Toll-like receptors in sepsis-associated cytokine storm and their endogenous negative regulators as future immunomodulatory targets

Kumar, Vijay

doi:10.1016/j.intimp.2020.107087

Cited by 153 publications

(116 citation statements)

References 356 publications

(514 reference statements)

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“…Each receptor type is specific for limited classes of PAMPs and DAMPs. Among the most common PAMPs, TLR 1 recognizes triacyl lipopeptides; TLR2, diacyl lipopeptides and glycolipids; TLR3, double-stranded RNA and polyI:C, an artificial double-stranded RNA-like polymer used as an adjuvant; TLR4 recognizes lipopolysaccharides (LPS), heat shock proteins, fibrinogen and related proteins; TLR 5, flagellins; TLR6, diacyl lipoproteins; TLRs 7 and 8, single-stranded RNA; TLR9, viral and bacterial (CpG) DNA, which differs from eukaryotic DNA in having unmodified bases singularly characteristic of microbes and TLR10 recognizes retroviral proteins [ 47 ]. (Note that TLR10 has been omitted from the schematic diagrams below and further text discussions, because there is no evidence at present that retroviruses play a role in sepsis, ALI or ARDS in general or in COVID-19 in particular.)…”

Section: Innate Immune System Receptor Activation In Cytokine Stormentioning

confidence: 99%

Innate Receptor Activation Patterns Involving TLR and NLR Synergisms in COVID-19, ALI/ARDS and Sepsis Cytokine Storms: A Review and Model Making Novel Predictions and Therapeutic Suggestions

Root‐Bernstein

2021

IJMS

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Severe COVID-19 is characterized by a “cytokine storm”, the mechanism of which is not yet understood. I propose that cytokine storms result from synergistic interactions among Toll-like receptors (TLR) and nucleotide-binding oligomerization domain-like receptors (NLR) due to combined infections of SARS-CoV-2 with other microbes, mainly bacterial and fungal. This proposition is based on eight linked types of evidence and their logical connections. (1) Severe cases of COVID-19 differ from healthy controls and mild COVID-19 patients in exhibiting increased TLR4, TLR7, TLR9 and NLRP3 activity. (2) SARS-CoV-2 and related coronaviruses activate TLR3, TLR7, RIG1 and NLRP3. (3) SARS-CoV-2 cannot, therefore, account for the innate receptor activation pattern (IRAP) found in severe COVID-19 patients. (4) Severe COVID-19 also differs from its mild form in being characterized by bacterial and fungal infections. (5) Respiratory bacterial and fungal infections activate TLR2, TLR4, TLR9 and NLRP3. (6) A combination of SARS-CoV-2 with bacterial/fungal coinfections accounts for the IRAP found in severe COVID-19 and why it differs from mild cases. (7) Notably, TLR7 (viral) and TLR4 (bacterial/fungal) synergize, TLR9 and TLR4 (both bacterial/fungal) synergize and TLR2 and TLR4 (both bacterial/fungal) synergize with NLRP3 (viral and bacterial). (8) Thus, a SARS-CoV-2-bacterium/fungus coinfection produces synergistic innate activation, resulting in the hyperinflammation characteristic of a cytokine storm. Unique clinical, experimental and therapeutic predictions (such as why melatonin is effective in treating COVID-19) are discussed, and broader implications are outlined for understanding why other syndromes such as acute lung injury, acute respiratory distress syndrome and sepsis display varied cytokine storm symptoms.

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Section: Innate Immune System Receptor Activation In Cytokine Stormentioning

confidence: 99%

Innate Receptor Activation Patterns Involving TLR and NLR Synergisms in COVID-19, ALI/ARDS and Sepsis Cytokine Storms: A Review and Model Making Novel Predictions and Therapeutic Suggestions

Root‐Bernstein

2021

IJMS

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“…The author has discussed the details of TLRs-based therapeutics for different inflammatory and infectious diseases somewhere else (Kumar, 2018[ 101 ]). Also, different host-derived endogenous negative regulators of TLR signaling have been described that have a potential for gene-based therapeutics to modulate TLR signaling (Kumar, 2020[ 102 ]). Thus, depending on the skin-inflammatory conditions, these endogenous negative regulators of TLR signaling, along with TLR agonists and antagonists, may have great potential in these skin-inflammatory diseases.…”

Section: Future Perspectives and Conclusionmentioning

confidence: 99%

“…They include nod-like receptors (NLR), RIG-like helicases (RLH), C-type lectin-like receptors (CLRs), Triggering receptors expressed on myeloid cells (TREM-1), and more recently described DNA sensors, cyclic GMP-AMP synthase (cGAS) and gamma-interferon-inducible protein Ifi-16 (IFI-16) or p204 (a PYHIN (pyrin and HIN200 domain-containing protein) protein that serves as an intracellular DNA sensor to mediate type 1 interferon or IFN production) (Almine et al, 2017[ 7 ]; Brown et al, 2018[ 16 ]; Kawai and Akira, 2009[ 93 ]; Kumar, 2019[ 99 ]; Roe et al, 2014[ 164 ]; Unterholzner et al, 2010[ 212 ]). By far, TLRs are the most studied PRRs in the context of immunity, inflammation, and inflammatory diseases, including cancer, sepsis, acute lung injury/inflammation (ALI), neuroinflammation, discussed somewhere else (Huang et al, 2018[ 72 ]; Kumar, 2018[ 101 ]; Kumar, 2019[ 103 ]; Kumar, 2020[ 102 ]; Rakoff-Nahoum and Medzhitov, 2009[ 161 ]). The current review discusses the role of TLRs in skin inflammation and inflammatory diseases.…”

Section: Introductionmentioning

confidence: 99%

Going, Toll-like receptors in skin inflammation and inflammatory diseases

Kumar

2021

EXCLI Journal; 20:Doc52; ISSN 1611-2156

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“…To date, 10 TLRs (TLR1-TLR10) in humans and 12 TLRs (TLR1-TLR13) in laboratory mice have been identified, and the TLR10 in mice is a defective pseudogene ( 5 ). These TLRs recognize different PAMPs and DAMPs to elicit the NF-κB activation-dependent pro-inflammatory signaling discussed in detail by the author somewhere else ( 5 , 8 , 9 ). However, these TLR signaling pathways have various host-derived endogenous negative regulators, which keep their activation in check through different mechanisms ( 9 ).…”

Section: Introductionmentioning

confidence: 99%

“…These TLRs recognize different PAMPs and DAMPs to elicit the NF-κB activation-dependent pro-inflammatory signaling discussed in detail by the author somewhere else ( 5 , 8 , 9 ). However, these TLR signaling pathways have various host-derived endogenous negative regulators, which keep their activation in check through different mechanisms ( 9 ). Hence, the TLR signaling activation pathway is a regulated pathway to protect against pathogens, PAMPs, and DAMPs, and any dysregulation causes exaggerated inflammatory signaling affecting different components of immunity causing infection-related or sterile inflammatory conditions.…”

Section: Introductionmentioning

confidence: 99%

The Trinity of cGAS, TLR9, and ALRs Guardians of the Cellular Galaxy Against Host-Derived Self-DNA

Kumar

2021

Front. Immunol.

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The immune system has evolved to protect the host from the pathogens and allergens surrounding their environment. The immune system develops in such a way to recognize self and non-self and develops self-tolerance against self-proteins, nucleic acids, and other larger molecules. However, the broken immunological self-tolerance leads to the development of autoimmune or autoinflammatory diseases. Pattern-recognition receptors (PRRs) are expressed by immunological cells on their cell membrane and in the cytosol. Different Toll-like receptors (TLRs), Nod-like receptors (NLRs) and absent in melanoma-2 (AIM-2)-like receptors (ALRs) forming inflammasomes in the cytosol, RIG (retinoic acid-inducible gene)-1-like receptors (RLRs), and C-type lectin receptors (CLRs) are some of the PRRs. The DNA-sensing receptor cyclic GMP–AMP synthase (cGAS) is another PRR present in the cytosol and the nucleus. The present review describes the role of ALRs (AIM2), TLR9, and cGAS in recognizing the host cell DNA as a potent damage/danger-associated molecular pattern (DAMP), which moves out to the cytosol from its housing organelles (nucleus and mitochondria). The introduction opens with the concept that the immune system has evolved to recognize pathogens, the idea of horror autotoxicus, and its failure due to the emergence of autoimmune diseases (ADs), and the discovery of PRRs revolutionizing immunology. The second section describes the cGAS-STING signaling pathway mediated cytosolic self-DNA recognition, its evolution, characteristics of self-DNAs activating it, and its role in different inflammatory conditions. The third section describes the role of TLR9 in recognizing self-DNA in the endolysosomes during infections depending on the self-DNA characteristics and various inflammatory diseases. The fourth section discusses about AIM2 (an ALR), which also binds cytosolic self-DNA (with 80–300 base pairs or bp) that inhibits cGAS-STING-dependent type 1 IFN generation but induces inflammation and pyroptosis during different inflammatory conditions. Hence, this trinity of PRRs has evolved to recognize self-DNA as a potential DAMP and comes into action to guard the cellular galaxy. However, their dysregulation proves dangerous to the host and leads to several inflammatory conditions, including sterile-inflammatory conditions autoinflammatory and ADs.

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Toll-like receptors in sepsis-associated cytokine storm and their endogenous negative regulators as future immunomodulatory targets

Abstract: Graphical abstract

Cited by 153 publications

References 356 publications

Innate Receptor Activation Patterns Involving TLR and NLR Synergisms in COVID-19, ALI/ARDS and Sepsis Cytokine Storms: A Review and Model Making Novel Predictions and Therapeutic Suggestions

Innate Receptor Activation Patterns Involving TLR and NLR Synergisms in COVID-19, ALI/ARDS and Sepsis Cytokine Storms: A Review and Model Making Novel Predictions and Therapeutic Suggestions

Going, Toll-like receptors in skin inflammation and inflammatory diseases

The Trinity of cGAS, TLR9, and ALRs Guardians of the Cellular Galaxy Against Host-Derived Self-DNA

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