolites that activate AHR, resulting in poly-ADP ribose polymerase activation, thrombosis, endothelial dysfunction, and immunosuppression. Therapeutically, metabolites from the NAD salvage pathway increase NAD production and subsequent sirtuin deacetylase activity, resulting in reduced activation of retinoic acid-inducible gene I, p53, NF-κB and SMAD2 but increased activation of FOXO1, PGC-1α, and DNA methyltransferase-1. These post-translational responses may also be initiated through non-coding RNAs (ncRNAs), which are additionally altered in CKD. Nanoparticles traverse biological systems and can penetrate almost all tissues as disease biomarkers and drug delivery carriers. Targeted delivery of non-coding RNAs or NAD metabolites with nanoparticles may enable the development of more effective diagnostics and therapies to treat CKD.

The aryl hydrocarbon receptor (AHR) is a basic helix-loop-helix transcription factor that binds diverse endogenous and xenobiotic ligands, which regulate AHR stability, transcriptional activity, and cell signaling. AHR activity is strongly implicated throughout the course of chronic kidney disease (CKD). Many diverse organic molecules bind and activate AHR and these ligands are reported to either promote glomerular and tubular damage or protect against kidney injury. AHR crosstalk with estrogen, peroxisome proliferator-activated receptor-γ, and NF-κB pathways may contribute to the diversity of AHR responses during the various forms and stages of CKD. The roles of AHR in kidney fibrosis, metabolism and the renin angiotensin system are described to offer insight into CKD pathogenesis and therapies.

: Background Programmed cell death protein (PD)-1 receptors and ligands on immune cells and kidney parenchymal cells help maintain immunological homeostasis in the kidney. Dysregulated PD-1:PD-L1 binding interactions occur during the pathogenesis of glomerulopathies and renal cell carcinoma (RCC). The regulation of these molecules in the kidney is important to PD-1/PD-L1 immunotherapies that treat RCC and may induce glomerulopathies as an adverse event. Methods The expression and function of PD-1 molecules on immune and kidney parenchymal cells were reviewed in the healthy kidney, PD-1 immunotherapy-induced nephrotoxicity, glomerulopathies and RCC. Results PD-1 and/or its ligands are expressed on kidney macrophages, dendritic cells, lymphocytes, and renal proximal tubule epithelial cells. Vitamin D3, glutathione and AMP-activated protein kinase (AMPK) regulate hypoxic cell signals involved in the expression and function of PD-1 molecules. These pathways are altered in kidney disease and are linked to the production of vascular endothelial growth factor, erythropoietin, adiponectin, interleukin (IL)-18, IL-23, and chemokines that bind CXCR3, CXCR4, and/or CXCR7. These factors are differentially produced in glomerulonephritis and RCC and may be important biomarkers in patients that receive PD-1 therapies and/or develop glomerulonephritis as an adverse event Conclusion By comparing the functions of the PD-1 axis in glomerulopathies and RCC, we identified similar chemokines involved in the recruitment of immune cells and distinct mediators in T cell differentiation. The expression and function of PD-1 and PD-1 ligands in diseased tissue and particularly on double-negative T cells and parenchymal kidney cells needs continued exploration. The possible regulation of the PD-1 axis by vitamin D3, glutathione and/or AMPK cell signals may be important to kidney disease and the PD-1 immunotherapeutic response.

The multi-ligand receptor for advanced glycation end-products (RAGE) and its ligands are contributing factors in autoimmunity, cancers, and infectious disease. RAGE activation is increased in chronic kidney disease (CKD) and coronavirus disease 2019 (COVID-19). CKD may increase the risk of COVID-19 severity and may also develop in the form of long COVID. RAGE is expressed in essentially all kidney cell types. Increased production of RAGE isoforms and RAGE ligands during CKD and COVID-19 promotes RAGE activity. The downstream effects include cellular dysfunction, tissue injury, fibrosis, and inflammation, which in turn contribute to a decline in kidney function, hypertension, thrombotic disorders, and cognitive impairment. In this review, we discuss the forms and mechanisms of RAGE and RAGE ligands in the kidney and COVID-19. Because various small molecules antagonize RAGE activity in animal models, targeting RAGE, its co-receptors, or its ligands may offer novel therapeutic approaches to slowing or halting progressive kidney disease, for which current therapies are often inadequate.

Disruption of nicotinamide adenine dinucleotide (NAD) biosynthesis and function during infection may impair host defenses and aggravate inflammatory and oxidative organ injury. Increasingly, studies are investigating whether niacin or NAD metabolite treatment is beneficial in infection and sepsis animal models. We examined whether this preclinical experience supports clinical trials. A systematic review of three data bases was conducted through 2/29/2024 and a meta-analysis was performed comparing niacin or NAD metabolite treatment to control in adult animal models employing microbial challenges. Fifty-six studies met inclusion criteria, with 24 published after 2019. Most studies employed mouse (n = 40 studies) or rat (n = 12) models and administered either a bacterial toxin (n = 28) or bacterial (n = 19) challenge. Four and three studies employed viral or fungal challenges respectively. Studies investigated an NAD metabolite alone (n = 44), niacin alone (n = 9), or both (n = 3), usually administered before or within 24h after challenge (n = 50). Only three and four studies included standard antimicrobial support or started treatment > 24h after challenge respectively. In similar patterns with differing animal types (p ≥ 0.06), compared to control across those studies investigating the parameter, niacin or NAD treatment decreased the odds ratio of mortality [95% confidence interval (CI)] [0.28 (0.17, 0.49)] and in blood or tissue increased antioxidant levels [standardized mean differences (95%CI)] (SMD) [3.61 (2.20,5.02)] and decreased levels of microbes [− 2.44 (− 3.34, − 1.55)], histologic and permeability organ injury scoring [− 1.62 (− 2.27, − 0.98) and − 1.31(− 1.77, − 0.86) respectively], levels of TNFα, IL-6 and IL-1β [− 2.47 (− 3.30, − 1.64), − 3.17 (− 4.74, − 1.60) and − 8.44 (− 12.4, − 4.5) respectively] and myeloperoxidase (MPO) [− 1.60 (− 2.06, − 1.14)], although with significant, primarily quantitative heterogeneity for each (I 2  ≥ 53%, p < 0.01) except MPO. Treatment increased blood or tissue NAD + levels and decreased chemical organ injury measures and oxidation markers but differently comparing species (p ≤ 0.05). Only 2 and 9 survival studies described power analyses or animal randomization respectively and no study described treatment or non-histologic outcome measure blinding. Among survival studies, Egger’s analysis (p = 0.002) suggested publication bias. While suggestive, published animal studies do not yet support clinical trials testing niacin and NAD metabolite treatment for infection and sepsis. Animal studies simulating clinical conditions and with randomized, blinded designs are needed to investigate this potentially promising therapeutic approach.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection causes coronavirus disease 2019 (COVID-19). SARS-CoV-2 binds the angiotensin-converting enzyme 2 (ACE2) on the cell surface and this complex is internalized. ACE2 serves as an endogenous inhibitor of inflammatory signals associated with four major regulator systems: the renin-angiotensin-aldosterone system (RAAS), the complement system, the coagulation cascade, and the kallikrein-kinin system (KKS). Understanding the pathophysiological effects of SARS-CoV-2 on these pathways is needed, particularly given the current lack of proven, effective treatments. The vasoconstrictive, prothrombotic and pro-inflammatory conditions induced by SARS-CoV-2 can be ascribed, at least in part, to the activation of these intersecting physiological networks. Moreover, patients with immune deficiencies, hypertension, diabetes, coronary heart disease, and kidney disease often have altered activation of these pathways, either due to underlying disease or to medications, and may be more susceptible to SARS-CoV-2 infection. Certain characteristic COVID-associated skin, sensory, and central nervous system manifestations may also be linked to viral activation of the RAAS, complement, coagulation, and KKS pathways. Pharmacological interventions that target molecules along these pathways may be useful in mitigating symptoms and preventing organ or tissue damage. While effective anti-viral therapies are critically needed, further study of these pathways may identify effective adjunctive treatments and patients most likely to benefit.

Abstract Pseudomonas aeruginosa is a complex gram-negative facultative anaerobe replete with a variety of arsenals to activate, modify, and destroy host defense mechanisms. The microbe is a common cause of nosocomial infections and an antibiotic-resistant priority pathogen. In the lung, P. aeruginosa disrupts upper and lower airway homeostasis by damaging the epithelium and evading innate and adaptive immune responses. The biology of these interactions is essential to understand P. aeruginosa pathogenesis. P. aeruginosa interacts directly with host cells via flagella, pili, lipoproteins, lipopolysaccharides, and the type III secretion system localized in the outer membrane. P. aeruginosa quorum-sensing molecules regulate the release of soluble factors that enhance the spread of infection. These characteristics of P. aeruginosa differentially affect lung epithelial, innate, and adaptive immune cells involved in the production of mediators and the recruitment of additional immune cell subsets. Pathogen interactions with individual host cells and in the context of host acute lung infection are discussed to reveal pathways that may be targeted therapeutically.

Because prior immune checkpoint inhibitor (ICI) therapy in cancer patients presenting with COVID-19 may affect outcomes, we investigated the beta-coronavirus, murine hepatitis virus (MHV)-1, in a lethal pneumonia model in the absence (Study 1) or presence of prior programmed cell death ligand-1 (PD-L1) antibody (PD-L1mAb) treatment (Study 2). In Study 1, animals were inoculated intratracheally with MHV-1 or vehicle and evaluated at day 2, 5, and 10 after infection. In Study 2, uninfected or MHV-1-infected animals were pretreated intraperitoneally with control or PD-L1-blocking antibodies (PD-L1mAb) and evaluated at day 2 and 5 after infection. Each study examined survival, physiologic and histologic parameters, viral titers, lung immunophenotypes, and mediator production. Study 1 results recapitulated the pathogenesis of COVID-19 and revealed increased cell surface expression of checkpoint molecules (PD-L1, PD-1), higher expression of the immune activation marker angiotensin converting enzyme (ACE), but reduced detection of the MHV-1 receptor CD66a on immune cells in the lung, liver, and spleen. In addition to reduced detection of PD-L1 on all immune cells assayed, PD-L1 blockade was associated with increased cell surface expression of PD-1 and ACE, decreased cell surface detection of CD66a, and improved oxygen saturation despite reduced blood glucose levels and increased signs of tissue hypoxia. In the lung, PD-L1mAb promoted S100A9 but inhibited ACE2 production concomitantly with pAKT activation and reduced FOXO1 levels. PD-L1mAb promoted interferon-γ but inhibited IL-5 and granulocyte-macrophage colony-stimulating factor (GM-CSF) production, contributing to reduced bronchoalveolar lavage levels of eosinophils and neutrophils. In the liver, PD-L1mAb increased viral clearance in association with increased macrophage and lymphocyte recruitment and liver injury. PD-L1mAb increased the production of virally induced mediators of injury, angiogenesis, and neuronal activity that may play role in COVID-19 and ICI-related neurotoxicity. PD-L1mAb did not affect survival in this murine model. In Study 1 and Study 2, ACE was upregulated and CD66a and ACE2 were downregulated by either MHV-1 or PD-L1mAb. CD66a is not only the MHV-1 receptor but also an identified immune checkpoint and a negative regulator of ACE. Crosstalk between CD66a and PD-L1 or ACE/ACE2 may provide insight into ICI therapies. These networks may also play role in the increased production of S100A9 and neurological mediators in response to MHV-1 and/or PD-L1mAb, which warrant further study. Overall, these findings support observational data suggesting that prior ICI treatment does not alter survival in patients presenting with COVID-19.

Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults. The development of this malignant glial lesion involves a multi-faceted process that results in a loss of genetic or epigenetic gene control, un-regulated cell growth, and immune tolerance. Of interest, atopic diseases are characterized by a lack of immune tolerance and are inversely associated with glioma risk. One cell type that is an established effector cell in the pathobiology of atopic disease is the eosinophil. In response to various stimuli, the eosinophil is able to produce cytotoxic granules, neuromediators, and pro-inflammatory cytokines as well as pro-fibrotic and angiogenic factors involved in pathogen clearance and tissue remodeling and repair. These various biological properties reveal that the eosinophil is a key immunoregulatory cell capable of influencing the activity of both innate and adaptive immune responses. Of central importance to this report is the observation that eosinophil migration to the brain occurs in response to traumatic brain injury and following certain immunotherapeutic treatments for GBM. Although eosinophils have been identified in various central nervous system pathologies, and are known to operate in wound/repair and tumorstatic models, the potential roles of eosinophils in GBM development and the tumor immunological response are only beginning to be recognized and are therefore the subject of the present review.