Innate immune cells have complex signalling pathways for sensing pathogens and initiating innate immune responses against infection. These pathways are tightly regulated at different levels, ...including by epigenetic regulators. In this Review, we discuss studies revealing the epigenetic mechanisms, as well as the post-transcriptional and post-translational modifications by chromatin modifiers, that underlie the establishment of these signalling networks and the rapid induction of innate immune molecules during infection. We also discuss how pathogens use their own products, as well as host components, to target host epigenomes for immune evasion and survival. We describe the crosstalk between epigenetic regulators and new modulators, such as inflammation-specific metabolites, and how we might deconstruct dynamic chromatin patterns and identify critical chromatin modifiers of host-pathogen interactions.
Primary tumors create a favorable microenvironment, namely, pre-metastatic niche, in secondary organs and tissue sites for subsequent metastases. The pre-metastatic niche can be primed and ...established through a complex interplay among primary tumor-derived factors, tumor-mobilized bone marrow-derived cells, and local stromal components. We review here our current understanding of the key components and underlying mechanisms for pre-metastatic niche formation. We propose six characteristics that define the pre-metastatic niche, which enable tumor cell colonization and promote metastasis, including immunosuppression, inflammation, angiogenesis/vascular permeability, lymphangiogenesis, organotropism, and reprogramming. We highlight the significance of the pre-metastatic niche, and discuss potential implications and future research directions.
Primary tumors create a favorable microenvironment, namely, pre-metastatic niche, in secondary organs and tissue sites for subsequent metastases. The pre-metastatic niche can be primed and established through a complex interplay among primary tumor-derived factors, tumor-mobilized bone marrow-derived cells, and local stromal components. Liu and Cao review the current understanding of key components and the underlying mechanisms for pre-metastatic niche formation. Six characteristics are proposed that define the pre-metastatic niche which enable tumor cell colonization and promote metastasis, including immunosuppression, inflammation, angiogenesis/vascular permeability, lymphangiogenesis, organotropism, and reprogramming. The significance of the pre-metastatic niche is highlighted, and potential implications and future research directions are discussed.
Dendritic cells (DCs) are the key link between innate immunity and adaptive immunity and play crucial roles in both the promotion of immune defense and the maintenance of immune tolerance. The ...trafficking of distinct DC subsets across lymphoid and nonlymphoid tissues is essential for DC-dependent activation and regulation of inflammation and immunity. DC chemotaxis and migration are triggered by interactions between chemokines and their receptors and regulated by multiple intracellular mechanisms, such as protein modification, epigenetic reprogramming, metabolic remodeling, and cytoskeletal rearrangement, in a tissue-specific manner. Dysregulation of DC migration may lead to abnormal positioning or activation of DCs, resulting in an imbalance of immune responses and even immune pathologies, including autoimmune responses, infectious diseases, allergic diseases and tumors. New strategies targeting the migration of distinct DC subsets are being explored for the treatment of inflammatory and infectious diseases and the development of novel DC-based vaccines. In this review, we will discuss the migratory routes and immunological consequences of distinct DC subsets, the molecular basis and regulatory mechanisms of migratory signaling in DCs, and the association of DC migration with the pathogenesis of autoimmune and infectious diseases.
Viruses regulate host metabolic networks to improve their survival. The molecules that are responsive to viral infection and regulate such metabolic changes are hardly known, but are essential for ...understanding viral infection. Here we identify a long noncoding RNA (lncRNA) that is induced by multiple viruses, but not by type I interferon (IFN-I), and facilitates viral replication in mouse and human cells. In vivo deficiency of lncRNA-ACOD1 (a lncRNA identified by its nearest coding gene Acod1, aconitate decarboxylase 1) significantly attenuates viral infection through IFN-I–IRF3 (interferon regulatory factor 3)–independent pathways. Cytoplasmic lncRNA-ACOD1 directly binds the metabolic enzyme glutamic-oxaloacetic transaminase (GOT2) near the substrate niche, enhancing its catalytic activity. Recombinant GOT2 protein and its metabolites could rescue viral replication upon lncRNA-ACOD1 deficiency and increase lethality. This work reveals a feedback mechanism of virus-induced lncRNA-mediated metabolic promotion of viral infection and a potential target for developing broad-acting antiviral therapeutics.
Colonization of intestine by oral bacteria can induce inflammatory disorders
Numerous microorganisms, including bacteria, colonize the intestine where they play important roles in maintaining ...homeostasis. However, commensal bacteria with pathogenic potential, such as
Helicobacter hepaticus
, can also induce intestinal inflammation. Cross-talk between gut microbiota and the host immune system can prevent or mediate chronic intestinal inflammation, the outcome of which depends on gut microbiota composition, immune response, host genetic factors, and how these factors interact (
1
,
2
). Physiologically, the intestine has developed several strategies to resist colonization by non-native bacteria and control the expansion of pathobionts that have the potential to cause pathology. Intestinal colonization by bacteria from the oral cavity has been suggested to be extensively involved in inflammatory diseases (
3
,
4
). However, it remains unclear what subset of oral microbiota may ectopically colonize the intestine and whether they induce inflammatory immune responses. On page 359 of this issue, Atarashi
et al.
(
5
) show that strains of
Klebsiella
spp. from the salivary microbiota colonize in the gut and can potently induce chronic intestinal inflammation.
The innate immune response is a rapid response to pathogens or danger signals. It is precisely activated not only to efficiently eliminate pathogens but also to avoid excessive inflammation and ...tissue damage.
cis
-Regulatory element-associated chromatin architecture shaped by epigenetic factors, which we define as the epiregulome, endows innate immune cells with specialized phenotypes and unique functions by establishing cell-specific gene expression patterns, and it also contributes to resolution of the inflammatory response. In this review, we focus on two aspects: (
a
) how niche signals during lineage commitment or following infection and pathogenic stress program epiregulomes by regulating gene expression levels, enzymatic activities, or gene-specific targeting of chromatin modifiers and (
b
) how the programed epiregulomes in turn mediate regulation of gene-specific expression, which contributes to controlling the development of innate cells, or the response to infection and inflammation, in a timely manner. We also discuss the effects of innate immunometabolic rewiring on epiregulomes and speculate on several future challenges to be encountered during the exploration of the master regulators of epiregulomes in innate immunity and inflammation.
DNA viruses typically eject genomic DNA into the nuclei of host cells after entry. It is unclear, however, how nuclear pathogen-derived DNA triggers innate immune responses. We report that ...heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1) recognizes pathogenic DNA and amplifies interferon-α/β (IFN-α/β) production. Upon DNA virus infection, nuclear-localized hnRNPA2B1 senses viral DNA, homodimerizes, and is then demethylated at arginine-226 by the arginine demethylase JMJD6. This results in hnRNPA2B1 translocation to the cytoplasm where it activates the TANK-binding kinase 1-interferon regulatory factor 3 (TBK1-IRF3) pathway, leading to IFN-α/β production. Additionally, hnRNPA2B1 facilitates
-methyladenosine (m
A) modification and nucleocytoplasmic trafficking of
,
, and
messenger RNAs. This, in turn, amplifies the activation of cytoplasmic TBK1-IRF3 mediated by these factors. Thus, hnRNPA2B1 plays important roles in initiating IFN-α/β production and enhancing stimulator of interferon genes (STING)-dependent cytoplasmic antiviral signaling.
A coordinated balance between the positive and negative regulation of pattern-recognition receptor (PRR)-initiated innate inflammatory responses is required to ensure the most favorable outcome for ...the host. Post-translational modifications (PTMs) of innate sensors and downstream signaling molecules influence their activity and function by inducing their covalent linkage to new functional groups. PTMs including phosphorylation and polyubiquitination have been shown to potently regulate innate inflammatory responses through the activation, cellular translocation, and interaction of innate receptors, adaptors, and downstream signaling molecules in response to infectious and dangerous signals. Other PTMs such as methylation, acetylation, SUMOylation, and succinylation are increasingly implicated in the regulation of innate immunity and inflammation. In this review, we focus on the roles of PTMs in controlling PRR-triggered innate immunity and inflammatory responses. The emerging roles of PTMs in the pathogenesis and potential treatment of infectious and inflammatory immune diseases are also discussed.
Post-translational modifications (PTMs) of innate sensors and downstream signaling molecules influence their activity and function, and this regulation is crucial to maintain host immunity. Cao and colleagues discuss the emerging roles of PTMs in the pathogenesis and potential treatment of infectious and inflammatory immune diseases.
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