• inflammatory bowel disease
• microfluidics
• on-a-chip
• wound healing

• biomarkers
• cancer stem cells
• gastrointestinal cancer
• inflammation
• stem cells

• W81XWH-22-1-0038 United States Department of Defense
• W81XWH-22-1-0001 United States Department of Defense
• SRG/2023/002556 Science and Engineering Research Board

• Drosophila
• KO mouse
• Wnt/β-catenin signaling
• inflammatory bowel disease
• phospholipase C-β3

• Crohn Disease/pathology
• Crohn Disease/metabolism
• Crohn Disease/genetics
• Wnt Signaling Pathway
• Phospholipase C beta/metabolism
• Phospholipase C beta/genetics
• Animals
• Humans
• Mice
• beta Catenin/metabolism
• Intestinal Mucosa/metabolism
• Intestinal Mucosa/pathology
• Ileum/pathology
• Ileum/metabolism
• Mice, Inbred C57BL
• Mice, Knockout

• R01 AI146042 NIAID NIH HHS
• R01 AR064418 NIAMS NIH HHS
• R35 GM136233 NIGMS NIH HHS
• R01 AR064418 (T.K.), R01 AI146042 (T.K.), and R35 GM136233 (Y.A.) US National Institutes of Health

• Science and Engineering Research Board

• inflammatory bowel disease (IBD)
• intestinal epithelial cells (IECs)
• intestinal homeostasis
• microbiome
• mucosal immunity
• pattern recognition receptors (PRRs)

• Deutsche Forschungsgemeinschaft

• connexin 43
• intercellular communication
• phosphorylation
• the cardiovascular system
• the nervous system

• 82130109, 81773924, 81573636 National Natural Science Foundation of China

• bile acids
• blood glucose regulation
• intestinal flora
• pectin
• short-chain fatty acids

• Pectins/pharmacology
• Pectins/metabolism
• Gastrointestinal Microbiome/physiology
• Humans
• Blood Glucose/metabolism
• Fatty Acids, Volatile/metabolism
• Animals
• Glucagon-Like Peptide 1/metabolism
• Lipopolysaccharides/metabolism
• Bile Acids and Salts/metabolism
• Insulin Resistance

• Cell line
• Characterization
• Gene expression
• Intestine
• Turbot

• Animals
• Flatfishes/genetics
• Cell Line
• Karyotyping
• NF-kappa B
• Intestines

• 31902403 National Science Foundation of China
• 663-1120029 Talents Foundation of QAU grant
• tsqn201909130 Young Experts of Taishan Scholars

• Bifidobacterium
• Cx26
• Cx43
• Gap junctions
• Lactobacillus
• Probiotic

• extracellular signalling molecules
• cell death

Although all countries have taken corresponding measures, the coronavirus disease 2019 (COVID-19) is still ravaging the world. To consolidate the existing anti-epidemic results and further strengthen the prevention and control measures against the new coronavirus, we are now actively pioneering a novel research idea of regulating the intestinal microbiota through tea polyphenols for reference. Although studies have long revealed the regulatory effect of tea polyphenols on the intestinal microbiota to various gastrointestinal inflammations, little is known about the prevention and intervention of COVID-19. This review summarizes the possible mechanism of the influence of tea polyphenols on COVID-19 mediated by the intestinal microbiota. In this review, the latest studies of tea polyphenols exhibiting their own antibacterial and anti-inflammatory activities and protective effects on the intestinal mucosal barrier are combed through and summarized. Among them, (−)-epigallocatechin-3-gallate (EGCG), one of the main monomers of catechins, may be activated as nuclear factor erythroid 2 p45-related factor 2 (Nrf2). The agent inhibits the expression of ACE2 (a cellular receptor for SARS-CoV-2) and TMPRSS2 to inhibit SARS-CoV-2 infection, inhibiting the life cycle of SARS-CoV-2. Thus, preliminary reasoning and judgments have been made about the possible mechanism of the effect of tea polyphenols on the COVID-19 control and prevention mediated by the microbiota. These results may be of great significance to the future exploration of specialized research in this field.

• Connexin
• Gap Junction
• Immunity
• Inflammation
• Therapeutics

Research on inflammatory bowel disease (IBD) has produced mounting evidence for the modulation of microRNAs (miRNAs) during pathogenesis. MiRNAs are small, non-coding RNAs that interfere with the translation of mRNAs. Their high stability in free circulation at various regions of the body allows researchers to utilise miRNAs as biomarkers and as a focus for potential treatments of IBD. Yet, their distinct regulatory roles at the gut epithelial barrier remain elusive due to the fact that there are several external and cellular factors contributing to gut permeability. This review focuses on how miRNAs may compromise two components of the gut epithelium that together form the initial physical barrier: the mucus layer and the intercellular epithelial junctions. Here, we summarise the impact of miRNAs on goblet cell secretion and mucin structure, along with the proper function of various junctional proteins involved in paracellular transport, cell adhesion and communication. Knowledge of how this elaborate network of cells at the gut epithelial barrier becomes compromised as a result of dysregulated miRNA expression, thereby contributing to the development of IBD, will support the generation of miRNA-associated biomarker panels and therapeutic strategies that detect and ameliorate gut permeability.

• gut epithelial barrier
• inflammatory bowel disease
• intercellular junctions
• microRNAs
• mucus layer

Inflammatory bowel disease (IBD), Crohn’s disease, and ulcerative colitis are characterized by chronic and relapsing inflammation, while their pathogenesis remains mostly unelucidated. Gut commensal microbiota seem to be one of the various implicated factors, as several studies have shown a significant decrease in the microbiome diversity of patients with IBD. Although the question of whether microbiota dysbiosis is a causal factor or the result of chronic inflammation remains unanswered, one fact is clear; active inflammation in IBD results in the disruption of the mucus layer structure, barrier function, and also, colonization sites. Recently, many studies on IBD have been focusing on the interplay between mucosal and luminal microbiota, underlining their possible beneficial effect on mucosal healing. Regarding this notion, it has now been shown that specific probiotic strains, when administrated, lead to significantly decreased inflammation, amelioration of colitis, and improved mucosal healing. Probiotics are live microorganisms exerting beneficial effects on the host’s health when administered in adequate quantity. The aim of this review was to present and discuss the current findings on the role of gut microbiota and their metabolites in intestinal wound healing and the effects of probiotics on intestinal mucosal wound closure.

• gut microbiota
• inflammatory bowel disease
• intestinal wound healing
• mucosal healing
• probiotics

• Anti-inflammatory drugs
• Inflammatory bowel disease
• Intestinal epithelium
• Toll-like receptors

• cell communication
• connective tissue growth factor
• gap junctions
• periodontal ligament

Dysregulation of gap junction intercellular communication (GJIC) is recognized as one of the key hallmarks for identifying non-genotoxic carcinogens (NGTxC). Currently, there is a demand for in vitro assays addressing the gap junction hallmark, which would have the potential to eventually become an integral part of an integrated approach to the testing and assessment (IATA) of NGTxC. The scrape loading-dye transfer (SL-DT) technique is a simple assay for the functional evaluation of GJIC in various in vitro cultured mammalian cells and represents an interesting candidate assay. Out of the various techniques for evaluating GJIC, the SL-DT assay has been used frequently to assess the effects of various chemicals on GJIC in toxicological and tumor promotion research. In this review, we systematically searched the existing literature to gather papers assessing GJIC using the SL-DT assay in a rat liver epithelial cell line, WB-F344, after treating with chemicals, especially environmental and food toxicants, drugs, reproductive-, cardio- and neuro-toxicants and chemical tumor promoters. We discuss findings derived from the SL-DT assay with the known knowledge about the tumor-promoting activity and carcinogenicity of the assessed chemicals to evaluate the predictive capacity of the SL-DT assay in terms of its sensitivity, specificity and accuracy for identifying carcinogens. These data represent important information with respect to the applicability of the SL-DT assay for the testing of NGTxC within the IATA framework.

• carcinogenesis
• carcinogens
• gap junction intercellular communication
• scrape loading-dye transfer

The intestinal epithelial barrier is carrying out two major functions: restricting the entry of potentially harmful substances while on the other hand allowing the selective passage of nutrients. Thus, an intact epithelial barrier is vital to preserve the integrity of the host and to prevent development of disease. Vice versa, an impaired intestinal epithelial barrier function is a hallmark in the development and perpetuation of inflammatory bowel disease (IBD). Besides a multitude of genetic, molecular and cellular alterations predisposing for or driving barrier dysintegrity in IBD, the appearance of intestinal mucosal wounds is a characteristic event of intestinal inflammation apparently inducing breakdown of the intestinal epithelial barrier. Upon injury, the intestinal mucosa undergoes a wound healing process counteracting this breakdown, which is controlled by complex mechanisms such as epithelial restitution, proliferation and differentiation, but also immune cells like macrophages, granulocytes and lymphocytes. Consequently, the repair of mucosal wounds is dependent on a series of events including coordinated trafficking of immune cells to dedicated sites and complex interactions among the cellular players and other mediators involved. Therefore, a better understanding of the crosstalk between epithelial and immune cells as well as cell trafficking during intestinal wound repair is necessary for the development of improved future therapies. In this review, we summarize current concepts on intestinal mucosal wound healing introducing the main cellular mediators and their interplay as well as their trafficking characteristics, before finally discussing the clinical relevance and translational approaches to therapeutically target this process in a clinical setting.

• IBD
• intestinal epithelial barrier function
• intestinal epithelial cells
• mucosal healing
• wound healing

• Gut Barrier Function
• Microbial Metabolites
• Microbiota
• Permeability
• Tight Junction Proteins

• Animals
• Cell Membrane Permeability
• Gastrointestinal Microbiome
• Humans
• Intestinal Mucosa/microbiology
• Intestinal Mucosa/physiology
• Metabolome

• P30 ES030283 NIEHS NIH HHS
• R21 CA216090 NCI NIH HHS
• P20 GM125504 NIGMS NIH HHS
• T32 AI132146 NIAID NIH HHS
• R21 CA191683 NCI NIH HHS

Tissues that face the external environment are known as ‘epithelial tissue’ and form barriers between different body compartments. This includes the outer layer of the skin, linings of the intestine and airways that project into the lumen connecting with the external environment, and the cornea of the eye. These tissues do not have a direct blood supply and are dependent on exchange of regulatory molecules between cells to ensure co-ordination of tissue events. Proteins known as connexins form channels linking cells directly and permit exchange of small regulatory signals. A range of environmental stimuli can dysregulate the level of connexin proteins and or protein function within the epithelia, leading to pathologies including non-healing wounds. Mutations in these proteins are linked with hearing loss, skin and eye disorders of differing severity. As such, connexins emerge as prime therapeutic targets with several agents currently in clinical trials. This review outlines the role of connexins in epithelial tissue and how their dysregulation contributes to pathological pathways.

Epithelial tissue responds rapidly to environmental triggers and is constantly renewed. This tissue is also highly accessible for therapeutic targeting. This review highlights the role of connexin mediated communication in avascular epithelial tissue. These proteins form communication conduits with the extracellular space (hemichannels) and between neighboring cells (gap junctions). Regulated exchange of small metabolites less than 1kDa aide the co-ordination of cellular activities and in spatial communication compartments segregating tissue networks. Dysregulation of connexin expression and function has profound impact on physiological processes in epithelial tissue including wound healing. Connexin 26, one of the smallest connexins, is expressed in diverse epithelial tissue and mutations in this protein are associated with hearing loss, skin and eye conditions of differing severity. The functional consequences of dysregulated connexin activity is discussed and the development of connexin targeted therapeutic strategies highlighted.

• connexin
• epithelial tissue
• gap junction
• purinergic signaling

• HMGB-1
• JNK
• TLR-4
• adipocyte
• mechanical pain hypersensitivity

Sepsis is associated with global cardiac dysfunction and with high mortality rate. The development of septic cardiomyopathy is due to complex interactions of damage-associated molecular patters, cytokines, and complement activation products. The aim of this study was to define the effects of sepsis on cardiac structure, gap junction, and tight junction (TJ) proteins. Sepsis was induced by cecal ligation and puncture in male C57BL/6 mice. After a period of 24 h, the expression of cardiac structure, gap junction, and TJ proteins was determined. Murine HL-1 cells were stimulated with LPS, and mRNA expression of cardiac structure and gap junction proteins, intracellular reactive oxygen species, and troponin I release was analyzed. Furthermore, pyrogenic receptor subtype 7 (P2X7) expression and troponin I release of human cardiomyocytes (iPS) were determined after LPS exposure. In vivo, protein expression of connexin43 and α-actinin was decreased after the onset of polymicrobial sepsis, whereas in HL-1 cells, mRNA expression of connexin43, α-actinin, and desmin was increased in the presence of LPS. Expression of TJ proteins was not affected in vivo during sepsis. Although the presence of LPS and nigericin resulted in a significant troponin I release from HL-1 cells. Sepsis affected cardiac structure and gap junction proteins in mice, potentially contributing to compromised cardiac function.

• NF-κβ
• Toll-like repector 2
• connexin 26
• connexin 43
• epidermis
• inflammation
• intercellular signalling
• pannexin 1
• peptidoglycan
• purinergic signalling

• Autophagy
• Epithelial Homeostasis
• IBD
• Mucosal Defense

• diabetic nephropathy
• renal insufficiency
• stem cells
• urine

• Apical polarity
• Cancer risk
• Epithelial differentiation
• Gap junction
• PI3K
• Quiescence

• AST-120
• chronic kidney disease
• indoxyl sulfate
• intestinal epithelial cells
• oxidative stress

• Animals
• Antioxidants/pharmacology
• Carbon/pharmacology
• Cell Movement/drug effects
• Cell Survival/drug effects
• Connexin 43/genetics
• Epithelial Cells/drug effects
• Humans
• Indican/pharmacology
• Intestines/drug effects
• Intestines/pathology
• NF-E2-Related Factor 2/genetics
• Oxidative Stress/drug effects
• Oxides/pharmacology
• Rats
• Reactive Oxygen Species/metabolism
• Renal Insufficiency, Chronic/drug therapy
• Renal Insufficiency, Chronic/genetics
• Renal Insufficiency, Chronic/pathology
• Uremia/drug therapy
• Uremia/metabolism
• Uremia/pathology

Intestinal injury has long been considered to play a crucial role in the pathophysiology of sepsis and has even been characterized as the “motor” of it. Thus, we explored the effects of connexin43 (Cx43) on sepsis-induced intestinal injury in order to provide potential therapeutic strategies. Rat cecal ligation and puncture (CLP) models in vivo and cell models (IEC-6 cells) pretreated with LPS in vitro were used in the current study. Firstly, different methods, such as Cx43 inhibitors (18-α-GA and oleamide) or siRNA targeting Cx43 and N-acetyl cysteine (NAC) (a kind of ROS scavenger), were used to observe the effects of Cx43 channels mediating ROS transfer on intestinal injury. Secondly, the influence of ROS content on the activity of the JNK1/Sirt1/FoxO3a signaling pathway was explored through the application of NAC, sp600125 (a JNK1 inhibitor), and nicotinamide (a Sirt1 inhibitor). Finally, luciferase assays and ChIP were used to determine the direct regulation of FoxO3a on proapoptotic proteins, Bim and Puma. The results showed that sepsis-induced intestinal injury presented a dynamic change, coincident with the alternation of Cx43 expression. The inhibition of Cx43 attenuated CLP-induced intestinal injury in vivo and LPS-induced IEC-6 injury in vitro. The changes of Cx43 channel function regulated ROS transfer between the neighboring cells, which mediated the activation of the JNK1/Sirt1/FoxO3a signaling pathway. FoxO3a directly affected its downstream target genes, Bim and Puma, which are responsible for cell or tissue apoptosis. In summary, our results suggest that Cx43 inhibition suppresses ROS transfer and inactivates the JNK1/Sirt1/FoxO3a signaling pathway to protect against sepsis-induced intestinal injury.

• autistic spectrum disorder
• connexins
• gap junctions
• gastrointestinal infection
• inflammatory bowel disease

• Adherens Junctions/physiology
• Animals
• Cell Movement
• Cell Proliferation
• Desmosomes/physiology
• Epithelial Cells/cytology
• Epithelial Cells/metabolism
• Epithelial Cells/ultrastructure
• Epithelium/metabolism
• Homeostasis
• Humans
• Intercellular Junctions/physiology
• Intestinal Mucosa/cytology
• Intestinal Mucosa/metabolism
• Intestinal Mucosa/physiology
• Signal Transduction
• Tight Junctions/physiology
• Wound Healing

• R35 GM118064 NIGMS NIH HHS
• T32 GM007276 NIGMS NIH HHS

• ELBW
• Genetics
• extreme prematurity
• infection

• ATP-Binding Cassette Transporters/genetics
• Adaptor Proteins, Signal Transducing/genetics
• Cohort Studies
• Endopeptidases/genetics
• Female
• Forkhead Transcription Factors/genetics
• GTPase-Activating Proteins/genetics
• Genome-Wide Association Study
• Genotype
• Humans
• Infant, Extremely Premature
• Infant, Newborn
• Ion Channels/genetics
• Male
• Microfilament Proteins/genetics
• Polymorphism, Single Nucleotide
• Sepsis/genetics
• Sepsis/microbiology

• U10 HD021385 NICHD NIH HHS
• K08 GM106143 NIGMS NIH HHS
• U01 HD036790 NICHD NIH HHS
• U10 HD021364 NICHD NIH HHS
• M01 RR000030 NCRR NIH HHS
• M01 RR000633 NCRR NIH HHS
• UG1 HD034216 NICHD NIH HHS
• U10 HD027871 NICHD NIH HHS
• UG1 HD027904 NICHD NIH HHS
• UG1 HD027880 NICHD NIH HHS
• M01 RR000997 NCRR NIH HHS
• UG1 HD027851 NICHD NIH HHS
• U10 HD027856 NICHD NIH HHS
• U10 HD021373 NICHD NIH HHS
• U10 HD027880 NICHD NIH HHS
• UG1 HD027853 NICHD NIH HHS
• U10 HD053109 NICHD NIH HHS
• M01 RR000039 NCRR NIH HHS
• UG1 HD087229 NICHD NIH HHS
• M01 RR008084 NCRR NIH HHS
• R01 HD089939 NICHD NIH HHS
• U10 HD040461 NICHD NIH HHS
• M01 RR016587 NCRR NIH HHS
• M01 RR000750 NCRR NIH HHS
• U10 HD040689 NICHD NIH HHS
• U10 HD040492 NICHD NIH HHS
• U10 HD027853 NICHD NIH HHS
• U10 HD027904 NICHD NIH HHS
• U10 HD021397 NICHD NIH HHS
• U10 HD068244 NICHD NIH HHS
• M01 RR007122 NCRR NIH HHS
• U10 HD027851 NICHD NIH HHS
• M01 RR000032 NCRR NIH HHS
• UG1 HD040492 NICHD NIH HHS
• UG1 HD021364 NICHD NIH HHS
• UG1 HD053109 NICHD NIH HHS
• U01 HG004423 NHGRI NIH HHS
• M01 RR000070 NCRR NIH HHS
• M01 RR000080 NCRR NIH HHS
• U10 HD034216 NICHD NIH HHS
• U10 HD036790 NICHD NIH HHS
• U10 HD040498 NICHD NIH HHS
• UG1 HD068278 NICHD NIH HHS
• M01 RR006022 NCRR NIH HHS
• UL1 RR024979 NCRR NIH HHS

Gap junctions (GJs)-mediated intercellular communications (GJICs) are connexin (Cx)-formed plasma membrane channels that allow for the passage of small molecules between adjacent cells, and are involved in several physiopathological processes, including immune responses against cancer. In general, tumor cells are poorly coupled through GJs, mainly due to low Cx expression or reduced channel activity, suggesting that Cxs may have tumor suppressor roles. However, more recent data indicate that Cxs and/or GJICs may also in some cases promote tumor progression. This dual role of Cx channels in tumor outcome may be due, at least partially, to the fact that GJs not only interconnect cells from the same type, such as cancer cells, but also promote the intercellular communication of tumor cells with different types of cells from their microenvironment, and such diverse intercellular interactions have distinctive impact on tumor development. For example, whereas GJ-mediated interactions among tumor cells and microglia have been implicated in promotion of tumor growth, tumor cells delivery to dendritic cells of antigenic peptides through GJs have been associated with enhanced immune-mediated tumor elimination. In this review, we provide an updated overview on the role of GJICs in tumor immunity, focusing on the pro-tumor and antitumor effect of GJs occurring among tumor and immune cells. Accumulated data suggest that GJICs may act as tumor suppressors or enhancers depending on whether tumor cells interact predominantly with antitumor immune cells or with stromal cells. The complex modulation of immune-tumor cell GJICs should be taken into consideration in order to potentiate current cancer immunotherapies.

• connexin
• gap junction
• stromal cells
• tumor immunity
• tumor microenvironment

• ATP Binding Cassette Transporter, Subfamily B/deficiency
• ATP Binding Cassette Transporter, Subfamily B/genetics
• ATP Binding Cassette Transporter, Subfamily B/immunology
• Animals
• B-Lymphocytes/immunology
• B-Lymphocytes/pathology
• Carcinogenesis/genetics
• Carcinogenesis/immunology
• Carcinogenesis/pathology
• Chemotaxis
• Colitis, Ulcerative/complications
• Colitis, Ulcerative/genetics
• Colitis, Ulcerative/immunology
• Colitis, Ulcerative/pathology
• Colorectal Neoplasms/complications
• Colorectal Neoplasms/genetics
• Colorectal Neoplasms/immunology
• Colorectal Neoplasms/pathology
• Cyclooxygenase 2/genetics
• Cyclooxygenase 2/immunology
• DNA-Binding Proteins/deficiency
• DNA-Binding Proteins/genetics
• DNA-Binding Proteins/immunology
• Disease Models, Animal
• Epiregulin/genetics
• Epiregulin/immunology
• Gene Expression Regulation, Neoplastic
• Genes, Immunoglobulin Light Chain/genetics
• Humans
• Interleukin-11/genetics
• Interleukin-11/immunology
• Intestinal Mucosa/immunology
• Intestinal Mucosa/pathology
• Leukocyte Common Antigens/genetics
• Leukocyte Common Antigens/immunology
• Male
• Mice
• Mice, Knockout
• Monocyte Chemoattractant Proteins/genetics
• Monocyte Chemoattractant Proteins/immunology
• Signal Transduction
• TNF-Related Apoptosis-Inducing Ligand/genetics
• TNF-Related Apoptosis-Inducing Ligand/immunology

• Deutsche Forschungsgemeinschaft

The gastrointestinal barrier is constantly exposed to numerous environmental substrates that are foreign and potentially harmful. These xenobiotics can cause shifts in the intestinal microbiota composition, affect mucosal immune responses, disturb tissue integrity and impair regeneration. The multidrug transporter ABCB1/MDR1 p-glycoprotein (p-gp) plays a key role at the front line of host defence by efficiently protecting the gastrointestinal barrier from xenobiotic accumulation. This Editorial discusses how altered expression and function of ABCB1/MDR1 p-gp may contribute to the development and persistence of chronic intestinal inflammation in inflammatory bowel diseases (IBD). Recent evidence implies multiple interactions between intestinal microbiota, innate immunity and xenobiotic metabolism via p-gp. While decreased efflux activity may promote disease susceptibility and drug toxicity, increased efflux activity may confer resistance to therapeutic drugs in IBD. Mice deficient in MDR1A develop spontaneously chronic colitis, providing a highly valuable murine IBD model for the study of intestinal epithelial barrier function, immunoregulation, infectious co-triggers and novel therapeutic approaches. Possible associations of human ABCB1 gene polymorphisms with IBD susceptibility have been evaluated, but results are inconsistent. Future studies must focus on further elucidation of the pathophysiological relevance and immunological functions of p-gp and how its ambiguous effects could be therapeutically targeted in IBD.

• Inflammatory bowel diseases
• Multidrug resistance
• Innate immunity
• Microbiota
• Xenobiotics

• ATP Binding Cassette Transporter, Subfamily B/genetics
• ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism
• Animals
• Chronic Disease
• Colitis/genetics
• Colitis/metabolism
• Drug Resistance, Multiple
• Gastrointestinal Microbiome
• Gene Expression Regulation
• Homeostasis
• Humans
• Immunity, Innate
• Inflammation
• Inflammatory Bowel Diseases/immunology
• Inflammatory Bowel Diseases/metabolism
• Mice
• Mice, Knockout
• Polymorphism, Single Nucleotide
• Xenobiotics/metabolism

• Intestinal function
• N-Acetylcysteine
• Piglets
• Signaling pathway

• Corticosterone
• Cytokines
• Heat stress
• Neuroimmunomodulation
• Salmonella
• Toll-like receptor

Under physiological conditions, microglia adopt a resting phenotype associated with the production of anti-inflammatory and neurotrophic factors. In response to a wide variety of insults, these cells shift to an activated phenotype that is necessary for the proper restoration of brain homeostasis. However, when the intensity of a threat is relatively high, microglial activation worsens the progression of damage rather than providing protection, with potentially significant consequences for neuronal survival. Coordinated interactions among microglia and other brain cells, including astrocytes and neurons, are critical for the development of timely and optimal inflammatory responses in the brain parenchyma. Tissue synchronization is in part mediated by connexins and pannexins, which are protein families that form different plasma membrane channels to communicate with neighboring cells. Gap junction channels (which are exclusively formed by connexins in vertebrates) connect the cytoplasm of contacting cells to coordinate electrical and metabolic coupling. Hemichannels (HCs) and pannexons (which are formed by connexins and pannexins, respectively) communicate the intra- and extracellular compartments and serve as diffusion pathways for the exchange of ions and small molecules. In this review article, we discuss the available evidence concerning the functional expression and regulation of connexin- and pannexin-based channels in microglia and their contributions to microglial function and dysfunction. Specifically, we focus on the possible implications of these channels in microglia-to-microglia, microglia-to-astrocyte and neuron-to-microglia interactions in the inflamed brain.

• brain
• gap junctions
• gliotransmitters
• hemichannels
• microglia
• pannexons

• cardiac electrophysiology
• conduction
• electrical excitation
• gastrointestinal electrophysiology
• propagation

• Akt kinase, G protein-coupled receptor (GPCR)
• Connexon (hemichannel)
• FFAR1
• Polyunsaturated fatty acid (PUFA)
• Protein phosphorylation
• Transmembrane permeability

• stomach
• intestine
• liver
• connexin
• pannexin
• disease