Molecular Mechanisms of Target Recognition in an Innate Immune System: Interactions Among Factor H, C3b, and Target in the Alternative Pathway of Human Complement

Complement is the canonical innate immune system involved in host defense and tissue repair with the clearance of cell debris. In contrast to the robust armory mounted against microbial nonself-pathogens, complement is selectively activated on altered self (i.e. apoptotic and necrotic cells) to instruct the safe demise by poorly characterized mechanisms. Our data shed new light on the role of complement C1q in sensing nucleic acids (NA) rapidly exposed on apoptotic Jurkat T cell membranes and in driving C3 opsonization but without the lytic membrane attack complex. DNA/RNase-treated apoptotic cells failed to activate complement. We found that several other apoptotic cell models, including senescent keratinocytes, ionophore-treated sperm cells, and CMK-derived platelets, stained for cleaved caspase 3 were rapidly losing the key complement regulator CD46. CD46 from nuclear and membrane stores was found to cluster into blebs and shed into microparticles together with NA, phosphatidylserine, C1q, and factor H. Classical and alternative pathways of complement were involved in the recognition of H2O2-treated necrotic cells. Membrane attack complex was detected on necrotic cells possibly as a result of CD46 and CD59 shedding into soluble forms. Our data highlight a novel and universal paradigm whereby the complement innate immune system is using two synergistic strategies with the recognition of altered self-NA and missing self-CD46 signals to instruct and tailor the efficient removal of apoptotic and necrotic cells in immunoprivileged sites.

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Molecular mechanisms of non‐self nucleic acid recognition by the innate immune system

European Journal of Immunology ◽

10.1002/eji.202049116 ◽

2021 ◽

Author(s):

Carina C. de Oliveira Mann ◽

Veit Hornung

Keyword(s):

Immune System ◽

Nucleic Acid ◽

Innate Immune System ◽

Molecular Mechanisms ◽

Innate Immune

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A Novel Regulatory Player in the Innate Immune System: Long Non-Coding RNAs

International Journal of Molecular Sciences ◽

10.3390/ijms22179535 ◽

2021 ◽

Vol 22 (17) ◽

pp. 9535

Author(s):

Yuhuai Xie ◽

Yuanyuan Wei

Keyword(s):

Immune System ◽

Immune Cells ◽

Innate Immune System ◽

Molecular Mechanisms ◽

Innate Immune ◽

Innate Immune Cells ◽

Immune Mediated ◽

Development And Differentiation ◽

Non Coding Rnas ◽

And Function

Long non-coding RNAs (lncRNAs) represent crucial transcriptional and post-transcriptional gene regulators during antimicrobial responses in the host innate immune system. Studies have shown that lncRNAs are expressed in a highly tissue- and cell-specific- manner and are involved in the differentiation and function of innate immune cells, as well as inflammatory and antiviral processes, through versatile molecular mechanisms. These lncRNAs function via the interactions with DNA, RNA, or protein in either cis or trans pattern, relying on their specific sequences or their transcriptions and processing. The dysregulation of lncRNA function is associated with various human non-infectious diseases, such as inflammatory bowel disease, cardiovascular diseases, and diabetes mellitus. Here, we provide an overview of the regulation and mechanisms of lncRNA function in the development and differentiation of innate immune cells, and during the activation or repression of innate immune responses. These elucidations might be beneficial for the development of therapeutic strategies targeting inflammatory and innate immune-mediated diseases.

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Identification of hub genes related to the progression of type 1 diabetes by computational analysis

BMC Endocrine Disorders ◽

10.1186/s12902-021-00709-6 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

G. Prashanth ◽

Basavaraj Vastrad ◽

Anandkumar Tengli ◽

Chanabasayya Vastrad ◽

Iranna Kotturshetti

Keyword(s):

Immune System ◽

Regulatory Network ◽

Innate Immune System ◽

Target Gene ◽

Molecular Mechanisms ◽

Innate Immune ◽

Pcr Analysis ◽

Rt Pcr ◽

Hub Genes

Abstract Background Type 1 diabetes (T1D) is a serious threat to childhood life and has fairly complicated pathogenesis. Profound attempts have been made to enlighten the pathogenesis, but the molecular mechanisms of T1D are still not well known. Methods To identify the candidate genes in the progression of T1D, expression profiling by high throughput sequencing dataset GSE123658 was downloaded from Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) were identified, and gene ontology (GO) and pathway enrichment analyses were performed. The protein-protein interaction network (PPI), modules, target gene - miRNA regulatory network and target gene - TF regulatory network analysis were constructed and analyzed using HIPPIE, miRNet, NetworkAnalyst and Cytoscape. Finally, validation of hub genes was conducted by using ROC (Receiver operating characteristic) curve and RT-PCR analysis. A molecular docking study was performed. Results A total of 284 DEGs were identified, consisting of 142 up regulated genes and 142 down regulated genes. The gene ontology (GO) and pathways of the DEGs include cell-cell signaling, vesicle fusion, plasma membrane, signaling receptor activity, lipid binding, signaling by GPCR and innate immune system. Four hub genes were identified and biological process analysis revealed that these genes were mainly enriched in cell-cell signaling, cytokine signaling in immune system, signaling by GPCR and innate immune system. ROC curve and RT-PCR analysis showed that EGFR, GRIN2B, GJA1, CAP2, MIF, POLR2A, PRKACA, GABARAP, TLN1 and PXN might be involved in the advancement of T1D. Molecular docking studies showed high docking score. Conclusions DEGs and hub genes identified in the present investigation help us understand the molecular mechanisms underlying the advancement of T1D, and provide candidate targets for diagnosis and treatment of T1D.

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Receptor Mincle promotes skin allergies and is capable of recognizing cholesterol sulfate

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1611665114 ◽

2017 ◽

Vol 114 (13) ◽

pp. E2758-E2765 ◽

Cited By ~ 31

Author(s):

Alexey V. Kostarnoy ◽

Petya G. Gancheva ◽

Bernd Lepenies ◽

Amir I. Tukhvatulin ◽

Alina S. Dzharullaeva ◽

...

Keyword(s):

Immune System ◽

Inflammatory Response ◽

Innate Immune System ◽

Molecular Mechanisms ◽

Tissue Injury ◽

Innate Immune ◽

Sterile Inflammation ◽

Skin Damage ◽

Cholesterol Sulfate ◽

Local Inflammatory Response

Sterile (noninfected) inflammation underlies the pathogenesis of many widespread diseases, such as allergies and autoimmune diseases. The evolutionarily conserved innate immune system is considered to play a key role in tissue injury recognition and the subsequent development of sterile inflammation; however, the underlying molecular mechanisms are not yet completely understood. Here, we show that cholesterol sulfate, a molecule present in relatively high concentrations in the epithelial layer of barrier tissues, is selectively recognized by Mincle (Clec4e), a C-type lectin receptor of the innate immune system that is strongly up-regulated in response to skin damage. Mincle activation by cholesterol sulfate causes the secretion of a range of proinflammatory mediators, and s.c. injection of cholesterol sulfate results in a Mincle-mediated induction of a severe local inflammatory response. In addition, our study reveals a role of Mincle as a driving component in the pathogenesis of allergic skin inflammation. In a well-established model of allergic contact dermatitis, the absence of Mincle leads to a significant suppression of the magnitude of the skin inflammatory response as assessed by changes in ear thickness, myeloid cell infiltration, and cytokine and chemokine secretion. Taken together, our results provide a deeper understanding of the fundamental mechanisms underlying sterile inflammation.

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Lipopolysaccharide of the Yersinia pseudotuberculosis Complex

Biomolecules ◽

10.3390/biom11101410 ◽

2021 ◽

Vol 11 (10) ◽

pp. 1410

Author(s):

Yuriy A. Knirel ◽

Andrey P. Anisimov ◽

Angelina A. Kislichkina ◽

Anna N. Kondakova ◽

Olga V. Bystrova ◽

...

Keyword(s):

Immune System ◽

Innate Immune System ◽

Molecular Mechanisms ◽

Yersinia Pseudotuberculosis ◽

Cell Envelope ◽

Innate Immune ◽

Gram Negative Bacteria ◽

Gram Negative ◽

Outer Leaflet ◽

Major Surface

Lipopolysaccharide (LPS), localized in the outer leaflet of the outer membrane, serves as the major surface component of the Gram-negative bacterial cell envelope responsible for the activation of the host’s innate immune system. Variations of the LPS structure utilized by Gram-negative bacteria promote survival by providing resistance to components of the innate immune system and preventing recognition by TLR4. This review summarizes studies of the biosynthesis of Yersinia pseudotuberculosis complex LPSs, and the roles of their structural components in molecular mechanisms of yersiniae pathogenesis and immunogenesis.

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HDACi: molecular mechanisms and therapeutic implications in the innate immune system

Immunology and Cell Biology ◽

10.1038/icb.2011.92 ◽

2011 ◽

Vol 90 (1) ◽

pp. 23-32 ◽

Cited By ~ 27

Author(s):

Bandar Ali Suliman ◽

Dakang Xu ◽

Bryan RG Williams

Keyword(s):

Immune System ◽

Innate Immune System ◽

Molecular Mechanisms ◽

Innate Immune ◽

Therapeutic Implications

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Regulation of plant antiviral defense genes via host RNA-silencing mechanisms

Virology Journal ◽

10.1186/s12985-021-01664-3 ◽

2021 ◽

Vol 18 (1) ◽

Author(s):

Paola Leonetti ◽

Johannes Stuttmann ◽

Vitantonio Pantaleo

Keyword(s):

Immune System ◽

Innate Immune System ◽

Rna Silencing ◽

Molecular Mechanisms ◽

Limited Range ◽

Innate Immune ◽

Transcriptional Level ◽

Regulatory Systems ◽

Viral Components ◽

Resistance To Viruses

Abstract Background Plants in nature or crops in the field interact with a multitude of beneficial or parasitic organisms, including bacteria, fungi and viruses. Viruses are highly specialized to infect a limited range of host plants, leading in extreme cases to the full invasion of the host and a diseased phenotype. Resistance to viruses can be mediated by various passive or active mechanisms, including the RNA-silencing machinery and the innate immune system. Main text RNA-silencing mechanisms may inhibit viral replication, while viral components can elicit the innate immune system. Viruses that successfully enter the plant cell can elicit pattern-triggered immunity (PTI), albeit by yet unknown mechanisms. As a counter defense, viruses suppress PTI. Furthermore, viral Avirulence proteins (Avr) may be detected by intracellular immune receptors (Resistance proteins) to elicit effector-triggered immunity (ETI). ETI often culminates in a localized programmed cell death reaction, the hypersensitive response (HR), and is accompanied by a potent systemic defense response. In a dichotomous view, RNA silencing and innate immunity are seen as two separate mechanisms of resistance. Here, we review the intricate connections and similarities between these two regulatory systems, which are collectively required to ensure plant fitness and resilience. Conclusions The detailed understanding of immune regulation at the transcriptional level provides novel opportunities for enhancing plant resistance to viruses by RNA-based technologies. However, extensive use of RNA technologies requires a thorough understanding of the molecular mechanisms of RNA gene regulation. We describe the main examples of host RNA-mediated regulation of virus resistance.

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