Pattern Recognition Receptors: Sensing Immunity and Disease

Omar Hussein^*
*Correspondence: Omar Hussein, Department of Vaccinology, Nile Delta University of Science, Alexandria, Egypt, Email:

Introduction

Recent advancements in understanding RNA sensing by Pattern Recognition Receptors (PRRs) highlight their critical roles in antiviral immunity and the pathogenesis of autoimmune diseases. These receptors, including RIG-I-like receptors (RLRs) and Toll-like receptors (TLRs), detect specific RNA patterns, initiating downstream signaling pathways that lead to interferon production and inflammatory responses. Dysregulation in these pathways can contribute significantly to immune pathologies [1].

PRRs are increasingly recognized for their multifaceted roles in cancer development and progression, extending beyond their traditional function in antimicrobial immunity. They can influence tumor initiation, growth, metastasis, and the efficacy of cancer therapies by modulating the tumor microenvironment and immune cell responses. Understanding these interactions offers new avenues for therapeutic intervention [2].

RNA PRRs are central to antiviral immunity, detecting viral RNA to trigger innate immune responses. This includes key classes like RLRs and TLRs that sense diverse RNA structures, initiating signaling cascades that lead to the production of Type I Interferons and inflammatory cytokines, essential for host defense against viral pathogens [3].

TLRs are vital PRRs involved in recognizing microbial lipoproteins, initiating immune responses against various pathogens. This recognition is critical for differentiating between host and pathogen components and for orchestrating both innate and adaptive immunity. Specific TLRs, such as TLR1, TLR2, and TLR6, form heterodimers to detect distinct lipid modifications of lipoproteins, highlighting the intricate nature of microbial sensing [4].

The cGAS-STING pathway represents a fundamental innate immune sensing mechanism, primarily detecting cytosolic DNA to trigger robust Type I Interferon responses. Recent work illuminates the complex activation and regulatory mechanisms governing this pathway, revealing how it contributes to both host defense against pathogens and the development of autoimmune diseases and anti-tumor immunity. Understanding its intricacies offers promising therapeutic targets [5].

PRRs profoundly impact the immune response to COVID-19. They recognize SARS-CoV-2 Pathogen-Associated Molecular Patterns (PAMPs), triggering innate antiviral defenses. However, dysregulated PRR signaling can also contribute to excessive inflammation and severe disease outcomes. Modulating PRR pathways could offer novel strategies for managing COVID-19 severity [6].

Nucleic acid sensing TLRs are pivotal PRRs, crucial for detecting viral and bacterial nucleic acids and initiating innate immune responses. Recent progress reveals their complex regulatory mechanisms and expanding therapeutic potential in infectious diseases, autoimmune disorders, and cancer. Targeting these TLRs offers opportunities for immune modulation [7].

Nucleotide-binding Oligomerization Domain-like Receptors (NLRs) are intracellular PRRs that form inflammasomes, playing essential roles in inflammation and immunity. Beyond their traditional infectious disease context, NLRs are increasingly recognized for their involvement in autoimmune and autoinflammatory diseases. Dysregulation of NLR activation can drive chronic inflammation and tissue damage, making them promising therapeutic targets [8].

C-type Lectin Receptors (CLRs) function as critical PRRs in sensing fungal infections. They recognize specific carbohydrate structures on fungal cell walls, initiating downstream signaling pathways that lead to antifungal immunity. This overview highlights the diversity of CLRs and their nuanced roles in host defense against various fungal pathogens, influencing both protective immunity and immune evasion strategies [9].

Scavenger Receptors (SRs), a diverse family of cell surface receptors, play expanding roles beyond lipid metabolism, functioning as crucial PRRs in immunity. They recognize a wide array of modified self and non-self molecules, influencing processes like efferocytosis, pathogen clearance, and inflammation. Their versatility means they are involved in many aspects of health and disease, presenting exciting avenues for research and therapeutic development [10].

Description

Pattern Recognition Receptors (PRRs) stand as foundational components of the innate immune system, recognizing diverse molecular patterns associated with pathogens or cellular stress. These receptors are crucial for initiating rapid immune responses against invading microbes, and their roles extend significantly into various disease pathologies, including autoimmune conditions, cancer, and severe infectious diseases like COVID-19. Understanding the intricate mechanisms by which PRRs operate offers valuable insights into host defense and potential therapeutic interventions [1, 2, 6].

A significant aspect of PRR function involves the sensing of nucleic acids. RIG-I-like receptors (RLRs) and Toll-like receptors (TLRs) are primary examples of RNA PRRs, adept at detecting specific viral and bacterial RNA patterns. This recognition triggers signaling cascades culminating in the production of Type I Interferons and inflammatory cytokines, essential for antiviral immunity [1, 3, 7]. Similarly, the cGAS-STING pathway plays a fundamental role in detecting cytosolic DNA, eliciting robust Type I Interferon responses critical for defense against pathogens. Beyond direct pathogen detection, this pathway is also implicated in autoimmune diseases and anti-tumor immunity, highlighting its dual role in health and disease [5]. Nucleic acid sensing TLRs, in particular, are pivotal in detecting both viral and bacterial nucleic acids, with ongoing research revealing their complex regulatory mechanisms and expanding therapeutic potential across infectious diseases, autoimmune disorders, and cancer [7].

PRRs also encompass mechanisms for recognizing other microbial components. Toll-like receptors are not only involved in nucleic acid sensing but also critically recognize microbial lipoproteins, orchestrating immune responses by differentiating host from pathogen components. Specific TLRs, such as TLR1, TLR2, and TLR6, form heterodimers to detect distinct lipid modifications, showcasing the precise nature of microbial sensing by these receptors [4]. Furthermore, C-type Lectin Receptors (CLRs) are indispensable PRRs for sensing fungal infections. They identify specific carbohydrate structures on fungal cell walls, activating downstream signaling pathways that are vital for antifungal immunity and influencing strategies of both protective immunity and immune evasion [9].

Beyond direct pathogen recognition, intracellular PRRs like Nucleotide-binding Oligomerization Domain-like Receptors (NLRs) are central to inflammation and immunity through inflammasome formation. While traditionally linked to infectious diseases, NLRs are increasingly recognized for their involvement in autoimmune and autoinflammatory conditions. Dysregulation of NLR activation can lead to chronic inflammation and tissue damage, making them attractive targets for therapy [8]. Adding to this complexity, Scavenger Receptors (SRs), a diverse family of cell surface receptors, function as PRRs that recognize a broad spectrum of modified self and non-self molecules. These receptors influence critical biological processes such as efferocytosis, pathogen clearance, and inflammation, demonstrating their wide-ranging impact on health and disease and presenting novel avenues for therapeutic development [10].

The broader implications of PRR activity are evident in conditions like cancer, where they profoundly influence tumor initiation, growth, metastasis, and the efficacy of various cancer therapies. This occurs through their modulation of the tumor microenvironment and immune cell responses, presenting significant opportunities for therapeutic intervention strategies [2]. Similarly, in the context of COVID-19, PRRs are vital in recognizing SARS-CoV-2 Pathogen-Associated Molecular Patterns (PAMPs) to initiate antiviral defenses. However, an uncontrolled or dysregulated PRR signaling can exacerbate inflammation, leading to severe disease outcomes. Modulating these pathways thus offers potential new strategies for managing COVID-19 severity and other inflammatory diseases [6].

Conclusion

Pattern Recognition Receptors (PRRs) are critical components of the innate immune system, recognizing diverse molecular patterns to initiate protective responses. This complex family of receptors, including RIG-I-like receptors (RLRs), Toll-like receptors (TLRs), Nucleotide-binding Oligomerization Domain-like Receptors (NLRs), C-type Lectin Receptors (CLRs), and Scavenger Receptors (SRs), along with pathways like cGAS-STING, play extensive roles beyond antimicrobial immunity. They are vital for sensing RNA and DNA from pathogens, triggering interferon and inflammatory responses essential for antiviral and antibacterial defense. For instance, RNA sensing by RLRs and TLRs is crucial for combating viral pathogens and plays a part in autoimmune disease pathogenesis. PRRs also have significant implications in various health conditions. In cancer, they influence tumor development, progression, and treatment efficacy by modulating the tumor microenvironment. During infections like COVID-19, PRRs recognize viral components, activating defenses, though their dysregulation can lead to excessive inflammation and severe disease. NLRs form inflammasomes, contributing to inflammation in both infectious and autoimmune/autoinflammatory diseases. CLRs are key in sensing fungal infections through carbohydrate recognition, while SRs detect modified self and non-self molecules, impacting pathogen clearance and inflammation. Targeting these diverse PRR pathways offers promising therapeutic avenues for modulating immune responses in infectious diseases, autoimmune disorders, and cancer.

Acknowledgement

None

Conflict of Interest

None

References

Jia L, Huimin W, Tao X. "Recent advances in RNA sensing by pattern recognition receptors and their roles in antiviral immunity and autoimmune diseases".Cell Mol Immunol 20 (2023):602-613.

Indexed at, Google Scholar, Crossref

Wei X, Jian L, Xi S. "Pattern recognition receptors (PRRs) in cancer development and therapy".Cancer Lett 519 (2021):153-162.

Indexed at, Google Scholar, Crossref

Jiaqi Z, Huichao Z, Han C. "RNA Pattern Recognition Receptors in Antiviral Immunity".Front Immunol 11 (2020):605139.

Indexed at, Google Scholar, Crossref

Kenta N, Kenta M, Yasuhiro K. "Recognition of Microbial Lipoproteins by Toll-like Receptors".Front Immunol 12 (2021):733878.

Indexed at, Google Scholar, Crossref

Yajuan W, Cong Z, Yang W. "Advances in the mechanism of cGAS-STING pathway activation and regulation".Signal Transduct Target Ther 8 (2023):38.

Indexed at, Google Scholar, Crossref

Meihua L, Yingying W, Yong P. "The role of pattern recognition receptors in COVID-19: a narrative review".Inflamm Res 72 (2023):873-890.

Indexed at, Google Scholar, Crossref

Yuan L, Xiao W, Yan Y. "Recent advances in nucleic acid sensing Toll-like receptors: Function, regulation, and therapeutic potential".Immunol Rev 310 (2023):172-192.

Indexed at, Google Scholar, Crossref

Jie W, Haichun M, Qian S. "Nucleotide-binding Oligomerization Domain-like Receptors (NLRs) and Their Roles in Autoimmune and Autoinflammatory Diseases".Front Immunol 13 (2022):902251.

Indexed at, Google Scholar, Crossref

Xi T, Junjie J, Qisheng L. "C-type Lectin Receptors (CLRs) as Pattern Recognition Receptors in Fungal Infections: An Overview".Front Immunol 13 (2022):954848.

Indexed at, Google Scholar, Crossref

Andreas P, Debbie G, Emily H. "Scavenger Receptors: Expanding Roles in Health and Disease".Annu Rev Immunol 40 (2022):651-678.

Indexed at, Google Scholar, Crossref