The landscape of different molecular modules in an immune microenvironment during tuberculosis infection

Abstract Tuberculosis is a chronic inflammatory disease caused by Mycobacterium tuberculosis. When tuberculosis invades the human body, innate immunity is the first line of defense. However, how the innate immune microenvironment responds remains unclear. In this research, we studied the function of each type of cell and explained the principle of an immune microenvironment. Based on the differences in the innate immune microenvironment, we modularized the analysis of the response of five immune cells and two structural cells. The results showed that in the innate immune stress response, the genes CXCL3, PTGS2 and TNFAIP6 regulated by the nuclear factor kappa B(NK-KB) pathway played a crucial role in fighting against tuberculosis. Based on the active pathway algorithm, each immune cell showed metabolic heterogeneity. Besides, after tuberculosis infection, structural cells showed a chemotactic immunity effect based on the co-expression immunoregulatory module.

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Novel Functions of IFI44L as a Feedback Regulator of Host Antiviral Responses

Journal of Virology ◽

10.1128/jvi.01159-19 ◽

2019 ◽

Vol 93 (21) ◽

Cited By ~ 9

Author(s):

Marta L. DeDiego ◽

Luis Martinez-Sobrido ◽

David J. Topham

Keyword(s):

Immune Responses ◽

Nuclear Factor Kappa B ◽

Virus Production ◽

Innate Immune ◽

Type I ◽

Nuclear Factor ◽

Innate Immune Responses ◽

Virus Infections ◽

Nuclear Factor Kappa ◽

Ifn Treatment

ABSTRACT We describe a novel function for the interferon (IFN)-induced protein 44-like (IFI44L) gene in negatively modulating innate immune responses induced after virus infections. Furthermore, we show that decreasing IFI44L expression impairs virus production and that IFI44L expression negatively modulates the antiviral state induced by an analog of double-stranded RNA (dsRNA) or by IFN treatment. The mechanism likely involves the interaction of IFI44L with cellular FK506-binding protein 5 (FKBP5), which in turn interacts with kinases essential for type I and III IFN responses, such as inhibitor of nuclear factor kappa B (IκB) kinase alpha (IKKα), IKKβ, and IKKε. Consequently, binding of IFI44L to FKBP5 decreased interferon regulatory factor 3 (IRF-3)-mediated and nuclear factor kappa-B (NF-κB) inhibitor (IκBα)-mediated phosphorylation by IKKε and IKKβ, respectively. According to these results, IFI44L is a good target for treatment of diseases associated with excessive IFN levels and/or proinflammatory responses and for reduction of viral replication. IMPORTANCE Excessive innate immune responses can be deleterious for the host, and therefore, negative feedback is needed. Here, we describe a completely novel function for IFI44L in negatively modulating innate immune responses induced after virus infections. In addition, we show that decreasing IFI44L expression impairs virus production and that IFI44L expression negatively modulates the antiviral state induced by an analog of dsRNA or by IFN treatment. IFI44L binds to the cellular protein FKBP5, which in turn interacts with kinases essential for type I and III IFN induction and signaling, such as the kinases IKKα, IKKβ, and IKKε. IFI44L binding to FKBP5 decreased the phosphorylation of IRF-3 and IκBα mediated by IKKε and IKKβ, respectively, providing an explanation for the function of IFI44L in negatively modulating IFN responses. Therefore, IFI44L is a candidate target for reducing virus replication.

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Lack of NOD2 attenuates ovariectomy-induced bone loss via inhibition of osteoclasts

Journal of Endocrinology ◽

10.1530/joe-16-0591 ◽

2017 ◽

Vol 235 (2) ◽

pp. 85-96 ◽

Cited By ~ 8

Author(s):

Ke Ke ◽

Ok-Joo Sul ◽

Soo-Wol Chung ◽

Jae-Hee Suh ◽

Hye-Seon Choi

Keyword(s):

Bone Loss ◽

Nuclear Factor Kappa B ◽

Nicotinamide Adenine Dinucleotide Phosphate ◽

Nuclear Factor Κb ◽

Innate Immune ◽

Nuclear Factor ◽

Oxygen Species ◽

Receptor Activator ◽

Recognition Receptor ◽

Oligomerization Domain

Nucleotide-binding oligomerization domain-2 (NOD2) is a pattern recognition receptor of the innate immune system. It interacts with serine–threonine kinases to induce activation of nuclear factor κB (NF-κB), which is important for receptor activator of nuclear factor kappa-B ligand (RANKL) signaling. We tested the idea that NOD2 modulates bone metabolism via an action on osteoclasts (OCs). The absence of NOD2 reduced ovariectomy-induced bone loss in mice, and lowered the area and the activity of OCs, by impairing RANKL signaling. It also reduced the level of reactive oxygen species (ROS), as well as of NF-κB-DNA binding upon RANKL exposure. NOD2 was found to physically interact with nicotinamide adenine dinucleotide phosphate oxidase 1, and this led to increased production of ROS in OCs. Our data suggest that NOD2 contributes to bone loss in estrogen deficiency by elevating ROS levels in OCs.

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The Cutaneous Wound Innate Immunological Microenvironment

International Journal of Molecular Sciences ◽

10.3390/ijms21228748 ◽

2020 ◽

Vol 21 (22) ◽

pp. 8748

Author(s):

Stephen Kirchner ◽

Vivian Lei ◽

Amanda S. MacLeod

Keyword(s):

Immune Response ◽

Wound Repair ◽

Immune Cell ◽

Skin Barrier ◽

Innate Immune ◽

Immune Microenvironment ◽

Cell Recruitment ◽

Adaptive Processes ◽

Immune Cell Recruitment

The skin represents the first line of defense and innate immune protection against pathogens. Skin normally provides a physical barrier to prevent infection by pathogens; however, wounds, microinjuries, and minor barrier impediments can present open avenues for invasion through the skin. Accordingly, wound repair and protection from invading pathogens are essential processes in successful skin barrier regeneration. To repair and protect wounds, skin promotes the development of a specific and complex immunological microenvironment within and surrounding the disrupted tissue. This immune microenvironment includes both innate and adaptive processes, including immune cell recruitment to the wound and secretion of extracellular factors that can act directly to promote wound closure and wound antimicrobial defense. Recent work has shown that this immune microenvironment also varies according to the specific context of the wound: the microbiome, neuroimmune signaling, environmental effects, and age play roles in altering the innate immune response to wounding. This review will focus on the role of these factors in shaping the cutaneous microenvironment and how this ultimately impacts the immune response to wounding.

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The link between the genetic polymorphisms of the innate immune signaling molecular factors with periodontitis

Journal of Biological Research - Bollettino della Società Italiana di Biologia Sperimentale ◽

10.4081/jbr.2018.7202 ◽

2018 ◽

Vol 91 (1) ◽

Author(s):

Gurumoorthy Kaarthikeyan ◽

Anandan Balakrishnan ◽

Nadathur Doraisamy Jayakumar

Keyword(s):

Genetic Polymorphisms ◽

Chronic Inflammatory Disease ◽

Innate Immune ◽

Periodontal Pathogens ◽

First Line ◽

Immune Signaling ◽

Multiple Risk Factors ◽

Innate Immune Signaling ◽

Innate Immune Mechanism ◽

Periodontal Destruction

Periodontitis is a chronic inflammatory disease causing destruction of supporting tissues of teeth. Even though the gramnegative anaerobes are essential for the initiation of periodontal destruction, multiple risk factors are essential for the progression of the disease. The genetic risk factor plays a significant role in the etiopathogenesis of periodontal disease. The innate immune mechanism is the first line of defense in screening and combating the invading periodontal pathogens. The genetic polymorphisms in the 3’UTR region of the innate immune signaling molecular factors like toll-like receptors, nod-like receptors and the polymorphisms in the epigenetic regulators of these factors like microRNA146a, apolipoproteinE might play an important role in the etiopathogenesis of periodontal destruction.

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Altered gene expression of the innate immune, neuroendocrine, and nuclear factor-kappa B (NF-κB) systems is associated with posttraumatic stress disorder in military personnel

Journal of Anxiety Disorders ◽

10.1016/j.janxdis.2015.12.004 ◽

2016 ◽

Vol 38 ◽

pp. 9-20 ◽

Cited By ~ 26

Author(s):

Pedro Guardado ◽

Anlys Olivera ◽

Heather L. Rusch ◽

Michael Roy ◽

Christiana Martin ◽

...

Keyword(s):

Gene Expression ◽

Posttraumatic Stress Disorder ◽

Posttraumatic Stress ◽

Military Personnel ◽

Nuclear Factor Kappa B ◽

Stress Disorder ◽

Innate Immune ◽

Nuclear Factor ◽

Altered Gene Expression ◽

Altered Gene

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A nuclear factor-kappa B inhibiting peptide suppresses innate immune receptors and gliosis in a transgenic mouse model of Alzheimer’s disease

Biomedicine & Pharmacotherapy ◽

10.1016/j.biopha.2021.111405 ◽

2021 ◽

Vol 138 ◽

pp. 111405

Author(s):

Alison Lindsay ◽

Deborah Hickman ◽

Mythily Srinivasan

Keyword(s):

Alzheimer’S Disease ◽

Mouse Model ◽

Transgenic Mouse ◽

Nuclear Factor Kappa B ◽

Transgenic Mouse Model ◽

Innate Immune ◽

Nuclear Factor ◽

Immune Receptors ◽

Nuclear Factor Kappa ◽

Model Of Alzheimer’S Disease

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Hepatitis B Surface Antigen Suppresses the Activation of Nuclear Factor Kappa B Pathway via Interaction With the TAK1-TAB2 Complex

Frontiers in Immunology ◽

10.3389/fimmu.2021.618196 ◽

2021 ◽

Vol 12 ◽

Author(s):

Feiyan Deng ◽

Gang Xu ◽

Zhikui Cheng ◽

Yu Huang ◽

Caijiao Ma ◽

...

Keyword(s):

Hepatitis B ◽

Immune Responses ◽

Nuclear Factor Kappa B ◽

Immune Escape ◽

Hepatitis B Surface Antigen ◽

Innate Immune ◽

Nuclear Factor ◽

Major Health Problem ◽

Nuclear Factor Kappa ◽

Autophagic Degradation

Chronic hepatitis B is a major health problem worldwide, with more than 250 million chronic carriers. Hepatitis B virus interferes with the host innate immune system so as to evade elimination via almost all of its constituent proteins; nevertheless, the function of HBsAg with respect to immune escape remains unclear. This study aimed to determine the role HBsAg plays in assisting HBV to escape from immune responses. We found that HBsAg suppressed the activation of the nuclear factor kappa B (NF-кB) pathway, leading to downregulation of innate immune responses. HBsAg interacted with TAK1 and TAB2 specifically, inhibiting the phosphorylation and polyubiquitination of TAK1 and the K63-linked polyubiquitination of TAB2. Autophagy is a major catabolic process participating in many cellular processes, including the life cycle of HBV. We found that HBsAg promoted the autophagic degradation of TAK1 and TAB2 via the formation of complexes with TAK1 and TAB2, resulting in suppression of the NF-κB pathway. The expression of TAK1, TAB2, and the translocation of NF-κB inversely correlated with HBsAg levels in clinical liver tissues. Taken together, our findings suggest a novel mechanism by which HBsAg interacts with TAK1-TAB2 complex and suppresses the activation of NF-κB signaling pathway via reduction of the post-translational modifications and autophagic degradation.

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Interferon-Induced Protein 44 Interacts with Cellular FK506-Binding Protein 5, Negatively Regulates Host Antiviral Responses, and Supports Virus Replication

mBio ◽

10.1128/mbio.01839-19 ◽

2019 ◽

Vol 10 (4) ◽

Cited By ~ 12

Author(s):

Marta L. DeDiego ◽

Aitor Nogales ◽

Luis Martinez-Sobrido ◽

David J. Topham

Keyword(s):

Immune Responses ◽

Virus Replication ◽

Nuclear Factor Kappa B ◽

Viral Infections ◽

Binding Protein ◽

Virus Production ◽

Innate Immune ◽

Nuclear Factor ◽

Innate Immune Responses ◽

Fk506 Binding Protein

ABSTRACT Using multiple viral systems, and performing silencing approaches, overexpression approaches, and experiments in knockout cells, we report, for the first time, that interferon (IFN)-induced protein 44 (IFI44) positively affects virus production and negatively modulates innate immune responses induced after viral infections. Moreover, IFI44 is able to rescue poly(I·C)- and IFN-mediated inhibition of virus growth. Furthermore, we report a novel interaction of IFI44 with the cellular factor FK506-binding protein 5 (FKBP5), which binds to cellular kinases such as the inhibitor of nuclear factor kappa B (IκB) kinases (IKKα, IKKβ, and IKKε). Importantly, in the presence of FKBP5, IFI44 decreases the ability of IKKβ to phosphorylate IκBα and the ability of IKKε to phosphorylate interferon regulatory factor 3 (IRF-3), providing a novel mechanism for the function of IFI44 in negatively modulating IFN responses. Remarkably, these new IFI44 functions may have implications for diseases associated with excessive immune signaling and for controlling virus infections mediated by IFN responses. IMPORTANCE Innate immune responses mediated by IFN and inflammatory cytokines are critical for controlling virus replication. Nevertheless, exacerbated innate immune responses could be detrimental for the host and feedback mechanisms are needed to maintain the cellular homeostasis. In this work, we describe a completely novel function for IFI44 in negatively modulating the innate immune responses induced after viral infections. We show that decreasing IFI44 expression by using small interfering RNAs (siRNAs) or by generating knockout (KO) cells impairs virus production and increases the levels of IFN responses. Moreover, we report a novel interaction of IFI44 with the cellular protein FKBP5, which in turn interacts with kinases essential for type I and III IFN induction and signaling, such as the inhibitor of nuclear factor kappa B (IκB) kinases IKKα, IKKβ, and IKKε. Our data indicate that binding of IFI44 to FKBP5 decreased the phosphorylation of IRF-3 and IκBα mediated by IKKε and IKKβ, respectively, providing a likely explanation for the function of IFI44 in negatively modulating IFN responses. These results provide new insights into the induction of innate immune responses and suggest that IFI44 is a new potential antiviral target for reducing virus replication.

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