The human immune defense system can be divided into innate and adaptive immunity. The innate immune system can initiate defense mechanisms in response to pathogens (bacteria, viruses, fungi, etc.), tissue damage, or genotoxic stress. These so called damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs) are being recognized and sensed by various types of reception such as pattern recognition receptors (PRRs), i.e. Toll-like receptors (TLR), nucleotide-binding oligomerization domain (NOD)-like receptors, intracellular nucleic acid-sensing receptors (e.g. RIG-I-like receptors, cyclic guanosine-monophosphate adenosine-monophosphate synthase (cGAS), absent in melanoma 2, and C-type lectin receptors (such as mannose-binding proteins, dectin-1, dectin-2, and DC-SIGN). Innate immune cells express a very diverse set of PRRs, which upon recognition of PAMPs and DAMPs can trigger intracellular signaling cascades to produce important inflammatory cytokines and chemokines. The innate immune response contributes not only to immunity but also to the control of tissue homeostasis.
Furthermore, it also plays a central role in many pathological conditions, such as cancer, microbial infections, atherosclerosis, autoimmune and inflammatory diseases (e. g. rheumatoid arthritis), fibrosis and neurodegenerative disorders to name a few. Consequently, targeting innate immunity via the modulation of PPRs (especially by small molecules) can help to unlock a therapeutic potential that needs to be explored. In addition to PRRs, checkpoint molecules (e.g. TAM receptors, siglecs, CD47) expressed by innate immune cells, which regulate their function, are also interesting targets for potential therapeutic interventions in the future.
Among other signaling pathways, which can also be modulated by small molecules and are closely interconnected with innate immunity, are cyclic guanosine monophosphate-adenosine monophosphate synthase‒stimulator of interferon genes‒TANK-binding kinase 1 (cGAS‒STING‒TBK1) and nuclear factor erythroid-2-related factor 2 /Kelch-like ECH-associated protein 1 (Nrf2/Keap 1) signaling pathway. Upon detection and binding of double-stranded DNA, cGAS synthesizes the second messenger cyclic GMP-AMP (cGAMP) leading to activation of the transmembrane protein stimulator of interferon genes (STING) and recruitment of TANK-binding kinase-1 (TBK1), which activates both interferon regulatory factor-3 (IRF3) and NF-κB that mediate immune defense against tumors and viral infections. Nrf2 is an important negative regulator of STING affecting the antiviral cytosolic DNA sensing in human cells. Another linkage between PPRs (i.e. TLR) signaling and Nrf2-Keap1 pathway has also been reported, enabling the regulation of inflammation and immune defense against tissue damage caused by microbial infections or inflammation-associated diseases.
The aim of this collection is to gather novel findings about structural characteristics of PPRs, their recognition and binding to different ligands and modulators, and their linkage to related signaling pathways. The connection between PPRs, signaling pathways and several conditions (e.g. cancer, infections, autoimmune and inflammatory diseases) is also of interest. Furthermore, the emphasis is also placed on past, current and future strategies for the design of novel modulators (especially small molecules) and challenges to discover any potential drugs acting on targets of innate immunity. Moreover, the challenges that many clinical trials studies face may be also addressed.
With this Research Topic, we welcome Original Research, Reviews, Brief Research Reports and Data Reports, and Clinical trial articles that cover the strategies targeting innate immunity using small molecules, more specifically those that induce pharmacological modulation of PPRs or other related receptors and signaling pathways that finetune innate immune responses in the human body. Submission discussing the following themes, including but not limited to, will be considered:
• Mechanism of pharmacological modulation of PPRs and signaling pathways.
• Linkage between PPRs, signaling pathways and pathological conditions.
• PPRs as therapeutic targets for cancer, microbial infections, autoimmune or inflammatory diseases.
• Targeting innate immunity using small molecules.
• Clinical aspects of modulating innate immune system receptors and signaling pathways.
The human immune defense system can be divided into innate and adaptive immunity. The innate immune system can initiate defense mechanisms in response to pathogens (bacteria, viruses, fungi, etc.), tissue damage, or genotoxic stress. These so called damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs) are being recognized and sensed by various types of reception such as pattern recognition receptors (PRRs), i.e. Toll-like receptors (TLR), nucleotide-binding oligomerization domain (NOD)-like receptors, intracellular nucleic acid-sensing receptors (e.g. RIG-I-like receptors, cyclic guanosine-monophosphate adenosine-monophosphate synthase (cGAS), absent in melanoma 2, and C-type lectin receptors (such as mannose-binding proteins, dectin-1, dectin-2, and DC-SIGN). Innate immune cells express a very diverse set of PRRs, which upon recognition of PAMPs and DAMPs can trigger intracellular signaling cascades to produce important inflammatory cytokines and chemokines. The innate immune response contributes not only to immunity but also to the control of tissue homeostasis.
Furthermore, it also plays a central role in many pathological conditions, such as cancer, microbial infections, atherosclerosis, autoimmune and inflammatory diseases (e. g. rheumatoid arthritis), fibrosis and neurodegenerative disorders to name a few. Consequently, targeting innate immunity via the modulation of PPRs (especially by small molecules) can help to unlock a therapeutic potential that needs to be explored. In addition to PRRs, checkpoint molecules (e.g. TAM receptors, siglecs, CD47) expressed by innate immune cells, which regulate their function, are also interesting targets for potential therapeutic interventions in the future.
Among other signaling pathways, which can also be modulated by small molecules and are closely interconnected with innate immunity, are cyclic guanosine monophosphate-adenosine monophosphate synthase‒stimulator of interferon genes‒TANK-binding kinase 1 (cGAS‒STING‒TBK1) and nuclear factor erythroid-2-related factor 2 /Kelch-like ECH-associated protein 1 (Nrf2/Keap 1) signaling pathway. Upon detection and binding of double-stranded DNA, cGAS synthesizes the second messenger cyclic GMP-AMP (cGAMP) leading to activation of the transmembrane protein stimulator of interferon genes (STING) and recruitment of TANK-binding kinase-1 (TBK1), which activates both interferon regulatory factor-3 (IRF3) and NF-κB that mediate immune defense against tumors and viral infections. Nrf2 is an important negative regulator of STING affecting the antiviral cytosolic DNA sensing in human cells. Another linkage between PPRs (i.e. TLR) signaling and Nrf2-Keap1 pathway has also been reported, enabling the regulation of inflammation and immune defense against tissue damage caused by microbial infections or inflammation-associated diseases.
The aim of this collection is to gather novel findings about structural characteristics of PPRs, their recognition and binding to different ligands and modulators, and their linkage to related signaling pathways. The connection between PPRs, signaling pathways and several conditions (e.g. cancer, infections, autoimmune and inflammatory diseases) is also of interest. Furthermore, the emphasis is also placed on past, current and future strategies for the design of novel modulators (especially small molecules) and challenges to discover any potential drugs acting on targets of innate immunity. Moreover, the challenges that many clinical trials studies face may be also addressed.
With this Research Topic, we welcome Original Research, Reviews, Brief Research Reports and Data Reports, and Clinical trial articles that cover the strategies targeting innate immunity using small molecules, more specifically those that induce pharmacological modulation of PPRs or other related receptors and signaling pathways that finetune innate immune responses in the human body. Submission discussing the following themes, including but not limited to, will be considered:
• Mechanism of pharmacological modulation of PPRs and signaling pathways.
• Linkage between PPRs, signaling pathways and pathological conditions.
• PPRs as therapeutic targets for cancer, microbial infections, autoimmune or inflammatory diseases.
• Targeting innate immunity using small molecules.
• Clinical aspects of modulating innate immune system receptors and signaling pathways.