The possibility of a viral cause of POIS was discussed before, but it was not explored in adequate depth. In my case POIS was most probably developed after a childhood mumps infection, that involved prolonged orchitis (testicular inflammation), which must have done some permanent damage. This damage established a major sexual dysfunction that precipitated and culminated in POIS. While it is clear that symptoms are the result of excessive oxidative stress and subsequent production of an exorbitant amount of lipid peroxides, the exact nature of the original cause is less tangible. For now senescence and/or autoimmunity seem to be the most likely culprits, however the involvement of other factors can't be excluded. One such factor that piqued my interest recently is
retinoic acid-inducible gene I (RIG-I). There is emerging evidence for RIG-I's involvement in autoimmune and neurodegenerative diseases. RIG-I is a retinoic acid inducible receptor that plays a major role in viral defense through viral RNA pattern recognition. It is possible for RIG-I to become sensitized to self-RNA, which causes abnormal activation. It was also found that such dsRNA can be found in seminal plasma, which may be the trigger upon ejaculation that starts the autoinflammatory cascade. Retinoic acid is also involved in several steps throughout spermatogenesis. Thus as an alternative explanation the disruption of retinoic acid signaling may lead to immature spermatozoa, which were shown to be possible sources of ROS.
The scientific background:
Toll-like receptors (TLRs) and the retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) are major cellular receptors that recognize viral pathogen-associated molecular patterns (PAMPs) during viral infection.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3935722/The discovery of the localization of the mitochondrial antiviral signaling protein (MAVS) in these organelles highlighted its role especially for innate antiviral responses. MAVS is an essential adaptor protein of the retinoic-inducible gene-I (RIG-I)-like receptors (RLR), which can sense the presence of cytosolic viral RNA upon infection, and trigger the production of interferons (IFNs) and IFN-stimulated genes (ISGs) that act as direct antiviral effectors. Deficiencies in peroxisomal functions were, therefore, implicated in abnormal immune responses against several viruses (HIV, CMV, Hepatitis viruses), increased viral escape from immune effectors, and abnormal virus-induced pathology.https://www.sciencedirect.com/science/article/pii/S0361923023001272Recently, human semen was shown to contain cell-free nucleic acids, such as DNA, long single stranded RNA, and small RNAs–miRNA and piRNA. The RNAs have been suggested to have potential biological roles as communication molecules between cells and in the temporal and spatial regulation of gene expression in the male reproductive system. Here we demonstrate that human seminal plasma contains a variety of cell-free dsRNAs. dsRNA plays a role in a variety of biological processes, including gene regulation, is extremely stable and can gain access to cells from the extracellular medium. We suggest that one of the possible functions of dsRNA in human seminal plasma may be to influence human oocytes and therefore, influence the offspring. One possible function of the cell-free RNAs in seminal plasma may be to contribute regulatory information between cells (possibly including sperm cells) and contribute to changes in gene expression. The RNA may provide key temporal and spatial regulation of gene expression in the testis and epididymis required for normal spermatogenesis and sperm maturation.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5651240/We found that retinoic acid-inducible gene-I (RIG-1) is significantly elevated in the temporal cortex and plasma in patients with mild cognitive impairment (MCI). In addition, primary human astrocytes stimulated with the RIG-1 ligand 5'ppp RNA showed increased expression of amyloid precursor protein (APP) and amyloid-beta (AB), supporting the idea that RIG-1 is involved in the pathology of MCI associated with early progression to AD.
Amyloid-beta (AB) fibrils trigger inflammatory responses mediated by Toll-like receptors (TLR)4/TLR6 in the presence of CD36. In addition, TLR2 has been shown to act as a receptor for AB, and to trigger an inflammatory response.
The initial sensing of infection is mediated by pattern recognition receptors, which include TLRs, RIG-I-like receptors (RLR), NOD-like receptors (NLR), and C-type lectin receptors (CLR).
RLRs are localized in the cytoplasm and recognize the genomic RNA of dsRNA viruses and dsRNA generated as the replication intermediate of ssRNA viruses and also act as sensors of cellular damage.
RIG-1 signaling may be activated by small self-RNA cleavage products generated by RNase L that stimulate signaling of RIG-1 or by reactive oxygen species (ROS). Since damaged CNS cells release small self-nucleic acids and ROS, these molecules may play an important role in the initiation of the innate immune response in MCI. Alternatively, foreign nucleic acids, the signature of invading viruses and certain bacteria, are sensed intracellularly and then stimulate RIG-1 signaling. Our data suggest that RIG-1 signaling activation results in increased expression of APP and AB, and that in addition AB contributes to the expression of RIG-1.https://link.springer.com/article/10.1186/1742-2094-11-67Retinoids are known to contribute to axonal outgrowth, neuronal recovery from injuries, differentiation, and stability of the rhodopsin structure. Interestingly, some of these molecular species, including all-trans-retinoic acid and 9-cis-retinoic acid, can open TRPV1, indicating that its abnormally increased levels in neural disorders may involve a TRPV1-mediated mechanism. Similar to DAG, such retinoids seem to bind to the capsaicin-binding site. Overall, TRPV1 appears to be an extremely polymodal sensor for detection of painful insults.https://www.mdpi.com/1422-0067/15/9/16430To understand the mechanisms underlying MuV-induced orchitis, a recent study investigated the pattern recognition receptors-initiated innate immune responses of testicular cells to Mumps virus (MuV) infection. Mumps virus (MuV) induces innate immune responses in mouse Sertoli cells and Leydig cells through the activation of Toll-like receptor 2 (TLR2) and retinoic acid-inducible gene I (RIG-I) signaling pathways. MuV-initiated TLR2 signaling mainly induces pro-inflammatory cytokines (TNF-a and IL-6) as well as chemokines (MCP-1 and CXCL10), whereas the RIG-I pathway principally participated in the induction of type 1 interferons (IFN-alpha and IFN-beta).https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2021.582946/fullSeveral inflammatory factors were detected differentially expressed in the lung tissues of COVID-19 patients, suggesting the presence of a cytokine storm in the lung. Our results showed that the highly expressed proteins in the COVID-19 livers were enriched in RIG-I, TNF, and IL1R signals, which finally integrated into the NF-kB-mediated inflammatory pathway.
Notably, the expression of interferon (IFNa) and interleukin (IL8) downstream of the NF-kB/RELA pathway was significantly higher in the COVID-19 hepatocytes than in the control group.https://www.nature.com/articles/s41392-020-00406-1.pdfSeveral lines of evidence indicate that deregulated RIG-I signaling is associated with autoimmune disorders. Further studies suggest that RIG-I has functions in addition to those directly related to its role in RNA sensing and host defense.
RIG-I (retinoic acid-inducible gene-I)-like receptors (RLRs) detect viral nucleic acids in the cytosol.
RIG-I recognizes viruses that broadly impact human health such as influenza and hepatitis C viruses.
Deregulation of RIG-I-mediated events has been reported to contribute to the pathogenesis of human diseases, with an emphasis on autoimmune disorders.
RIG-I was identified as one of the genes whose expression was induced by all-trans retinoic acid (ATRA) treatment.
Stimulation of vascular cells with lipopolysaccharide (LPS), a well-recognized inducer of inflammation, led to up-regulation of RIG-I expression.
RIG-I has been reported to recognize RNA derived from 25 viruses. It has specificity for RNA viruses and does not bind viral dsDNA (except Epstein-Barr virus).
Cells lacking TRIM25 have impaired production of type I IFNs in response to viral infection. Interestingly, TRIM25 is inhibited by NS1, an influenza protein known for its ability to antagonize the immune system. NS1 directly interacts with TRIM25 and prevents activation of RIG-I, emphasizing the importance of TRIM25 in RIG-I function.
In addition to the ubiquitin-mediated and related strategies, naturally occurring mechanisms have evolved to inhibit interaction between MAVS and RIG-I, presumably to prevent unwanted or prolonged activation of antiviral signaling that may be harmful for host survival.
Some virally encoded proteins can both sequester RNA and bind to RIG-I directly, again suggesting the use of multiple strategies to inhibit host responses.
Other Functions of RIG-I:
RIG-I may play important roles in mammalian granulocyte production and differentiation.
RIG-I plays an important role during antibacterial responses.
RIG-I acts as a sensor for inflammasome activation, leading to caspase-1 activation and generation of mature IL-1B.
RIG-I may possess tumor-suppressor properties through its ability to activate IFN responses.
In addition to ATRA and LPS, type I IFNs (IFN-a and IFN-B) up-regulate RIG-I expression in a variety of cell types. IFN-gamma, a member of the type II IFN family, also stimulates RIG-I expression in various cell types.
The expression of RIG-I is blocked by type I IFN receptor-specific neutralizing antibodies.
RIG-I may be involved in innate immune mechanisms to protect the host against parasitic infections.
RIG-I may play an active role in the pathogenesis of atherosclerosis through currently unknown mechanisms.
The levels of IFN-g and RIG-I are significantly elevated in the epidermis of psoriasis patients compared with normal skin cells. It is tempting to speculate that expression of RIG-I in psoriatic lesions represents a regional immune response, and that IFN-g may be important for this process.
Interestingly, RIG-I expression mirrored that of IFN-B: that is, it was high in fibroblast-like synoviocytes from rheumatoid arthritis patients and low in tissues isolated from subjects diagnosed with osteoarthritis. TNF-a, one of the main cytokines produced during the development of rheumatoid arthritis and a prime target for immunotherapy, induces RIG-I expression in rheumatoid synoviocytes in an IFN-g-dependent fashion.
RIG-I is constitutively expressed on epithelial cells lining the gut mucosa, and has been proposed to be important for innate antiviral responses in this organ, including inhibition of both viral replication and virus-induced apoptosis.
A variety of studies indicate that viral infections also play causal roles as modulators of type 1 diabetes development through multiple mechanisms. The presence of enterovirus or enteroviral RNA in the serum and in pancreatic islets of newly diagnosed type 1 diabetes in children and adults supports this possibility.
Inhibition of RIG-I-mediated signaling has potential utility for the treatment of exacerbated immune responses, such as those typical of autoimmune disorders.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3099591/Retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs), which are pivotal sensors of RNA virus invasions, mediate the transcriptional induction of genes encoding type I interferons (IFNs) and proinflammatory cytokines, successfully establishing host antiviral immune response.
Furthermore, we pay particular attention to the relationship between RLRs and diseases, especially how RLRs participate in SARS-CoV-2, malaria or bacterial infections, how single-nucleotide polymorphisms (SNPs) or mutations in RLRs and antibodies against RLRs lead to autoinflammatory diseases and autoimmune diseases, and how RLRs are involved in anti-tumor immunity.
Generally, RIG-I mainly detects RNA species from plenty of viruses belonging to Flaviviridae, Paramyxoviridae, Orthomyxoviridae, and Rhabdoviridae, whereas MDA5 detects RNA mainly from Picornaviridae.
Functional studies have suggested that RNA-dependent ATP hydrolysis activity plays a critical role in distinguishing non-self RNA from self-RNA using RIG-I and MDA5.
Control on RLR antiviral cascade signaling is essential not only to prevent harmful and unwanted type I IFN responses in the absence of infection but also to initiate timely and sensitive pathogen recognition in the presence of pathogen invasion. Moreover, the host has developed a lot of mechanisms to regulate the activity of RLRs, such as miRNAs, interacting proteins and post-translational modifications (PTMs). Through these delicate modulations, the feedback or feedforward regulatory loops of antiviral response can be successfully established.
Post-translational modifications (PTMs) are crucial for the activation and deactivation of RIG-I and MDA5. By regulating the activity, stability, cellular compartment, conformation and interactions with additional factors, PTMs precisely alter the functionality of RLRs. PTMs mainly include ubiquitination, phosphorylation, SUMOylation and acetylation.
After the invasion of the RNA virus, RIG-I is rapidly dephosphorylated to elicit innate antiviral response. Conventional protein kinase C-alpha (PKC-a) and PKC-B are mainly responsible for the phosphorylation of RIG-I CARD, which suppresses CARD ubiquitination by TRIM25. Based on the pivotal role of phosphorylation regulation in RLRs activation, the agonist or antagonist of kinase and phosphatase might be potential therapeutics for RLRs-related diseases.
Reversible acetylation also regulates RIG-I activation by controlling its viral RNA-binding activity.
RLRs are also involved in the innate immune response against parasite and bacterium infections.
Many studies have focused on developing synthetic agonists of RLRs, especially RIG-I, to serve as potent pan-antivirals and vaccine adjuvants via the activation of IFN signaling and immune response.
IFIH1 has been identified as a susceptible gene for a series of autoimmune diseases. IFIH1 gene is associated with the risk for type 1 diabetes (T1D), autoimmune thyroid disease, psoriasis, systemic lupus erythematosus (SLE), and inflammatory bowel disease, rheumatoid arthritis, vitiligo and multiple sclerosis.
Viral infection and type I IFN production can induce ER stress in B-cells, which leads to the generation of neoantigen epitopes. This, in turn, results in the activation of B-cell-specific autoreactive T lymphocytes and damages B-cells.
Gain-of-function (GOF) mutations of RLRs often make the body mistake self-derived nucleic acids for viral products and lead to aberrant type I IFN signaling production (termed IFN-I signature), causing extensive organ damage and many rare disorders characterized by IFN-I signature.
Why changes in the function of one single gene can lead to so many different phenotypes of autoinflammation or autoimmune diseases remains to be further explored. One possible hypothesis is that these conformational changes induced by amino acid substitutions enable MDA5 and RIG-I to easily acquire activity to self dsRNA. Some also consider that genetically relevant factors may play a driving role in the onset and development of diseases.
The numbers and ratios of peripheral blood lymphocytes, especially CD4+ T cells and CD8+ T cells, decrease in some myositis patients with anti-MDA5 antibodies. It is associated with anaemia, thrombocytopenia, fibrinolytic abnormalities (such as increased D-dimer), liver function damage and elevated blood lipid levels. Many studies have found that the levels of TNF-a, IL-6, IL-8, IL-10, IL-18, IFN a/B/g, IP10 and other cytokines or chemokines are increased myositis patient serum with the anti-MDA5 antibodies, and the serum ferritin concentrations were also significantly elevated.
Lately, there is growing evidence that agonists of RIG-I and MDA5 can produce antiviral and anti-tumor effects in a type I IFN-dependent or -independent manner, leading to immunogenic tumor cell death and the regression of multiple types of tumors.
Inappropriate use of RLRs agonists may also result in an out-of-control inflammatory response. Therefore, the long-term use of RLRs agonists should be fully considered, and the periodicity and dose of administration should be further studied.
The RLRs family and its downstream IFN signaling pathway, as one of the critical cytoplasmic RNA sensors for pathogen recognition, play an indispensable part in mediating an effective immune response of the host. However, just as the coin has both sides, the role of the RLRS family in diseases can be a double-edged sword. Moderate and controlled activation of RLRs protects the host from invading pathogens, whereas excessive and uncontrolled RLR activation may lead to unexpected pathological damage and cytokine storms, and may even cause autoimmune diseases or autoinflammatory diseases.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9343065/Within spermatogenesis, it has been well established that retinoic acid (RA) is necessary for the proper formation of the blood–testis barrier, spermatogonial differentiation, spermiation, and assisting in meiotic completion.
RA is involved in mediating differentiation and pre-meiotic activation in spermatogonia. RA is also needed for signaling within the Sertoli cell to remodel tight junctions associated with the blood–testis barrier. This crucial RA-mediated signaling allows for preleptotene spermatocyte to progress toward the lumen to await their signaled release (spermiation). Spermiation is signaled by RA within the Sertoli cells prior to releasing mature spermatids.
Some of the first studies to reveal the importance of RA in spermatogenesis involved feeding rodents a vitamin A-deficient (VAD) diet, resulting in infertile animals incapable of producing viable sperm. However, if these VAD rodents were administered exogenous RA, spermatogenesis would be rescued.
If Rdh10 is ablated in both Sertoli and germ cells, the resulting testes will be void of RA; thus, spermatogenesis will halt before spermatogonial differentiation.
Studies have demonstrated the importance of RA in the formation of the blood–testis barrier (BTB) by inhibiting retinoic acid receptor (RAR) signaling in Sertoli cells.
Another result of impaired RA signaling is a defect in spermiation. Spermiation is the release of mature spermatids into the lumen of the seminiferous epithelium. When retinoid X receptor (RXR)B is ablated in Sertoli cells, the resulting mice are unable to complete RA-RARa/RXRB signaling and, thus, are unable to release their spermatids from Sertoli cells.
A recent clinical trial studied men experiencing oligoasthenozoospermia, resulting in infertility issues and provided them with supplemental RA in the form of isotretinoin. This study observed improvements in sperm counts and several successful pregnancies.
RA poses many potential avenues for non-hormonal contraception via manipulation of the synthesis or function of RA in the testis. In many cases, the disruption of RA synthesis causes spermatogonia to be halted in their A spermatogonia undifferentiated state.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8951023/Retinoic acid-inducible gene-I (RIG-I) like receptor (RLR) pathway is one of the most significant pathways supervising aberrant RNA in cells. In predominant conditions, the RLR pathway initiates anti-infection function via activating inflammatory effects, while recently it is discovered to be involved in cancer development as well, acting as a virus-mimicry responder. On one hand, the product IFNs induces tumor elimination. On the other hand, the NF-kB pathway is activated which may lead to tumor progression.
Pattern recognition receptors (PRRs) are representative immune receptors in innate immunity that detect foreign and harmful molecules, such as those from pathogens and damaged cells.
RIG-I preferentially binds to short dsRNAs with 5’ triphosphate, MDA5 is inclined to bind to longer dsRNAs.
There are multiple post-translational modifications, such as protein phosphorylation, ubiquitylation, methylation, etc., which influence the function of key members in RLR pathway.https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2023.1227041/fullAlthough we had shown that recruitment of the nuclear receptor retinoic acid receptor-alpha (RAR-a) to corticotropin-releasing hormone (CRH) promoter is implicated in activation of the hypothalamus–pituitary–adrenal (HPA) axis, further insight into how retinoids modulate HPA axis activity is lacking. Here we show that all-trans retinoic acid (RA)-induced HPA activation involves impairments in glucocorticoid receptor (GR) negative feedback.
Through dietary vitamin A consumption or treatment of severe acne with 13-cis-RA (isotretinoin), excessive retinoid intake in humans has been implicated in mood disorders like depression.
Hypothalamus–pituitary–adrenal (HPA) axis hyperactivity is often seen in depressive patients. CRH plays a central role in controlling stress response and regulating HPA axis activity. Chronic RA treatment further induces HPA axis hyperactivity and anxiety-related behavior.https://www.nature.com/articles/tp201398
