DNA sensor, a kind of pattern recognition receptor (PRR), is widely expressed in innate immune cells. It activates the inflammatory signaling pathways and triggers an innate immune response by recognizing the pathogens or DNA in abnormal host cells. DNA-dependent activator of IFN-regulatory factors (DAI) is the first cytoplasmic DNA receptor discovered, which plays an important role in regulating the innate immune responses characterized by induction of interferon and programmed cell death. The article summarizes the molecular characteristics of DAI, its downstream signaling pathways, and its role and mechanism in anti-infective immunity, tumor immunity and inflammatory diseases. It also makes a preliminary exploration of the correlation between DAI and transplantation immunology, and provides a new target for the therapy of various immune diseases.
DNA/metabolism* ; Receptors, Pattern Recognition ; Immunity, Innate ; Signal Transduction/genetics* ; DNA-Binding Proteins/genetics*

Diabetic nephropathy (DN) is currently the most common complication of diabetes. It is considered to be one of the leading causes of end-stage renal disease (ESRD) and affects many diabetic patients. The pathogenesis of DN is extremely complex and has not yet been clarified; however, in recent years, increasing evidence has shown the important role of innate immunity in DN pathogenesis. Pattern recognition receptors (PRRs) are important components of the innate immune system and have a significant impact on the occurrence and development of DN. In this review, we classify PRRs into secretory, endocytic, and signal transduction PRRs according to the relationship between the PRRs and subcellular compartments. PRRs can recognize related pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs), thus triggering a series of inflammatory responses, promoting renal fibrosis, and finally causing renal impairment. In this review, we describe the proposed role of each type of PRRs in the development and progression of DN.
Alarmins/physiology* ; C-Reactive Protein/physiology* ; Diabetic Nephropathies/etiology* ; Endocytosis ; Humans ; Immunity, Innate ; Mannose-Binding Lectin/physiology* ; Pathogen-Associated Molecular Pattern Molecules ; Receptors, Pattern Recognition/physiology* ; Serum Amyloid P-Component/physiology* ; Signal Transduction

The aim of this paper was to study the influence of triptolide in the immune response pathways of acquired immune deficiency syndrome( AIDS). Target proteins of triptolide and related genes of AIDS were searched in PubChem and Gene databases on line. Molecular networks and canonical pathways comparison analyses were performed by bioinformatics software( IPA). There were 15 targets proteins of triptolide and 258 related genes of AIDS. Close biological relationships of molecules of triptolide and AIDS were established by networks analysis. There were 21 common immune response pathways of triptolide and AIDS,including neuroinflammation signaling pathway,Th1 and Th2 activation pathway and role of pattern recognition receptors in recognition of bacteria and viruses. Triptolide stimulated immune response pathways by the main molecules of IFNγ,JAK2,NOD1,PTGS2,RORC. IFNγ is the focus nodes of triptolide and AIDS,and regulates genes of AIDS directly or indirectly. Triptolide may against AIDS by regulating molecules IFNγ in immune response pathways.
Acquired Immunodeficiency Syndrome ; drug therapy ; immunology ; Computational Biology ; Diterpenes ; pharmacology ; Epoxy Compounds ; pharmacology ; Gene Regulatory Networks ; Humans ; Interferon-gamma ; genetics ; Phenanthrenes ; pharmacology ; Receptors, Pattern Recognition ; immunology ; Signal Transduction ; T-Lymphocytes ; immunology

Toll-like receptors (TLR) are well-characterized pattern recognition receptors that can recognize and respond to diverse pathogen-associated or danger-associated molecular patterns during infection. TLR signaling in macrophages triggers in the intracellular signaling pathways through the recruitment of various adaptor and signaling proteins, and results in the activation of effector mechanisms and pathways that are important for host defense to intracellular bacteria. Effector mechanisms include inflammatory responses, cytokine generation, production of reactive oxygen species, and antimicrobial proteins. Accumulating studies showed that autophagy is a key pathway in the maintenance of homeostasis and housekeeping functions during infection and inflammation. In this review, we summarize the major effector pathways and mechanisms in the activation of TLR-inducible innate immune responses in macrophages. In addition, we focus the emerging evidence of crosstalk between autophagy and TLR-mediated signaling in terms of effector function of innate immune responses. A better understanding of effector functions by the activation of TLR-mediated signaling cascades contributes to the development of new therapeutics and vaccines against various intracellular pathogenic infections.
Autophagy ; Bacteria ; Homeostasis ; Housekeeping ; Immunity, Innate ; Inflammation ; Macrophages ; Reactive Oxygen Species ; Receptors, Pattern Recognition ; Toll-Like Receptors ; Vaccines

Damage-associated molecular patterns (DAMPs) are endogenous danger molecules that are released from damaged or dying cells and activate the innate immune system by interacting with pattern recognition receptors (PRRs). Although DAMPs contribute to the host's defense, they promote pathological inflammatory responses. Recent studies have suggested that various DAMPs, such as high-mobility group box 1 (HMGB1), S100 proteins, and heat shock proteins (HSPs), are increased and considered to have a pathogenic role in inflammatory diseases. Here, we review current research on the role of DAMPs in inflammatory diseases, including rheumatoid arthritis, systemic lupus erythematosus, osteoarthritis, atherosclerosis, Alzheimer's disease, Parkinson's disease, and cancer. We also discuss the possibility of DAMPs as biomarkers and therapeutic targets for these diseases.
Alzheimer Disease ; Arthritis, Rheumatoid ; Atherosclerosis ; Biomarkers ; Heat-Shock Proteins ; Immune System ; Inflammation ; Lupus Erythematosus, Systemic ; Osteoarthritis ; Parkinson Disease ; Receptors, Pattern Recognition ; S100 Proteins

Interaction between pathogen-associated molecular patterns and pattern recognition receptors triggers innate and adaptive immune responses. Several studies have reported that toll-like receptors (TLRs) are involved in B cell proliferation, differentiation, and Ig class switch recombination (CSR). However, roles of TLRs in B cell activation and differentiation are not completely understood. In this study, we investigated the direct effect of stimulation of TLR1/2 agonist Pam3CSK4 on mouse B cell viability, proliferation, activation, Ig production, and Ig CSR in vitro. Treatment with 0.5 µg/ml of Pam3CSK4 only barely induced IgG1 production although it enhanced B cell viability. In addition, high-dosage Pam3CSK4 diminished IgG1 production in a dose-dependent manner, whereas the production of other Igs, cell viability, and proliferation increased. Pam3CSK4 additively increased TLR4 agonist lipopolysaccharide (LPS)-induced mouse B cell growth and activation. However, interestingly, Pam3CSK4 abrogated LPS-induced IgG1 production but enhanced LPS-induced IgG2a production. Further, Pam3CSK4 decreased LPS-induced germline γ1 transcripts (GLTγ1)/GLTε expression but increased GLTγ2a expression. On the other hand, Pam3CSK4 had no effect on LPS-induced plasma cell differentiation. Taken together, these results suggest that TLR1/2 agonist Pam3CSK4 acts as a potent mouse B cell mitogen in combination with TLR4 agonist LPS, but these 2 different TLR agonists play diverse roles in regulating the Ig CSR of each isotype, particularly IgG1/IgE and IgG2a.
Animals ; B-Lymphocytes ; Cell Proliferation ; Cell Survival ; Hand ; Immunoglobulin Class Switching ; Immunoglobulin E ; Immunoglobulin G ; In Vitro Techniques ; Mice ; Pathogen-Associated Molecular Pattern Molecules ; Plasma Cells ; Receptors, Pattern Recognition ; Recombination, Genetic ; Toll-Like Receptors

Inflammation is an immune response mediated by innate immune cells of tissues, against invading microbes and cellular stress. The hallmark of inflammatory responses is the activation of inflammasomes — multiprotein oligomers comprising intracellular pattern recognition receptors and inflammatory effectors — such as ASC and pro-cysteine-aspartic protease (pro-caspase)-1. Inflammasomes can be classified as canonical or non-canonical, and their activation in response to various ligands commonly induces caspase-1 activation and gasdermin D (GSDMD) processing, leading to caspase-1-mediated maturation and secretion of the pro-inflammatory cytokines IL-1β and IL-18, and GSDMD-mediated pyroptosis through pore generation in cell membranes. Although inflammation protects the host from harmful stimuli, chronic inflammation is a critical risk factor for inflammatory diseases, and several studies have investigated the role of canonical inflammasomes in inflammatory responses and diseases, with emerging studies focusing on the role of non-canonical inflammasomes. This review discusses recent studies on the regulatory roles of the caspase-11 non-canonical inflammasome in the pathogenesis of inflammatory diseases. Additionally, it provides an insight into the development of novel therapeutics based on targeting caspase-11 non-canonical inflammasome and its downstream effectors to prevent and treat human inflammatory conditions.
Cell Membrane ; Cytokines ; Humans ; Inflammasomes* ; Inflammation ; Interleukin-18 ; Ligands ; Pyroptosis ; Receptors, Pattern Recognition ; Risk Factors

Ischemia-reperfusion injury (IRI) is a major complication in liver transplantation (LT) and it is closely related to the recovery of grafts' function. Researches has verified that both innate and adaptive immune system are involved in the development of IRI and Kupffer cell (KC), the resident macrophages in the liver, play a pivotal role both in triggering and sustaining the sterile inflammation. Damage-associated molecular patterns (DAMPs), released by the initial dead cell because of the ischemia insult, firstly activate the KC through pattern recognition receptors (PRRs) such as toll-like receptors. Activated KCs is the dominant players in the IRI as it can secret various pro-inflammatory cytokines to exacerbate the injury and recruit other types of immune cells from the circulation. On the other hand, KCs can also serve in a contrary way to ameliorate IRI by upregulating the anti-inflammatory factors. Moreover, new standpoint has been put forward that KCs and macrophages from the circulation may function in different way to influence the inflammation. Managements towards KCs are expected to be the effective way to improve the IRI.
Cytokines ; Hand ; Immune System ; Inflammation ; Ischemia* ; Kupffer Cells ; Liver Transplantation* ; Liver* ; Macrophages* ; Receptors, Pattern Recognition ; Reperfusion Injury* ; Reperfusion* ; Toll-Like Receptors

Despite paramount clinical significance of white matter stroke, there is a paucity of researches on the pathomechanism of ischemic white matter damage and accompanying oligodendrocyte (OL) death. Therefore, a large gap exists between clinical needs and laboratory researches in this disease entity. Recent works have started to elucidate cellular and molecular basis of white matter injury under ischemic stress. In this paper, we briefly introduce white matter stroke from a clinical point of view and review pathophysiology of ischemic white matter injury characterized by OL death and demyelination. We present a series of evidence that Toll-like receptor 2 (TLR2), one of the membranous pattern recognition receptors, plays a cell-autonomous protective role in ischemic OL death and ensuing demyelination. Moreover, we also discuss our recent findings that its endogenous ligand, high-mobility group box 1 (HMGB1), is released from dying OLs and exerts autocrine trophic effects on OLs and myelin sheath under ischemic condition. We propose that modulation of TLR2 and its endogenous ligand HMGB1 can be a novel therapeutic target for ischemic white matter disease.
Demyelinating Diseases ; HMGB1 Protein ; Ischemia ; Leukoencephalopathies ; Myelin Sheath ; Oligodendroglia* ; Receptors, Pattern Recognition ; Stroke ; Toll-Like Receptor 2* ; Toll-Like Receptors* ; White Matter*

Ischemia-reperfusion injury (IRI) is an inevitable consequence of organ transplantation that has major consequences for graft-and patient survival. During transplantation procedures, allografts are exposed to various periods of complete ischemia. Ischemic insult starts with brain death, and its associated hemodynamic disturbances continue during donor organ procurement, cold preservation, and implantation. Ischemia-reperfusion injury, which is a risk factor for acute graft injury, delayed graft function, and acute and chronic rejection, is triggered following reperfusion. Along the cascade of pathogenic events that accompany ischemic insults and cause IRI, there has been an appreciation for various immune mechanisms within the allograft itself. The pathophysiological events associated with IRI originate in signals derived from pattern recognition receptors (PRRs) expressed in the donor organ. Danger associated molecular patterns (DAMP) released from injured cells serve as ligands for PRRs expressed on many cells in the donor organ. Activation of PRR signaling in the donor organ leads to production of proinflammatory cytokines and activates the innate immune system, triggering adaptive immune responses as well as cell death signaling, ultimately worsening the initial ischemic injury. Accordingly, deciphering the inflammatory pathway of innate immunity in IRI may provide a good therapeutic target to block acute sterile inflammation caused by tissue damage.
Allografts ; Brain Death ; Cell Death ; Cytokines ; Delayed Graft Function ; Hemodynamics ; Humans ; Immune System ; Immunity, Innate ; Inflammation ; Ischemia* ; Ligands ; Organ Transplantation ; Porcine Reproductive and Respiratory Syndrome ; Receptors, Pattern Recognition ; Reperfusion ; Reperfusion Injury* ; Risk Factors ; Tissue and Organ Procurement ; Tissue Donors ; Transplantation ; Transplants