Remarkable Role of Indoleamine 2,3-Dioxygenase and Tryptophan Metabolites in Infectious Diseases: Potential Role in Macrophage-Mediated Inflammatory Diseases

Indoleamine 2,3-dioxygenase 1 (IDO1), the L-tryptophan-degrading enzyme, plays a key role in the immunomodulatory effects on several types of immune cells. Originally known for its regulatory function during pregnancy and chronic inflammation in tumorigenesis, the activity of IDO1 seems to modify the inflammatory state of infectious diseases. The pathophysiologic activity of L-tryptophan metabolites, kynurenines, is well recognized. Therefore, an understanding of the regulation of IDO1 and the subsequent biochemical reactions is essential for the design of therapeutic strategies in certain immune diseases. In this paper, current knowledge about the role of IDO1 and its metabolites during various infectious diseases is presented. Particularly, the regulation of type I interferons (IFNs) production via IDO1 in virus infection is discussed. This paper offers insights into new therapeutic strategies in the modulation of viral infection and several immune-related disorders.

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TBK1 recruitment to STING mediates autoinflammatory arthritis caused by defective DNA clearance

Journal of Experimental Medicine ◽

10.1084/jem.20211539 ◽

2021 ◽

Vol 219 (1) ◽

Author(s):

Tong Li ◽

Seoyun Yum ◽

Minghao Li ◽

Xiang Chen ◽

Xiaoxia Zuo ◽

...

Keyword(s):

Neutralizing Antibodies ◽

Therapeutic Strategy ◽

Inflammatory Diseases ◽

Type I Interferons ◽

Type I ◽

Disease Manifestation ◽

Dnase Ii ◽

Interferon Induction ◽

Tnf Α

Defective DNA clearance in DNase II−/− mice leads to lethal inflammatory diseases that can be rescued by deleting cGAS or STING, but the role of distinct signaling pathways downstream of STING in the disease manifestation is not known. We found that the STING S365A mutation, which abrogates IRF3 binding and type I interferon induction, rescued the embryonic lethality of DNase II−/− mice. However, the STING S365A mutant retains the ability to recruit TBK1 and activate NF-κB, and DNase II−/−STING-S365A mice exhibited severe polyarthritis, which was alleviated by neutralizing antibodies against TNF-α or IL-6 receptor. In contrast, the STING L373A mutation or C-terminal tail truncation, which disrupts TBK1 binding and therefore prevents activation of both IRF3 and NF-κB, completely rescued the phenotypes of DNase II−/− mice. These results demonstrate that TBK1 recruitment to STING mediates autoinflammatory arthritis independently of type I interferons. Inhibiting TBK1 binding to STING may be a therapeutic strategy for certain autoinflammatory diseases instigated by self-DNA.

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The Complexity of the cGAS-STING Pathway in CNS Pathologies

Frontiers in Neuroscience ◽

10.3389/fnins.2021.621501 ◽

2021 ◽

Vol 15 ◽

Author(s):

Amelia L. Fryer ◽

Amar Abdullah ◽

Juliet M. Taylor ◽

Peter J. Crack

Keyword(s):

Current Knowledge ◽

Adaptor Protein ◽

Type I Interferons ◽

Type I ◽

Type I Ifns ◽

Upstream Regulator ◽

Therapeutic Opportunity ◽

Sting Pathway ◽

Mediate Inflammation

Neuroinflammation driven by type-I interferons in the CNS is well established to exacerbate the progression of many CNS pathologies both acute and chronic. The role of adaptor protein Stimulator of Interferon Genes (STING) is increasingly appreciated to instigate type-I IFN-mediated neuroinflammation. As an upstream regulator of type-I IFNs, STING modulation presents a novel therapeutic opportunity to mediate inflammation in the CNS. This review will detail the current knowledge of protective and detrimental STING activity in acute and chronic CNS pathologies and the current therapeutic avenues being explored.

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The Role of Toll-Like Receptors and Type I Interferons in Host Responses to Bacteria

Current Immunology Reviews ◽

10.2174/157339509788166994 ◽

2009 ◽

Vol 5 (2) ◽

pp. 143-149

Author(s):

Marja Ojaniemi ◽

Mari Liljeroos ◽

Reetta Vuolteenaho

Keyword(s):

Type I Interferons ◽

Host Responses ◽

Type I ◽

Toll Like Receptors

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The Abstruse Side of Type I Interferon Immunotherapy for COVID-19 Cases with Comorbidities

Journal of Respiration ◽

10.3390/jor1010005 ◽

2021 ◽

Vol 1 (1) ◽

pp. 49-59

Author(s):

Selvakumar Subbian

Keyword(s):

Infectious Diseases ◽

Disease Severity ◽

Type I Interferon ◽

Host Factors ◽

Type I ◽

The Novel ◽

Inflammatory Drugs ◽

Precautionary Measures ◽

Inducible Genes

The Coronavirus Disease-2019 (COVID-19) pandemic, caused by the novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has claimed 1.2 million people globally since December 2019. Although the host factors underpinning COVID-19 pathology are not fully understood, type I interferon (IFN-I) response is considered crucial for SARS-CoV-2 pathogenesis. Perturbations in IFN-I signaling and associated interferon-inducible genes (ISG) are among the primary disease severity indicators in COVID-19. Consequently, IFN-I therapy, either alone or in- combination with existing antiviral or anti-inflammatory drugs, is tested in many ongoing clinical trials to reduce COVID-19 mortality. Since signaling by the IFN-I family of molecules regulates host immune response to other infectious and non-infectious diseases, any imbalance in this family of cytokines would impact the clinical outcome of COVID-19, as well as other co-existing diseases. Therefore, it is imperative to evaluate the beneficial-versus-detrimental effects of IFN-I immunotherapy for COVID-19 patients with divergent disease severity and other co-existing conditions. This review article summarizes the role of IFN-I signaling in infectious and non-infectious diseases of humans. It highlights the precautionary measures to be considered before administering IFN-I to COVID-19 patients having other co-existing disorders. Finally, suggestions are proposed to improve IFN-I immunotherapy to COVID-19.

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Bacterial Cyclic Dinucleotides and the cGAS–cGAMP–STING Pathway: A Role in Periodontitis?

Pathogens ◽

10.3390/pathogens10060675 ◽

2021 ◽

Vol 10 (6) ◽

pp. 675

Author(s):

Samira Elmanfi ◽

Mustafa Yilmaz ◽

Wilson W. S. Ong ◽

Kofi S. Yeboah ◽

Herman O. Sintim ◽

...

Keyword(s):

Immune Response ◽

Periodontal Disease ◽

Innate Immune ◽

Host Cells ◽

Type I Interferons ◽

Type I ◽

Vaccine Adjuvants ◽

Cyclic Dinucleotides ◽

Sting Pathway

Host cells can recognize cytosolic double-stranded DNAs and endogenous second messengers as cyclic dinucleotides—including c-di-GMP, c-di-AMP, and cGAMP—of invading microbes via the critical and essential innate immune signaling adaptor molecule known as STING. This recognition activates the innate immune system and leads to the production of Type I interferons and proinflammatory cytokines. In this review, we (1) focus on the possible role of bacterial cyclic dinucleotides and the STING/TBK1/IRF3 pathway in the pathogenesis of periodontal disease and the regulation of periodontal immune response, and (2) review and discuss activators and inhibitors of the STING pathway as immune response regulators and their potential utility in the treatment of periodontitis. PubMed/Medline, Scopus, and Web of Science were searched with the terms “STING”, “TBK 1”, “IRF3”, and “cGAS”—alone, or together with “periodontitis”. Current studies produced evidence for using STING-pathway-targeting molecules as part of anticancer therapy, and as vaccine adjuvants against microbial infections; however, the role of the STING/TBK1/IRF3 pathway in periodontal disease pathogenesis is still undiscovered. Understanding the stimulation of the innate immune response by cyclic dinucleotides opens a new approach to host modulation therapies in periodontology.

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Molecular pathogenesis and clinical implications of eczema herpeticum

Expert Reviews in Molecular Medicine ◽

10.1017/s1462399408000756 ◽

2008 ◽

Vol 10 ◽

Cited By ~ 27

Author(s):

Caroline Bussmann ◽

Wen-Ming Peng ◽

Thomas Bieber ◽

Natalija Novak

Keyword(s):

Atopic Dermatitis ◽

Age Of Onset ◽

Current Knowledge ◽

Allergen Challenge ◽

Skin Lesions ◽

Molecular Pathogenesis ◽

Type I Interferons ◽

Total Serum ◽

Type I ◽

Eczema Herpeticum

A subgroup of patients with atopic dermatitis develops one or more episodes of a severe viral skin infection caused by herpes simplex virus superimposed on eczematous skin lesions. This condition is named atopic dermatitis complicated by eczema herpeticum. Characteristic features of patients developing eczema herpeticum include an early age of onset of atopic dermatitis with a persistent and severe course into adulthood, predilection for eczematous skin lesions in the head and neck area, elevated total serum IgE levels and increased allergen sensitisation. Deficiencies at the level of both the innate and the adaptive immune system, which have been identified in atopic dermatitis, are much more pronounced in this subgroup. Predisposing cellular factors include a reduced number of plasmacytoid dendritic cells in the epidermis and a modified capacity of these cells to produce type I interferons after allergen challenge. In addition, lower levels of antimicrobial peptides in the skin of atopic dermatitis patients, resulting in part from a Th2-prone micromilieu, contribute to the lack of an effective defence against viral attack. In this review, we summarise the current knowledge of the molecular pathogenesis of eczema herpeticum.

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