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Irritable bowel syndrome (IBS), one of the most prevalent functional gastrointestinal disorders, is characterized by recurrent abdominal pain and abnormal defecation habits, resulting in a severe healthcare burden worldwide. The pathophysiological mechanisms of IBS are multi‐factorially involved, including food antigens, visceral hypersensitivity reactions, and the brain–gut axis. Numerous studies have found that gut microbiota and intestinal mucosal immunity play an important role in the development of IBS in crosstalk with multiple mechanisms. Therefore, based on existing evidence, this paper elaborates that the damage and activation of intestinal mucosal immunity and the disturbance of gut microbiota are closely related to the progression of IBS. Combined with the application prospect, it also provides references for further in‐depth exploration and clinical practice. [ABSTRACT FROM AUTHOR]

Summary: The concept of trained immunity refers to remodelling of the monocyte and macrophage metabolic and epigenetic landscape, conferring an amplified inflammatory response upon secondary stimulation. This effect is typically modelled in vitro by stimulating monocytes with either Bacillus Calmette Guerin (BCG) or β‐Glucan for 24 hr, before subsequent stimulation with LPS or Pam‐3‐Cys (P3C) as a secondary stimulus 6 days later. Here, we focus on a recent paper which interrogated the role of the anti‐inflammatory TLR, TLR10, on trained immunity. Using both an in vitro model of trained immunity, and analysis of BCG vaccinated individuals, the authors interestingly demonstrate that, despite its ability to regulate aspects of innate immunity, TLR10 does not have a significant role in this process. [ABSTRACT FROM AUTHOR]

The cyclic GMP–AMP synthase–stimulator of interferon genes (cGAS–STING) pathway is an essential component of the innate immune system and is central to the identification of abnormal DNA leakage caused by ionising radiation (IR) damage. Cell‐intrinsic cGAS–STING initiation has been revealed to have tremendous potential for facilitating interferon synthesis and T‐cell priming. Targeting the cGAS–STING axis has been proposed as a strategy to improve radiosensitivity or enhance immunosurveillance. However, due to the complex biology of the irradiated tumour microenvironment and the extensive involvement of the cGAS–STING pathway in various physiological and pathological processes, many defects in this strategy limit the therapeutic effect. Here, we outline the molecular mechanisms by which IR activates the cGAS–STING pathway and analyse the dichotomous roles of the cGAS–STING pathway in modulating cancer immunity after radiotherapy (RT). Then, based on the crosstalk between the cGAS–STING pathway and other signalling events induced by IR, such as necroptosis, autophagy and other cellular effects, we discuss the immunomodulatory actions of the broad cGAS–STING signalling network in RT and their potential therapeutic applications. Finally, recent advances in combination therapeutic strategies targeting cGAS–STING in RT are explored. [ABSTRACT FROM AUTHOR]

The relative abundance of myeloid‐derived suppressor cells (MDSCs) compared to cytotoxic T cells determines the outcomes of diseases and the efficacy of immunotherapy. Ubiquitin‐specific peptidase 12 (USP12), a member of the USP family of deubiquitinases, targets multiple signalling pathways and regulates diverse biological processes, including cell proliferation and survival. It is well known that ubiquitylation is an important mechanism for regulating the immune response. However, it is unclear whether USP12 regulates tumour growth by influencing MDSCs. In the present study, we reported that USP12 deficiency decreased infiltration and impaired the suppressor function of monocytic (M)‐MDSCs, resulting in increased CD8+ T‐cell response and decelerated tumour growth. USP12‐knockout M‐MDSCs were less potent in inhibiting the proliferation of CD8+ T cells and their ability to secrete IFN‐γ. Furthermore, USP12 deficiency inhibited the suppressor function of M‐MDSCs by downregulating the negative regulatory molecules inducible nitric oxide synthase and PD‐L1, through deubiquitinating and stabilizing p65. Our results suggest that USP12 is a positive regulator of M‐MDSCs and may serve as a potential target for antitumor therapy. [ABSTRACT FROM AUTHOR]

Trained immunity (TRAIM) may be defined as a form of memory where innate immune cells such as monocytes, macrophages, dendritic and natural killer (NK) cells undergo an epigenetic reprogramming that enhances their primary defensive capabilities. Cross‐pathogen protective TRAIM can be triggered in different hosts by exposure to live microbes or microbe‐derived products such as heat‐inactivated Mycobacterium bovis or with the glycan α‐Gal to elicit protective responses against several pathogens. We review the TRAIM paradigm using two models representing distinct scales of immune sensitization: the whole bacterial cell and one of its building blocks, the polysaccharides or glycans. Observations point out to macrophage lytic capabilities and cytokine regulation as two key components in non‐specific innate immune responses against infections. The study of the TRAIM response deserves attention to better characterize the evolution of host–pathogen cooperation both for identifying the aetiology of some diseases and for finding new therapeutic strategies. In this field, the zebrafish provides a convenient and complete biological system that could help to deepen in the knowledge of TRAIM‐mediated mechanisms in pathogen–host interactions. [ABSTRACT FROM AUTHOR]

Immunotherapy has revolutionized cancer therapy by reactivating tumour‐resident cytotoxic lymphocytes. More recently, immunotherapy has emerged to restore immunity against infectious agents, including bacterial infections. Immunotherapy primarily targets inhibitory pathways in T cells, however interest in other effector populations, such as natural killer (NK) cells, is growing. We have previously discovered that NK cell metabolism, proliferation and activation can be neutralized through the immunosuppressive transforming growth factor (TGF)‐β pathway by inducing plasticity of NK cells and differentiation into innate lymphoid cell (ILC)1‐like subsets. NK cells are also regulated through cytokine‐inducible SH2‐containing protein (CIS), which is induced by interleukin (IL)‐15 and is a potent intracellular checkpoint suppressing NK cell survival and function. Targeting these two distinct pathways to restore NK cell function has shown promise in cancer models, but their application in bacterial infection remains unknown. Here, we investigate whether enhancement of NK cell function can improve anti‐bacterial immunity, using Salmonella Typhimurium as a model. We identified conversion of NK cells to ILC1‐like for the first time in the context of bacterial infection, where TGF‐β signalling contributed to this plasticity. Future study should focus on identifying further drivers of ILC1 plasticity and its functional implication in bacterial infection model. We further describe that CIS‐deficient mice displayed enhanced pro‐inflammatory function and dramatically enhanced anti‐bacterial immunity. Inhibition of CIS may present as a viable therapeutic option to enhance immunity towards bacterial infection. [ABSTRACT FROM AUTHOR]

There is growing interest in understanding antibody (Ab) function beyond neutralization. The non‐structural protein 1 (NS1) of Zika virus (ZIKV) is an attractive candidate for an effective vaccine as Abs against NS1, unlike the envelope or premembrane, do not carry the risk of mediating antibody‐dependent enhancement. Our aim was to evaluate whether ZIKV NS1 Abs elicited following natural infection in humans can mediate antibody‐dependent cellular cytotoxicity (ADCC). We evaluated the isotype specificity of ZIKV‐specific Abs in immune sera and supernatants from stimulated immune PBMC and found that Abs against ZIKV NS1 and virus‐like particles were predominantly of the IgG1 isotype. Using a recently developed FluoroSpot assay, we found robust frequencies of NS1‐specific Ab‐secreting cells in PBMC of individuals who were naturally infected with ZIKV. We developed assays to measure both natural killer cell activation by flow cytometry and target cell lysis of ZIKV NS1‐expressing cells using an image cytometry assay in the presence of ZIKV NS1 Abs. Our data indicate efficient opsonization of ZIKV NS1‐expressing CEM‐NKR cell lines using ZIKV‐immune but not ZIKV‐naïve sera, a prerequisite of ADCC. Furthermore, sera from immune donors were able to induce both NK cell degranulation and lysis of ZIKV NS1 CEM‐NKR cells in vitro. Our data suggest that ADCC is a possible mechanism for ZIKV NS1 Abs to eliminate virally infected target cells. [ABSTRACT FROM AUTHOR]

Summary: Serum amyloid A (SAA) is an acute‐phase protein (APP) to which multiple immunological functions have been attributed. Regardless, the true biological role of SAA remains poorly understood. SAA is remarkably conserved in mammalian evolution, thereby suggesting an important biological function. Since its discovery in the 1970s, the majority of researchers have investigated SAA using recombinant forms made available through bacterial expression. Nevertheless, recent studies indicate that these recombinant forms of SAA are unreliable. Indeed, commercial SAA variants have been shown to be contaminated with bacterial products including lipopolysaccharides and lipoproteins. As such, biological activities and receptor usage (TLR2, TLR4) revealed through the use of commercial SAA variants may not reflect the inherent nature of this APP. Within this review, we discuss the biological effects of SAA that have been demonstrated through more solid experimental approaches. SAA takes part in the innate immune response via the recruitment of leucocytes and executes, through pathogen recognition, antimicrobial activity. Knockout animal models implicate SAA in a range of functions, such as regulation of T‐cell‐mediated responses and monopoiesis. Moreover, through its structural motifs, not only does SAA function as an extracellular matrix protein, but it also binds extracellular matrix proteins. Finally, we here also provide an overview of definite SAA receptor‐mediated functions and highlight those that are yet to be validated. The role of FPR2 in SAA‐mediated leucocyte recruitment has been confirmed; nevertheless, SAA has been linked to a range of other receptors including CD36, SR‐BI/II, RAGE and P2RX7. [ABSTRACT FROM AUTHOR]

Summary : Th17‐derived IL‐17 might be considered the archetypal pro‐inflammatory cytokine of adaptive immunity, to be targeted by new therapeutics for alleviation of autoimmune and inflammatory disease. However, the IL‐17 family of cytokines is produced by diverse innate and adaptive cells, including Th17, Tc17, ILC3, NK cells and γδ T‐cells. These responses are appreciated to underpin diverse aspects of protective, physiological immunity, from dialogue with the gut microbiota to bacterial and fungal immunity in the lung. [ABSTRACT FROM AUTHOR]

Summary: Since the discovery of neuromedin U (NmU) from porcine spinal cord in 1985, this neuropeptide has been subsequently identified in many other species with multiple physiological and pathophysiological roles detected, ranging from smooth muscle contraction, feeding, energy balance to tumorigenesis. Intriguingly, NmU is also emerging to play pro‐inflammatory roles involving immune cell activation and cytokine release in a neuron‐dependent or neuron‐independent manner. The NmU‐mediated inflammatory responses have already been observed in worm infection, sepsis, autoimmune arthritis and allergic animal models. In this review, we focus on the roles of NmU in immunity and inflammation by highlighting the interactions between NmU and immune cells, summarizing the signalling mechanism involved in their reactions and discussing its potential contributions to inflammatory diseases. [ABSTRACT FROM AUTHOR]

Summary: The circadian clock provides organisms with the ability to track time of day, allowing them to predict and respond to cyclical changes in the external environment. In mammals this clock consists of multiple auto‐regulatory feedback loops generated by a network of circadian clock proteins. This network provides the fundamental basis for rhythms in behaviour and physiology. This clockwork machinery exists in most cells, including those of the immune system. In recent years evidence has emerged highlighting the important role of molecular clocks in dictating the response of immune pathways. While initial work highlighted the effect of the clock in the 'first line of defence', the innate immune system, it has become increasingly apparent that it also plays a role in the more tailored, later‐stage adaptive immune response. This review provides an overview of the role of the circadian cycle in the adaptive immune response. We interrogate the depth of knowledge on cell intrinsic clocks within adaptive immune cells and how these cells may be temporally directed by extrinsic rhythmic signals. We discuss the role of the circadian clock in diseases associated with adaptive immunity such as multiple sclerosis, asthma and parasitic infection. We also discuss the current knowledge on timing of vaccination, and the implications this may have on how we can harness and modulate temporal gating of the adaptive immune response in a clinical setting. [ABSTRACT FROM AUTHOR]

Summary: The skin is the outermost layer of the body with an extensive surface area of approximately 1·8 m2, and is the first line of defence against a multitude of external pathogens and environmental insults. The skin also has important homeostatic functions such as reducing water loss and contributing to thermoregulation of the body. The structure of the skin and its cellular composition work in harmony to prevent infections and to deal with physical and chemical challenges from the outside world. In this review, we discuss how the structural cells such as keratinocytes, fibroblasts and adipocytes contribute to barrier immunity. We also discuss specialized immune cells that are resident in steady‐state skin including mononuclear phagocytes, such as Langerhans cells, dermal macrophages and dermal dendritic cells in addition to the resident memory T cells. Ageing results in an increased incidence of cancer and skin infections. As we age, the skin structure changes with thinning of the epidermis and dermis, increased water loss, and fragmentation of collagen and elastin. In addition, the skin immune composition is altered with reduced Langerhans cells, decreased antigen‐specific immunity and increased regulatory populations such as Foxp3+ regulatory T cells. Together, these alterations result in decreased barrier immunity in the elderly, explaining in part their increased susceptiblity to cancer and infections. [ABSTRACT FROM AUTHOR]

Summary: Dendritic cells (DC) are a class of bone‐marrow‐derived cells arising from lympho‐myeloid haematopoiesis that form an essential interface between the innate sensing of pathogens and the activation of adaptive immunity. This task requires a wide range of mechanisms and responses, which are divided between three major DC subsets: plasmacytoid DC (pDC), myeloid/conventional DC1 (cDC1) and myeloid/conventional DC2 (cDC2). Each DC subset develops under the control of a specific repertoire of transcription factors involving differential levels of IRF8 and IRF4 in collaboration with PU.1, ID2, E2‐2, ZEB2, KLF4, IKZF1 and BATF3. DC haematopoiesis is conserved between mammalian species and is distinct from monocyte development. Although monocytes can differentiate into DC, especially during inflammation, most quiescent tissues contain significant resident populations of DC lineage cells. An extended range of surface markers facilitates the identification of specific DC subsets although it remains difficult to dissociate cDC2 from monocyte‐derived DC in some settings. Recent studies based on an increasing level of resolution of phenotype and gene expression have identified pre‐DC in human blood and heterogeneity among cDC2. These advances facilitate the integration of mouse and human immunology, support efforts to unravel human DC function in vivo and continue to present new translational opportunities to medicine. [ABSTRACT FROM AUTHOR]

Summary: Immunity to malaria could be categorized broadly as antiparasite or antidisease immunity. While most vaccine research efforts have focused on antiparasite immunity, the evidence from endemic populations suggest that antidisease immunity is an important component of natural immunity to malaria. The processes that mediate antidisease immunity have, however, attracted little to no attention, and most interests have been directed towards the antibody responses. This review evaluates the evidence for antidisease immunity in endemic areas and discusses the possible mechanisms responsible for it. Given the key role that inflammation plays in the pathogenesis of malaria, regulation of the inflammatory response appears to be a major mechanism for antidisease immunity in naturally exposed individuals. [ABSTRACT FROM AUTHOR]

Influenza causes significant morbidity and mortality annually. Although vaccination offers a considerable amount of protection, it is far from perfect, especially in aging populations. This is due to age-related defects in immune function, a process called immunosenescence. To date, there are no assays or methods to predict or explain variations in an individual's level of response to influenza vaccination. In this study, we measured levels of several immune cell subsets at baseline (Day 0) and at Days 3 and 28 post-vaccination using flow cytometry. Statistical modelling was performed to assess correlations between levels of cell subsets and Day 28 immune responses - haemagglutination inhibition ( HAI) assay, virus neutralizing antibody ( VNA) assay, and memory B cell ELISPOT. Changes in several groups of cell types from Day 0 to Day 28 and Day 3 to Day 28 were found to be significantly associated with immune response. Baseline levels of several immune cell subsets, including B cells and regulatory T cells, were able to partially explain variation in memory B-cell ELISPOT results. Increased expression of HLA- DR on plasmacytoid dendritic cells after vaccination was correlated with increased HAI and VNA responses. Our data suggest that the expression of activation markers ( HLA- DR and CD86) on various immune cell subsets, as well as the relative distribution of cell subsets, both have value in predicting immune responses to influenza vaccination in older individuals. [ABSTRACT FROM AUTHOR]