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iNature
Autoimmune and autoinflammatory responses result from abnormal immune and inflammatory responses to their own components and contribute to various autoimmune and autoinflammatory diseases
.
RNA-binding proteins (RBPs) are required for immune cell development and function, mainly through post-transcriptional regulation of RNA metabolism and function
.
RBPs dysfunction and RNA metabolism abnormalities are strongly associated
with a variety of autoimmune or autoinflammatory diseases.
Different RBPs play a key role
in abnormal autoreactive inflammatory responses by coordinating complex regulatory networks of DNA, RNA, and proteins within immune cells.
In-depth study of the characteristics of RBP-RNA interactions between autoimmunity and autoinflammatory processes will help to better understand the pathogenesis of autoimmunity and help develop effective treatment strategies
.
On January 5, 2023, Cao Xuetao and Liu Juan of the Naval Medical University published a review article entitled "RBP–RNA interactions in the control of autoimmunity and autoinflammation" online in Cell Research.
This review summarizes and discusses the function of RBP-RNA interactions in the control of abnormal autoimmune inflammation and its potential
as biomarkers and therapeutic targets.
for maintaining immune homeostasis and preventing unwanted autoimmune pathologies.
Immune tolerance can be divided into two categories
: central tolerance and peripheral tolerance.
Central tolerance is the first protective tolerance
to autoantigens through clonal deletion of autoreactive T cells in the thymus and incompetence, receptor editing and clonal deletion of autoreactive B cells in the bone marrow 。 Since a significant proportion of T cells and B cells can escape central tolerance, secondary peripheral tolerance is essential for eliminating or inactivating these escaped autoreactive lymphocytes, and the main mechanisms of peripheral tolerance include expression of immunosuppressive molecules, T cell incompetence, B cell incompetence, neglect of specific self-antigens in immunoprivileged tissues, and production of immunomodulatory cell types such as regulatory T (Treg) cells
.
Among immunosuppressive molecules are the well-known immune checkpoint molecules cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1).
。 T cell ineffectiveness is the result of a lack of co-stimulatory signaling in immature or regulatory antigen-presenting cells (APCs), while B cell ineffectiveness is due to the fact that continuous exposure to soluble antigens or failure of inhibitory intracellular signaling centers or peripheral immune tolerance may trigger a harmful immune response against its own components, tilting immune homeomy towards autoimmunity and autoinflammation
.
Although autoimmunity and autoinflammation have traditionally manifested themselves as overactivation of autoreactive adaptive immunity and innate immunity, respectively, they play overlapping roles
in the induction and persistence of inflammatory pathogenesis.
In different autoimmune diseases (AIDS) and autoinflammatory diseases, as well as a range of inflammatory diseases associated with aseptic inflammation, it has been established that the mixed spectrum of autoimmune and autoinflammatory AIDS is caused
by pathogenic autoimmunity and harmful inflammatory responses to its own components.
In general, AIDS can be divided into systemic (non-organ-specific) diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), as well as organ-specific diseases such as multiple sclerosis (MS) and type I diabetes diabetes, T1D)
。 Autoinflammatory diseases are characterized by overactivation of the innate immune system caused by single-gene mutations, such as cryopyrin-associated periodic syndromes associated with mutations in the NOD-like receptor family pyrin domain containing 3 (NLRP3), CAPS)
。 In addition, sterile inflammation induced by non-infectious stimuli is closely related
to various chronic inflammatory diseases such as atherosclerosis and neurodegenerative diseases.
In general, these inflammatory diseases are associated
with complex interactions between genetic, immune, and environmental factors.
The heterogeneity and diversity of underlying immune mechanisms greatly challenge the development of
effective prevention and treatment strategies for AIDS and autoinflammatory diseases.
Therefore, describing the factors that contribute to disruption of immune tolerance and ongoing onset of inflammation is essential
to better understand autoimmune pathophysiology and identify clinically meaningful diagnostic markers or drug targets.
RNA-protein interactions are essential
for a wide range of cellular processes related to immunity and homeostasis.
RNA-binding proteins (RBPs) are the basic mediators and regulators of RNA-protein interactions, controlling various genetic, epigenetic and metabolic events in immune and non-immune cells Typical RBPs have RNA-binding domains (RBDs) that can recognize and bind to specific sequence elements, such as adenine and uridine-rich elements (AREs), or the structure of the target mRNA.
Such as a stem ring
.
A large number of atypical RBPs without known RBDs have also been shown to interact with RNA and regulate immune processes
.
For example, many metabolic enzymes can bind to RNA and regulate RNA's function
.
After binding to RNA, RBPs regulate RNA metabolism and stability
primarily through post-transcriptional or translation mechanisms.
RBPs can also interact with chromatin to regulate gene expression at the transcriptional levelIn addition, RBDs have a broad role
in regulating protein expression, localization, modification, and activity through direct or indirect protein interactions.
Thus, under homeostatic and inflammatory conditions, RBPs regulate multiple cellular processes to regulate transcription, translation, and post-translational regulation of immune
responses.
These regulations of RBPs are sometimes through their interaction with noncoding RNAs (ncRNAs), such as microRNAs (miRNAs) and long noncoding RNAs (lncRNAs).
Therefore, RBPs play an important role
in controlling autoimmunity and autoinflammation through complex interactions between epigenetic, metabolic, and immune pathways.
Figure 1.
RBP-mediated regulation of autoimmune and autoinflammatory responses (Image from Cell Research) There is growing evidence that the accumulation and function of innate immune cells in autoimmune responses are disrupted
.
Activation of pattern recognition receptors (PRRs) leads to profound activation of innate signals, leading to immune cell activation and inflammatory responses
.
These events further recruit and activate inflammatory cells, leading to disruption of immune tolerance, producing autoinflammation and tissue damage
.
This review discusses how RBPs and RNA metabolism affect various stages of innate immune responses, including (1) innate perception, (2) inflammatory signaling, (3) pro-inflammatory cytokine production, and (4) innate immune cell development and function to modulate autoimmune responses and inflammatory pathologies
.
Figure 2.
Control of RNA metabolism and function by RBPs in autoimmune and autoinflammatory responses (Figure from Cell Research) T cell and B cell-dependent adaptive immune dysregulation plays an integral role
in the development of autoimmunity and tissue damage 。 Long-term stimulation of autoantigens and abnormal innate inflammatory response not only lead to abnormal activation and infiltration of T cells in inflammatory tissues, but also enhance the activation of B cells and increase the production
of autoantibodies.
Long-lived autoreactive memory T and B cells mediate a potent response to autoantigens and contribute to ongoing autoimmunity and chronic inflammation
.
This review discusses how RBP-RNA interactions affect differentiation, function, activation, or memory responses in adaptive immune cells, dysregulation that is critical
to autoimmune pathogenesis.
Figure 3: Control of RNA metabolism and function by RBPs in adaptive immune responses of autoimmunity and autoinflammation (Image from Cell Research) Overall, despite significant achievements in revealing the role of RBPs and RNA metabolism in autoimmune response and inflammatory pathogenesis, many important questions in this area remain unclear and require further study
。
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The content is [iNature]
