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Graphical abstract, The coronavirus disease-2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), appears with a wide spectrum of mild-to-critical clinical complications. Many clinical and experimental findings suggest the role of inflammatory mechanisms in the immunopathology of COVID-19. Hence, cellular and molecular mediators of the immune system can be potential targets for predicting, monitoring, and treating the progressive complications of COVID-19. In this review, we assess the latest cellular and molecular data on the immunopathology of COVID-19 according to the pathological evidence (e.g., mucus and surfactants), dysregulations of pro- and anti-inflammatory mediators (e.g., cytokines and chemokines), and impairments of innate and acquired immune system functions (e.g., mononuclear cells, neutrophils and antibodies). Furthermore, we determine the significance of immune biomarkers for predicting, monitoring, and treating the progressive complications of COVID-19. We also discuss the clinical importance of recent immune biomarkers in COVID-19, and at the end of each section, recent clinical trials in immune biomarkers for COVID-19 are mentioned.

The COVID-19-, SARS- and MERS-related coronaviruses share many genomic and structural similarities. However, the SARS-CoV-2 is less pathogenic than SARS-CoV and MERS-CoV. Despite some differences in the cytokine patterns, it seems that the cytokine storm plays a crucial role in the pathogenesis of COVID-19-, SARS- and MERS. Monocytes and macrophages may be infected by SARS-CoV-2 through ACE2-dependent and ACE2-independent pathways. SARS-CoV-2 can effectively suppress the anti-viral IFN response in monocytes and macrophages. Since macrophages and dendritic cells (DCs) act as antigen presenting cells (APCs), the infection of these cells by SARS-CoV-2 impairs the adaptive immune responses against the virus. Upon infection, monocytes migrate to the tissues where they become infected resident macrophages, allowing viruses to spread through all organs and tissues. The SARS-CoV-2-infected monocytes and macrophages can produce large amounts of numerous types of pro-inflammatory cytokines and chemokines, which contribute to local tissue inflammation and a dangerous systemic inflammatory response called cytokine storm. Both local tissue inflammation and the cytokine storm play a fundamental role in the development of COVID-19-related complications, such as acute respiratory distress syndrome (ARDS), which is a main cause of death in COVID-19 patients. Here, we describe the monocytes and macrophage responses during severe coronavirus infections, while highlighting potential therapeutic interventions to attenuate macrophage-related inflammatory reactions in possible approaches for COVID-19 treatment., Graphical abstract Unlabelled Image, Highlights • A subset of monocytes and macrophages may be infected by SARS-CoV-2. • Coronavirus-infected monocyte can migrate to tissue and become infected macrophage. • Coronavirus-infected monocyte/macrophage produces high level of inflammatory factors. • Monocyte/macrophage-related cytokines promote organ inflammation and cytokine storm. • Local tissue inflammation and cytokine storm cause multi-organ failure in COVID-19.

Morphine is frequently used for pain relief, but long-term morphine therapy in patients with chronic pain results in analgesic tolerance and hyperalgesia. There are no effective therapeutic treatments that limit these detrimental side effects. We found pretreatment with melatonin could decrease morphine-induced analgesic tolerance. There was a significant activation of the NLRP3 inflammasome in the prefrontal cortex and the peripheral blood of morphine-treated mice compared to control animals, which could be blocked by melatonin. The inflammasome activation induced by morphine was mediated by the microglia. SiRNA knockdown or pharmacological inhibition of the NLRP3 abolished the morphine-induced inflammasome activation. Co-administration of melatonin and low-dose morphine had better analgesia effects in the murine models of pain and led to a lower NLRP3 inflammasome activity in brain tissues. Mice deficient for Nlrp3 had a higher nociceptive threshold and were less sensitive to develop morphine-induced analgesic tolerance and acetic acid-induced pain relative to wild-type animals. Concordantly, we observed a significantly elevated level of serum IL-1β, which indicates an increase of NLRP3 inflammasome activity associated with the reduced level of serum melatonin, in heroin-addicted patients relative to healthy individuals. Our results provide a solid basis for conducting a clinical trial with the co-administration of melatonin and morphine for the relief of severe pain., Highlights • Melatonin blocks murine morphine analgesic tolerance via NLRP3 inflammasome. • Melatonin eliminates excessive ROS and CTSB induced by morphine. • Deficiency of Nlrp3 salvages morphine analgesic tolerance. • Melatonin combined with a low dose of morphine can be used for relieving pain.

Background & Aims: Microbial molecular products incite intestinal inflammation by activating Toll-like receptors (TLRs) and inflammasomes of the innate immune system. This systemâs contribution to esophageal inflammation is not known. Gram-negative bacteria, which dominate the esophageal microbiome in reflux esophagitis, produce lipopolysaccharide (LPS), a TLR4 ligand. TLR4 signaling produces pro-interleukin (IL)1β, pro-IL18, and NOD-like receptor protein 3 (NLRP3), which prime the NLRP3 inflammasome. Subsequent NLRP3 inflammasome activation cleaves caspase-1, inducing secretion of proinflammatory cytokines and pyroptosis (inflammatory cell death). We explored LPS effects on NLRP3 inflammasome priming and activation in esophageal cells. Methods: We exposed esophageal squamous and Barrettâs epithelial cells to LPS and measured the following: (1) TLR4, pro-IL1β, pro-IL18, and NLRP3 expression; (2) caspase-1 activity; (3) tumor necrosis factor-α, IL8, IL1β, and IL18 secretion; (4) lactate dehydrogenase (LDH) release (a pyroptosis marker); and (5) mitochondrial reactive oxygen species (ROS). As inhibitors, we used acetyl-Tyr-Val-Ala-Asp-CHO for caspase-1, small interfering RNA for NLRP3, and (2-(2,2,6,6,-Tetramethylpiperidin-1-oxyl-4-ylamino)-2-oxoethyl)triphenylphosphonium chloride for mitochondrial ROS. Results: Squamous and Barrettâs cells expressed similar levels of TLR4, but LPS induced TLR4 signaling that increased tumor necrosis factor-α and IL8 secretion only in Barrettâs cells. Barrettâs cells treated with LPS showed increased expression of pro-IL18, pro-IL1β, and NLRP3, and increased mitochondrial ROS levels, caspase-1 activity, IL1β and IL18 secretion, and LDH release. Acetyl-Tyr-Val-Ala-Asp-CHO, NLRP3 small interfering RNA, and Mito-TEMPO all blocked LPS-induced IL1β and IL18 secretion and LDH release. Conclusions: In Barrettâs cells, LPS both primes and activates the NLRP3 inflammasome, causing secretion of proinflammatory cytokines and pyroptosis. By triggering molecular events promoting inflammation, the esophageal microbiome might contribute to inflammation-mediated carcinogenesis in Barrettâs esophagus. Keywords: IL1β, Pyroptosis, Esophageal Squamous Cell, GERD, Cytokine