The Coronavirus Disease 2019 (COVID-19) pandemic has become a global crisis and is more devastating than any other previous infectious disease. It has affected a significant proportion of the global population both physically and mentally, and destroyed businesses and societies. Current evidence suggested that immunopathology may be responsible for COVID-19 pathogenesis, including lymphopenia, neutrophilia, dysregulation of monocytes and macrophages, reduced or delayed type I interferon (IFN-I) response, antibody-dependent enhancement, and especially, cytokine storm (CS). The CS is characterized by hyperproduction of an array of pro-inflammatory cytokines and is closely associated with poor prognosis. These excessively secreted pro-inflammatory cytokines initiate different inflammatory signaling pathways via their receptors on immune and tissue cells, resulting in complicated medical symptoms including fever, capillary leak syndrome, disseminated intravascular coagulation, acute respiratory distress syndrome, and multiorgan failure, ultimately leading to death in the most severe cases. Therefore, it is clinically important to understand the initiation and signaling pathways of CS to develop more effective treatment strategies for COVID-19. Herein, we discuss the latest developments in the immunopathological characteristics of COVID-19 and focus on CS including the current research status of the different cytokines involved. We also discuss the induction, function, downstream signaling, and existing and potential interventions for targeting these cytokines or related signal pathways. We believe that a comprehensive understanding of CS in COVID-19 will help to develop better strategies to effectively control immunopathology in this disease and other infectious and inflammatory diseases.

Over 100 types of cellular RNA modifications have been identified in both coding and a variety of non-coding RNAs. N6-methyladenosine (m6A) is the most prevalent and abundant post-transcriptional RNA modification on eukaryote mRNA, and its biological functions are mediated by special binding proteins (i.e., methyltransferases, demethylases, and effectors) that recognize this modification. The presence of m6A on transcripts contributes to diverse fundamental cellular functions, such as pre-mRNA splicing, nuclear transport, stability, translation, and microRNA biogenesis, implying an association with numerous human diseases. This review principally summarizes recent progress in the study of m6A methylation mechanisms and relevant roles they play in immunoregulation.

TSLP AhR IAId Tryptophan Epidermis Dermis AhRE TSLP IL-4,IL-5,IL-13,IL-22AD Background: Previous studies have revealed significant alterations in the skin microbiota of patients with atopic dermatitis (AD) not only in diversity and composition but also in function, and the tryptophan (Trp) metabolic pathway is attenuated in the skin microbiota of patients with AD. Objective: We sought to assess Trp metabolites on the skin surfaces of patients with AD and to explore the function of the microbial Trp metabolites in skin inflammation in patients with AD.Methods: A gel-patch method was developed to collect metabolites on the skin surface, which were then assessed by using liquid chromatography-tandem mass spectrometry. A mouse model of calcipotriol (MC903)-induced AD-like dermatitis was used to evaluate the effects of microbial metabolites on AD, and aryl hydrocarbon receptor (AhR)-null mice and keratinocyte cultures were used to investigate the mechanism.We thank Professor Shau-Ku Huang for helpful suggestions and reviewing the manuscript. Key messagesd Levels of microbial metabolites of Trp metabolism on skin surfaces of patients with AD were lower than those of healthy subjects.d IAId significantly attenuated skin inflammation in a mouse model of MC903-induced AD-like dermatitis.d IAId inhibited TSLP expression in keratinocytes in an AhR-dependent manner.

Background Mannose receptor (MRC1/CD206) has been suggested to mediate allergic sensitization and asthma to multiple glycoallergens, including cockroach allergens. Objective We sought to determine the existence of a protective mechanism through which MRC1 limits allergic inflammation through its intronic miR-511-3p. Methods We examined MRC1-mediated cockroach allergen uptake by lung macrophages and lung inflammation using C57BL/6 wild-type (WT) and Mrc1−/− mice. The role of miR-511-3p in macrophage polarization and cockroach allergen–induced lung inflammation in mice transfected with adeno-associated virus (AAV)–miR-511-3p (AAV– cytomegalovirus–miR-511-3p–enhanced green fluorescent protein) was analyzed. Gene profiling of macrophages with or without miR-511-3p overexpression was also performed. Results Mrc1−/− lung macrophages showed a significant reduction in cockroach allergen uptake compared with WT mice, and Mrc1−/− mice had an exacerbated lung inflammation with increased levels of cockroach allergen–specific IgE and TH2/TH17 cytokines in a cockroach allergen–induced mouse model compared with WT mice. Macrophages from Mrc1−/− mice showed significantly reduced levels of miR-511-3 and an M1 phenotype, whereas overexpression of miR-511-3p rendered macrophages to exhibit a M2 phenotype. Furthermore, mice transfected with AAV–miR-511-3p showed a significant reduction in cockroach allergen–induced inflammation. Profiling of macrophages with or without miR-511-3p overexpression identified 729 differentially expressed genes, wherein expression of prostaglandin D2 synthase (Ptgds) and its product PGD2 were significantly downregulated by miR-511-3p. Ptgds showed a robust binding to miR-511-3p, which might contribute to the protective effect of miR-511-3p. Plasma levels of miR-511-3p were significantly lower in human asthmatic patients compared with nonasthmatic subjects. Conclusion These studies support a critical but previously unrecognized role of MRC1 and miR-511-3p in protection against allergen-induced lung inflammation.

Key Points AhR ligands result in calcium- and ROS-dependent enhancement of mast cell activation. AhR is critical in controlling mast cell homeostasis.

Accumulating evidence indicates that metabolism reprogramming is critically important to T cell differentiation, and manipulating metabolic pathways in T cells can shape their fate and function. During T cell differentiation, metabolism provides T cells with energy as well as precursors for various biological processes. Some key metabolic reactions, such as glycolysis, oxidative phosphorylation and fatty acid oxidation, are also considered to play important roles in T cell activation and differentiation. In this review, we will explain why cellular metabolism is important for the Th17/T-regulatory (Treg) cell balance and how metabolism reprogramming impacts this balance. Moreover, we will also discuss some important metabolic sensors, such as mammalian target of rapamycin, AMP-activated protein kinase, and some nuclear receptors. In addition, we will review specific small molecular compounds, which can shift the Th17/Treg cell balance and, therefore, have promising therapeutic roles. Finally, potential methods of manipulating Th17 cell metabolism for treating Th17-associated diseases will be discussed.

We propose that a C-type lectin receptor, SIGNR-1, plays a role in conditioning gastrointestinal lamina propria (LP) DC subset for the induction of oral tolerance in a model of food-induced anaphylaxis. Oral delivery of bovine serum albumin (BSA) bearing 51 mols of mannosides (Man51-BSA) significantly reduced the levels of BSA-induced anaphylactic response. Man51-BSA was found to, selectively, target the LPDC subset expressing a member of the CLRs, SIGNR1, and induce the expression of IL-10, but not IL-6 and IL-12p70. This was noted also in Man51-BSA-treated IL-10-GFPknockin (tiger) mice. The Man51-BSA–SIGNR1 axis in LPDCs, both in vitro and in vivo, promoted the generation of CD4+ Tr1-like cells expressing IL-10 and IFN-γ, in a SIGNR-1- and IL-10-dependent manner, but not of CD4+CD25+Foxp3+ Tregs. The in vivo-generated Tr1-like cells were capable of transferring tolerance. These results suggest the potential utility of sugar-modified antigen in oral tolerance through targeting of SIGNR1 and LPDCs.

The incidence of allergic diseases continues to rise. Cross-sectional and longitudinal studies have indicated that allergic diseases occur in a time-based order: from atopic dermatitis and food allergy in infancy to gradual development into allergic asthma and allergic rhinitis in childhood. This phenomenon is defined as the “atopic march”. Some scholars have suggested that the atopic march does not progress completely in a temporal pattern with genetic and environmental factors. Also, the mechanisms underlying the atopic march are incompletely understood. Nevertheless, the concept of the atopic march provides a new perspective for the mechanistic research, prediction, prevention, and treatment of atopic diseases. Here, we review the epidemiology, related diseases, mechanistic studies, and treatment strategies for the atopic march.