The discovery of Toll-like receptors (TLRs) as components that recognize conserved structures in pathogens has greatly advanced understanding of how the body senses pathogen invasion, triggers innate immune responses and primes antigen-specific adaptive immunity. Although TLRs are critical for host defense, it has become apparent that loss of negative regulation of TLR signaling, as well as recognition of self molecules by TLRs, are strongly associated with the pathogenesis of inflammatory and autoimmune diseases. Furthermore, it is now clear that the interaction between TLRs and recently identified cytosolic innate immune sensors is crucial for mounting effective immune responses. Here we describe the recent advances that have been made by research into the role of TLR biology in host defense and disease.

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The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors

Inflammation underlies a wide variety of physiological and pathological processes. Although the pathological aspects of many types of inflammation are well appreciated, their physiological functions are mostly unknown. The classic instigators of inflammation - infection and tissue injury - are at one end of a large range of adverse conditions that induce inflammation, and they trigger the recruitment of leukocytes and plasma proteins to the affected tissue site. Tissue stress or malfunction similarly induces an adaptive response, which is referred to here as para-inflammation. This response relies mainly on tissue-resident macrophages and is intermediate between the basal homeostatic state and a classic inflammatory response. Para-inflammation is probably responsible for the chronic inflammatory conditions that are associated with modern human diseases.

Origin and Physiological Roles of Inflammation

Conventional cancer treatments rely on radiotherapy and chemotherapy. Such treatments supposedly mediate their effects via the direct elimination of tumor cells. Here we show that the success of some protocols for anticancer therapy depends on innate and adaptive antitumor immune responses. We describe in both mice and humans a previously unrecognized pathway for the activation of tumor antigen-specific T-cell immunity that involves secretion of the high-mobility-group box 1 (HMGB1) alarmin protein by dying tumor cells and the action of HMGB1 on Toll-like receptor 4 (TLR4) expressed by dendritic cells (DCs). During chemotherapy or radiotherapy, DCs require signaling through TLR4 and its adaptor MyD88 for efficient processing and cross-presentation of antigen from dying tumor cells. Patients with breast cancer who carry a TLR4 loss-of-function allele relapse more quickly after radiotherapy and chemotherapy than those carrying the normal TLR4 allele. These results delineate a clinically relevant immunoadjuvant pathway triggered by tumor cell death.

Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy.

Over the past several decades, much has been revealed about the nature of the host innate immune response to microorganisms, with the identification of pattern recognition receptors (PRRs) and pathogen-associated molecular patterns, which are the conserved microbial motifs sensed by these receptors. It is now apparent that these same PRRs can also be activated by non-microbial signals, many of which are considered as damage-associated molecular patterns. The sterile inflammation that ensues either resolves the initial insult or leads to disease. Here, we review the triggers and receptor pathways that result in sterile inflammation and its impact on human health.

Sterile inflammation: sensing and reacting to damage

Twenty years after the proposal that pattern recognition receptors detect invasion by microbial pathogens, the field of immunology has witnessed several discoveries that have elucidated receptors and signaling pathways of microbial recognition systems and how they control the generation of T and B lymphocyte-mediated immune responses. However, there are still many fundamental questions that remain poorly understood, even though sometimes the answers are assumed to be known. Here, we discuss some of these questions, including the mechanisms by which pathogen-specific innate immune recognition activates antigen-specific adaptive immune responses and the roles of different types of innate immune recognition in host defense from infection and injury.

/pdf/regulation-of-adaptive-immunity-by-the-innate-immune-system-2qyh2ea0oz.pdf

Regulation of Adaptive Immunity by the Innate Immune System

Mechanisms that regulate inflammation and repair after acute lung injury are incompletely understood. The extracellular matrix glycosaminoglycan hyaluronan is produced after tissue injury and impaired clearance results in unremitting inflammation. Here we report that hyaluronan degradation products require MyD88 and both Toll-like receptor (TLR)4 and TLR2 in vitro and in vivo to initiate inflammatory responses in acute lung injury. Hyaluronan fragments isolated from serum of individuals with acute lung injury stimulated macrophage chemokine production in a TLR4- and TLR2-dependent manner. Myd88(-/-) and Tlr4(-/-)Tlr2(-/-) mice showed impaired transepithelial migration of inflammatory cells but decreased survival and enhanced epithelial cell apoptosis after lung injury. Lung epithelial cell-specific overexpression of high-molecular-mass hyaluronan was protective against acute lung injury. Furthermore, epithelial cell-surface hyaluronan was protective against apoptosis, in part, through TLR-dependent basal activation of NF-kappaB. Hyaluronan-TLR2 and hyaluronan-TLR4 interactions provide signals that initiate inflammatory responses, maintain epithelial cell integrity and promote recovery from acute lung injury.

Regulation of lung injury and repair by Toll-like receptors and hyaluronan.

The mammalian chitinase family includes members both with and without enzymatic activity against chitin, a product of fungal cell walls, exoskeletons of crustaceans and insects, and the microfilarial sheaths of parasitic nematodes. Two members of that family, Ym1 and acidic mammalian chitinase (AMCase), are strongly upregulated in pulmonary T helper (Th) 2 inflammation but not in Th1 inflammation. The sites of expression of these products are incompletely known. We show here that, in two different models of Th2 inflammation, Ym1 and AMCase are mutually exclusively expressed in proximal vs. distal airway epithelium, respectively, whereas both are expressed in alveolar macrophages. This regional difference along the airway corresponds to the previously noted distinction between mucus positive proximal cells and mucus negative distal cells under the same conditions. Among distal cells, AMCase colocalizes with epithelial cells expressing the Clara cell marker Clara cell secretory protein. These AMCase-expressing cells retain expression of FOXA2, a transcription factor whose downregulation in association with IL-13 signaling has previously been associated with production of mucus in proximal airway epithelial cells. These results provide evidence that secretory cells of proximal and distal airways undergo fundamentally different gene expression programs in response to allergic inflammation. Furthermore, AMCase provides the first positive molecular marker of distal Clara cell secretory protein-expressing cells under these conditions.

https://www.physiology.org/doi/pdf/10.1152/ajplung.00364.2005

Differential expression of chitinases identify subsets of murine airway epithelial cells in allergic inflammation


 Microsatellite instability (MSI) and mismatch repair immunohistochemistry are biomarkers of defective MMR (dMMR) that predict response to immune checkpoint inhibitor therapy in solid tumors. The microsatellites in the Promega MSI Analysis System Version 1.2 may not be ideal to detect MSI in certain cancer types. Long mononucleotide repeat (LMR) markers may improve detection of microsatellite instability in early colorectal lesions and non-colorectal cancers.In this study, we compared the performance of the current gold standard, MSI Analysis System Version 1.2 (Promega), which consists of 5 mononucleotide repeat markers (21-27 bases), with a new LMR kit (Promega), which consists of 4 markers from the MSI V1.2 panel and 4 LMR loci (52-60 bases). We studied five cohorts including 24 MMR proficient (pMMR) and 24 dMMR colorectal cancer (CRC) samples, 24 pMMR and 42 dMMR endometrial cancer (EC) samples, 12 dMMR prostate cancer (PC) samples, 22 MSI-high (MSI-H) samples of other cancer types, and 12 MSI-low (MSI-L) samples, where MMR status was confirmed by immunohistochemical (IHC) staining and/or MSI Analysis System Version 1.2.The specificity and sensitivity of the LMR MSI panel for dMMR detection were both 100% in CRC. The specificity of the MSI V1.2 and LMR MSI panels in EC was both 100%, and the sensitivity was 88% versus 98%, respectively. The 22 MSI-high (MSI-H) samples of other cancer types, these include cholangiocarcinoma, appendix, duodenal, pancreatic and gastric cancer, which were previously classified as MSI-H by using the MSI V1.2 panel were also classified as MSI-H by using the LMR MSI panel. Among 12 samples that were previously classified as MSI-L by the MSI V1.2 panel, 9 of the samples were classified as MSI-L, and 3 of the samples were diagnosed as MSI-H using the MSI LMR panel. The LMR panel has performed well on 80 samples over the past 6 months.The LMR MSI panel is highly concordant with the MSI V1.2 panel for dMMR detection in colorectal cancer and showed increased sensitivity in endometrial cancer. The LMR MSI panel showed improved dMMR detection in non-colorectal cancers.
 Citation Format: Suping Chen, John H. Lin, Aparna Pallavajjala, Tamara L. Lotan, Jeffery W. Bacher, James R. Eshleman. Evaluation of long mononucleotide repeat markers for detection of microsatellite instability. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3954.

Abstract 3954: Evaluation of long mononucleotide repeat markers for detection of microsatellite instability

Effect of Rosiglitazone, the Peroxisome Proliferator-Activated Receptor (PPAR)-γ Agonist, on Apoptosis, Inflammatory Cytokines and Oxidative Stress in pentylenetetrazole-Induced Seizures in Kindled Mice

Background: Contrast-enhanced chest computed tomography (CT) is useful for the detection and follow-up of patients with lung cancer. However, reaching balance between diagnostic image quality, radiation dose, and iodixanol dose is a cause of concern. Objectives: To investigate the clinical value of adaptive statistical iterative reconstruction (ASIR) in reducing the iodixanol content and radiation dose during contrast-enhanced chest CT scan for patients diagnosed with lung masses/nodules based on the analysis of image quality. Patients and Methods: This prospective study was conducted on 80 patients diagnosed with nodules or masses, who required contrast-enhanced chest CT scans. The experimental group (n = 40) was subjected to iohexol at a high concentration (350 mgI/L) with a tube voltage of 120 kVp and a filter back projection (FBP) reconstruction algorithm. The comparison group (n = 40) was subject to iodixanol at a lower concentration (270 mgI/L) with a tube voltage of 100 kVp and ASIR (blending ratio, 40%). The radiation dose and total iodixanol content, as well as subjective and objective evaluations of image quality, were analyzed and compared. Results: The two groups obtained non-significantly different subjective scores for five structures detected in the lung window and five structures detected in the mediastinal window, as well as the overall image (P > 0.05 for all). Both the two-group images obtained diagnosis-acceptable scores (≥ 3 points) on displays of 10 structures and overall image quality. The mean CT value of vessels (100 kVp vs. 120 kVp: 314.90 ± 23.42 vs. 308.93 ± 21.40; P > 0.05), standard deviation (13.03 ± 0.88 vs. 12.83 ± 0.90; P > 0.05), and contrast-to-noise ratio (20.77 ± 2.20 vs. 20.36 ± 1.94; P > 0.05) were not significantly different between two groups. However, the CT dose index, dose-length product, effective dose, and total iodine dose were reduced by 27.58%, 36.65%, 36.59%, and 22.86% in the 100-kVp group compared to the 120-kVp group. Conclusion: The ASIR showed great potential in reducing the radiation dose and iodine contrast dose, while maintaining good image quality and providing strong confidence for the diagnosis of lung cancer.

Contrast-Enhanced Chest Computed Tomography (CT) Scan with Low Radiation and Total Iodine Dose for Lung Cancer Detection Using Adaptive Statistical Iterative Reconstruction

Suping Chen

Papers

Regulation of lung injury and repair by Toll-like receptors and hyaluronan.

Differential expression of chitinases identify subsets of murine airway epithelial cells in allergic inflammation

Abstract 3954: Evaluation of long mononucleotide repeat markers for detection of microsatellite instability

Effect of Rosiglitazone, the Peroxisome Proliferator-Activated Receptor (PPAR)-γ Agonist, on Apoptosis, Inflammatory Cytokines and Oxidative Stress in pentylenetetrazole-Induced Seizures in Kindled Mice

Contrast-Enhanced Chest Computed Tomography (CT) Scan with Low Radiation and Total Iodine Dose for Lung Cancer Detection Using Adaptive Statistical Iterative Reconstruction