Inborn Errors in the LRR Domain of Nod2 and Their Potential Consequences on the Function of the Receptor

The innate immune system plays a critical role in the early detection of pathogens, primarily by relying on pattern-recognition receptor (PRR) signaling molecules. Nucleotide-binding oligomerization domain 2 (NOD2) is a cytoplasmic receptor that recognizes invading molecules and danger signals inside the cells. Recent studies highlight the importance of NOD2′s function in maintaining the homeostasis of human body microbiota and innate immune responses, including induction of proinflammatory cytokines, regulation of autophagy, modulation of endoplasmic reticulum (ER) stress, etc. In addition, there is extensive cross-talk between NOD2 and the Toll-like receptors that are so important in the induction and tuning of adaptive immunity. Polymorphisms of NOD2′s encoding gene are associated with several pathological conditions, highlighting NOD2′s functional importance. In this study, we summarize NOD2′s role in cellular signaling pathways and take a look at the possible consequences of common NOD2 polymorphisms on the structure and function of this receptor.

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Critical Role of Plasmacytoid Dendritic Cells in Regulating Gene Expression and Innate Immune Responses to Human Rhinovirus-16

Frontiers in Immunology ◽

10.3389/fimmu.2017.01351 ◽

2017 ◽

Vol 8 ◽

Cited By ~ 6

Author(s):

Yang Xi ◽

Niamh M. Troy ◽

Denise Anderson ◽

Olga M. Pena ◽

Jason P. Lynch ◽

...

Keyword(s):

Gene Expression ◽

Dendritic Cells ◽

Immune Responses ◽

Critical Role ◽

Plasmacytoid Dendritic Cells ◽

Innate Immune ◽

Human Rhinovirus ◽

Innate Immune Responses

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The microbiota plays a critical role in the reactivity of lung immune components to innate ligands

10.1101/2020.10.19.345116 ◽

2020 ◽

Author(s):

Quentin Marquant ◽

Daphné Laubreton ◽

Carole Drajac ◽

Elliot Mathieu ◽

Edwige Bouguyon ◽

...

Keyword(s):

Immune Responses ◽

Critical Role ◽

Innate Immune ◽

Immune Reactivity ◽

Innate Immune Responses ◽

Plain Language ◽

Pulmonary Tissue ◽

Germ Free ◽

Syncytial Virus

AbstractThe microbiota contributes to shaping efficient and safe immune defenses in the gut. However, little is known about the role of the microbiota in the education of pulmonary innate immune responses. Here, we tested whether the endogenous microbiota can modulate reactivity of pulmonary tissue to pathogen stimuli by comparing the response of specific pathogen-free (SPF) and germ-free (GF) mice. Using SPF and GF mice intranasally exposed to lipopolysaccharide (LPS), a component of Gram-negative bacteria, we observed earlier and greater inflammation in the pulmonary compartment of GF mice than that of SPF mice. Toll-like receptor 4 (TLR4) was more abundantly expressed in the lungs of GF mice than those of SPF mice at steady state, which could predispose the innate immunity of GF mice to strongly react to environmental stimuli. Lung explants were stimulated with different TLR agonists or infected with the human airways pathogen, respiratory syncytial virus (RSV), resulting in greater inflammation under almost all conditions for the GF explants. Finally, alveolar macrophages (AM) from GF mice presented a higher innate immune response upon RSV infection than those of SPF mice. Overall, these data suggest that the presence of microbiota in SPF mice induced a process of innate immune tolerance in the lungs by a mechanism which remains to be elucidated. Our study represents a step forward to establishing the link between the microbiota and the immune reactivity of the lungs.Plain Language summaryMicrobiota represents an important partner of immunologic system at the interface between immune cells and epithelium. It is well known, notably in the gut, that the microbiota contributes in shaping efficient and safe defenses. However, little is known about the role of the microbiota in the education of pulmonary innate immune responses. In this study, we postulate that endogenous microbiota could dampen an excessive reactivity of pulmonary tissue to external stimuli. Thus, we sought to study the innate immune reaction switched on by viral or bacterial ligands in respiratory tract cells coming from mice with or without microbiota (germ-free condition, GF). Altogether, our results show a higher inflammatory reaction in GF condition. This study represents a step forward to better establish the link between the microbiota and the reactivity of the lung tissue. Not only these data demonstrate that the microbiota educates the pulmonary innate immune system, but also contributes the emerging concept of using respiratory commensal bacteria as potential next-generation probiotics to prevent susceptibility to respiratory diseases.

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Immunoglobulins with Non-Canonical Functions in Inflammatory and Autoimmune Disease States

International Journal of Molecular Sciences ◽

10.3390/ijms21155392 ◽

2020 ◽

Vol 21 (15) ◽

pp. 5392 ◽

Cited By ~ 1

Author(s):

Evgeny A. Ermakov ◽

Georgy A. Nevinsky ◽

Valentina N. Buneva

Keyword(s):

Ivig Therapy ◽

Intravenous Immunoglobulins ◽

Innate Immune ◽

Catalytic Antibodies ◽

Human Antibody ◽

Therapeutic Effects ◽

Innate Immune Responses ◽

Disease States ◽

Pathological Conditions ◽

Classical Immunoglobulin

Immunoglobulins are known to combine various effector mechanisms of the adaptive and the innate immune system. Classical immunoglobulin functions are associated with antigen recognition and the initiation of innate immune responses. However, in addition to classical functions, antibodies exhibit a variety of non-canonical functions related to the destruction of various pathogens due to catalytic activity and cofactor effects, the action of antibodies as agonists/antagonists of various receptors, the control of bacterial diversity of the intestine, etc. Canonical and non-canonical functions reflect the extreme human antibody repertoire and the variety of antibody types generated in the organism: antigen-specific, natural, polyreactive, broadly neutralizing, homophilic, bispecific and catalytic. The therapeutic effects of intravenous immunoglobulins (IVIg) are associated with both the canonical and non-canonical functions of antibodies. In this review, catalytic antibodies will be considered in more detail, since their formation is associated with inflammatory and autoimmune diseases. We will systematically summarize the diversity of catalytic antibodies in normal and pathological conditions. Translational perspectives of knowledge about natural antibodies for IVIg therapy will be also discussed.

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Nucleotide-binding oligomerization domain 2 (Nod2) is dispensable for the innate immune responses of macrophages against Yersinia enterocolitica

The Journal of Microbiology ◽

10.1007/s12275-012-1534-6 ◽

2012 ◽

Vol 50 (3) ◽

pp. 489-495 ◽

Cited By ~ 7

Author(s):

Yu-Jin Jeong ◽

Chang-Hwan Kim ◽

Eun-Jung Song ◽

Min-Jung Kang ◽

Jee-Cheon Kim ◽

...

Keyword(s):

Immune Responses ◽

Yersinia Enterocolitica ◽

Nucleotide Binding ◽

Innate Immune ◽

Innate Immune Responses ◽

Oligomerization Domain

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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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Osteoarthritis and Toll-Like Receptors: When Innate Immunity Meets Chondrocyte Apoptosis

Biology ◽

10.3390/biology9040065 ◽

2020 ◽

Vol 9 (4) ◽

pp. 65

Author(s):

Goncalo Barreto ◽

Mikko Manninen ◽

Kari K. Eklund

Keyword(s):

Inflammatory Responses ◽

Critical Role ◽

Innate Immune ◽

Chondrocyte Apoptosis ◽

Innate Immune Responses ◽

Toll Like Receptors ◽

Chondrocyte Death ◽

Dominant Feature ◽

Functional Relevance

Osteoarthritis (OA) has long been viewed as a degenerative disease of cartilage, but accumulating evidence indicates that inflammation has a critical role in its pathogenesis. In particular, chondrocyte-mediated inflammatory responses triggered by the activation of innate immune receptors by alarmins (also known as danger signals) are thought to be involved. Thus, toll-like receptors (TLRs) and their signaling pathways are of particular interest. Recent reports suggest that among the TLR-induced innate immune responses, apoptosis is one of the critical events. Apoptosis is of particular importance, given that chondrocyte death is a dominant feature in OA. This review focuses on the role of TLR signaling in chondrocytes and the role of TLR activation in chondrocyte apoptosis. The functional relevance of TLR and TLR-triggered apoptosis in OA are discussed as well as their relevance as candidates for novel disease-modifying OA drugs (DMOADs).

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Evolutionary and structural analysis of SARS-CoV-2 specific evasion of host immunity

Genes and Immunity ◽

10.1038/s41435-020-00120-6 ◽

2020 ◽

Vol 21 (6-8) ◽

pp. 409-419

Author(s):

Irfan Hussain ◽

Nashaiman Pervaiz ◽

Abbas Khan ◽

Shoaib Saleem ◽

Huma Shireen ◽

...

Keyword(s):

Immune Responses ◽

Nonstructural Protein ◽

Critical Role ◽

Clinical Manifestations ◽

Host Immunity ◽

Innate Immune ◽

Host Immune System ◽

Innate Immune Responses ◽

In Vivo Models

AbstractThe outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is spreading fast worldwide. There is a pressing need to understand how the virus counteracts host innate immune responses. Deleterious clinical manifestations of coronaviruses have been associated with virus-induced direct dysregulation of innate immune responses occurring via viral macrodomains located within nonstructural protein-3 (Nsp3). However, no substantial information is available concerning the relationship of macrodomains to the unusually high pathogenicity of SARS-CoV-2. Here, we show that structural evolution of macrodomains may impart a critical role to the unique pathogenicity of SARS-CoV-2. Using sequence, structural, and phylogenetic analysis, we identify a specific set of historical substitutions that recapitulate the evolution of the macrodomains that counteract host immune response. These evolutionary substitutions may alter and reposition the secondary structural elements to create new intra-protein contacts and, thereby, may enhance the ability of SARS-CoV-2 to inhibit host immunity. Further, we find that the unusual virulence of this virus is potentially the consequence of Darwinian selection‐driven epistasis in protein evolution. Our findings warrant further characterization of macrodomain-specific evolutionary substitutions in in vitro and in vivo models to determine their inhibitory effects on the host immune system.

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The Many Roles of Galectin-3, a Multifaceted Molecule, in Innate Immune Responses against Pathogens

Mediators of Inflammation ◽

10.1155/2017/9247574 ◽

2017 ◽

Vol 2017 ◽

pp. 1-10 ◽

Cited By ~ 42

Author(s):

Laura Díaz-Alvarez ◽

Enrique Ortega

Keyword(s):

Immune Responses ◽

Innate Immune ◽

Innate Immune Responses ◽

Terminal Protein ◽

Molecular Pattern ◽

Evolutionarily Conserved ◽

Carbohydrate Recognition Domains ◽

Galectin 3 ◽

The Many ◽

Recognition Receptor

Galectins are a group of evolutionarily conserved proteins with the ability to bindβ-galactosides through characteristic carbohydrate-recognition domains (CRD). Galectin-3 is structurally unique among all galectins as it contains a C-terminal CRD linked to an N-terminal protein-binding domain, being the only chimeric galectin. Galectin-3 participates in many functions, both intra- and extracellularly. Among them, a prominent role for Galectin-3 in inflammation has been recognized. Galectin-3 has also been shown to directly bind to pathogens and to have various effects on the functions of the cells of the innate immune system. Thanks to these two properties, Galectin-3 participates in several ways in the innate immune response against invading pathogens. Galectin-3 has been proposed to function not only as a pattern-recognition receptor (PRR) but also as a danger-associated molecular pattern (DAMP). In this review, we analyze the various roles that have been assigned to Galectin-3, both as a PRR and as a DAMP, in the context of immune responses against pathogenic microorganisms.

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