Role Of Pattern Recognition Receptors Research Articles

Unraveling the dynamics of Xanthomonas' flagella: insights into host-pathogen interactions.

Understanding the intricate interplay between plants and bacteria is paramount for elucidating mechanisms of immunity and disease. This review synthesizes current knowledge on the role of flagella in bacterial motility and host recognition, shedding light on the molecular mechanisms underlying plant immunity and bacterial pathogenicity. We delve into the sophisticated signaling network of plants, highlighting the pivotal role of pattern recognition receptors (PRRs) in detecting conserved molecular patterns known as microbe-associated molecular patterns (MAMPs), with a particular focus on flagellin as a key MAMP. Additionally, we explore recent discoveries of solanaceous-specific receptors, such as FLAGELLIN SENSING 3 (FLS3), and their implications for plant defense responses. Furthermore, we examine the role of bacterial motility in host colonization and infection, emphasizing the multifaceted relationship between flagella-mediated chemotaxis and bacterial virulence. Through a comprehensive analysis of flagellin polymorphisms within the genus Xanthomonas, we elucidate their potential impact on host recognition and bacterial pathogenicity, offering insights into strategies for developing disease-resistant crops. This review is intended for professionals within the fields of crops sciences and microbiology.

Host-microbiota interaction in intestinal stem cell homeostasis.

Intestinal stem cells (ISCs) play a pivotal role in gut physiology by governing intestinal epithelium renewal through the precise regulation of proliferation and differentiation. The gut microbiota interacts closely with the epithelium through myriad of actions, including immune and metabolic interactions, which translate into tight connections between microbial activity and ISC function. Given the diverse functions of the gut microbiota in affecting the metabolism of macronutrients and micronutrients, dietary nutrients exert pronounced effects on host-microbiota interactions and, consequently, the ISC fate. Therefore, understanding the intricate host-microbiota interaction in regulating ISC homeostasis is imperative for improving gut health. Here, we review recent advances in understanding host-microbiota immune and metabolic interactions that shape ISC function, such as the role of pattern-recognition receptors and microbial metabolites, including lactate and indole metabolites. Additionally, the diverse regulatory effects of the microbiota on dietary nutrients, including proteins, carbohydrates, vitamins, and minerals (e.g. iron and zinc), are thoroughly explored in relation to their impact on ISCs. Thus, we highlight the multifaceted mechanisms governing host-microbiota interactions in ISC homeostasis. Insights gained from this review provide strategies for the development of dietary or microbiota-based interventions to foster gut health.

Innate Immune Response-Mediated Inflammation in Viral Pneumonia

Abstract Objective This study aims to investigate the intricate interactions between viral infections, specifically within the context of community-acquired pneumonia. We seek to shed light on the underestimation of viral pneumonia cases, utilizing advancements in molecular diagnostic testing. Methods The investigation involves a comprehensive review of existing literature to explore the prevalence and impact of various viruses causing pneumonia in both children and adults. Our focus spans parainfluenza virus, respiratory syncytial virus, human bocavirus, human metapneumovirus, and rhinoviruses in children and coronaviruses, rhinoviruses, and influenza viruses in adults. The study further delves into the host's innate immune response, emphasizing the roles of pattern recognition receptors (PRRs), type I interferons (IFNs), proinflammatory cytokines, and other immune cells during viral infections. Results The analysis reveals a substantial global burden of viral community-acquired pneumonia, estimating approximately 200 million cases annually in children and adults combined. This study underscores viruses' significant, previously underestimated role in causing pneumonia. Insights into specific viruses affecting different age groups and their prevalence in various geographical settings are provided. Conclusion In conclusion, this review emphasizes the necessity of recognizing the substantial contribution of viral infections to community-acquired pneumonia cases. The host's innate immune response, mediated by PRRs, type I IFNs, and other immune mediators, is pivotal in preventing viral invasion and replication. The study accentuates the importance of continued research into understanding the innate immune mechanisms involved in viral infections and the resulting inflammation.

Role of pattern recognition receptors and microbiota-derived ligands in obesity

Obesity is associated with activation of low-grade inflammation in tissues metabolically relevant for the regulation glucose homeostasis. The gut microbiota has been extensively linked to the inflammatory responses observed during obesity emphasizing the interconnection between host immunity and metabolism during obesity. Gut microbiota together with alteration of the gut barrier functions provide a myriad of circulating ligands for the pattern recognition receptors (PRRs) expressed in innate immune cells and nonimmune cells. PRR-dependent signalling drives the expression of a wide range of genes beyond the inflammatory response depending on the specific functions of the targeted cells and on the physiological context. PRRs activation can have opposite effects on host metabolic inflammation. Nucleotide-binding oligomerization domain 1 (NOD1) or NOD-like Receptor pyrin domain containing 3 (NLRP3) activation promote metabolic inflammation and insulin resistance while NOD2 activation improves insulin sensitivity and glucose homeostasis during obesity. Toll-like receptors (TLRs) 2, 4 and 5 also display specific effects on metabolic tissues. TLR5 deficient mice are prone to obesity and inflammation in response to high fat diet, while injection of TLR5 ligand, flagellin, has a protective effect toward diet-induced obesity. To the opposite TLR2 and 4 activations are associated with deleterious metabolic outcome during obesity. TLR4 activation enhances metabolic inflammation and insulin resistance and TLR2 via its activation by molecules derived from the gut microbiota favours the onset of obesity. It is now clear that activation of PRRs by bacterial derived molecules plays a key role in the host metabolic regulation. PRRs are expressed in various cell types complicating the understanding of the mechanisms underlying the relationship between PRRs activation/silencing and metabolic inflammation in obesity context. This review presents an overview of the current understanding of the interrelationship between the gut microbiota and PRRs, with a focus on its consequences for obesity and related metabolic diseases.

Role of pattern recognition receptors in chemotherapy-induced neuropathic pain.

Progress in the development of effective chemotherapy is producing a growing population of patients with acute and chronic painful chemotherapy-induced peripheral neuropathy (CIPN), a serious treatment-limiting side effect for which there is currently no US Food and Drug Administration-approved treatment. CIPNs induced by diverse classes of chemotherapy drugs have remarkably similar clinical presentations, leading to the suggestion they share underlying mechanisms. Sensory neurons share with immune cells the ability to detect damage associated molecular patterns (DAMPs), molecules produced by diverse cell types in response to cellular stress and injury, including by chemotherapy drugs. DAMPs, in turn, are ligands for pattern recognition receptors (PRRs), several of which are found on sensory neurons, as well as satellite cells, and cells of the immune system. In the present experiments, we evaluated the role of two PRRs, TLR4 and RAGE, present in dorsal root ganglion (DRG), in CIPN. Antisense (AS)-oligodeoxynucleotides (ODN) against TLR4 and RAGE mRNA were administered intrathecally before ('prevention protocol') or 3 days after ('reversal protocol') the last administration of each of three chemotherapy drugs that treat cancer by different mechanisms (oxaliplatin, paclitaxel and bortezomib). TLR4 and RAGE AS-ODN prevented the development of CIPN induced by all three chemotherapy drugs. In the reversal protocol, however, while TLR4 AS-ODN completely reversed oxaliplatin- and paclitaxel-induced CIPN, in rats with bortezomib-induced CIPN it only produced a temporary attenuation. RAGE AS-ODN, in contrast, reversed CIPN induced by all three chemotherapy drugs. When a TLR4 antagonist was administered intradermally to the peripheral nociceptor terminal, it did not affect CIPN induced by any of the chemotherapy drugs. However, when administered intrathecally, to the central terminal, it attenuated hyperalgesia induced by all three chemotherapy drugs, compatible with a role of TLR4 in neurotransmission at the central terminal but not sensory transduction at the peripheral terminal. Finally, since it has been established that cultured DRG neurons can be used to study direct effects of chemotherapy on nociceptors, we also evaluated the role of TLR4 in CIPN at the cellular level, using patch-clamp electrophysiology in DRG neurons cultured from control and chemotherapy-treated rats. We found that increased excitability of small-diameter DRG neurons induced by in vivo and in vitro exposure to oxaliplatin is TLR4-dependent. Our findings suggest that in addition to the established contribution of PRR-dependent neuroimmune mechanisms, PRRs in DRG cells also have an important role in CIPN.

Inflammasomes in Atherosclerosis-From Pathophysiology to Treatment.

Atherosclerosis, a chronic inflammatory disease characterized by arterial plaque accumulation, remains a significant global health challenge. In recent years, inflammasomes, the intracellular multiprotein complexes crucial for initiating innate immune responses, have emerged as key players in atherosclerosis pathophysiology. This review article aims to provide a comprehensive overview of the current understanding of inflammasome activation and its impact on atherosclerosis development and progression. We explore the intricate interplay between traditional cardiovascular risk factors and inflammasome activation, leading to the perpetuation of inflammatory cascades that drive plaque formation and instability. The review focuses on the molecular mechanisms underlying inflammasome activation, including the role of pattern recognition receptors and cytokines in this process. Moreover, we discuss the contribution of inflammasomes to endothelial dysfunction, foam cell formation, and vascular inflammation. Additionally, recent advances in therapeutic strategies targeting inflammasomes are examined, including pharmacological agents and potential immunomodulatory approaches. By collating and analyzing the current evidence, this review provides valuable insights into the potential of inflammasome-targeted therapies for atherosclerosis management and treatment. Understanding the pivotal role of inflammasomes in atherosclerosis pathophysiology offers promising prospects for developing effective and personalized therapeutic interventions that can mitigate the burden of this prevalent cardiovascular disorder and improve patient outcomes.

Immune functions of pattern recognition receptors in Lepidoptera.

Pattern recognition receptors (PRRs), as the "sensors" in the immune response, play a prominent role in recognizing pathogen-associated molecular patterns (PAMPs) and initiating an effective defense response to pathogens in Lepidoptera. It is becoming increasingly clear that damage-associated molecular patterns (DAMPs) normally play a physiological role within cells; however, when exposed to extracellular, they may become "part-time" critical signals of the immune response. Based on research in recent years, we review herein typical PRRs of Lepidoptera, including peptidoglycan recognition protein (PGRP), gram-negative binding protein (GNBP), β-1,3-glucan recognition protein (βGRP), C-type lectin (CTL), and scavenger receptor (SR). We also outline the ways in which DAMPs participate in the immune response and the correlation between PRRs and immune escape. Taken together, these findings suggest that the role of PRRs in insect innate immunity may be much greater than expected and that it is possible to recognize a broader range of signaling molecules.

Identification of potent target and its mechanism of action of Tripterygium wilfordii Hook F in the treatment of lupus nephritis.

The Chinese anti-rheumatic herbal remedy Tripterygium wilfordii Hook F (TWHF) has been widely shown to be effective in treating lupus nephritis (LN), but the therapeutic targets and mechanisms of action are still unclear. In this study, we aimed to combine mRNA expression profile analysis and network pharmacology analysis to screen the pathogenic genes and pathways involved in LN and to explore the potential targets of TWHF in the treatment of LN. The mRNA expression profiles of LN patients were used to screen differentially expressed genes (DEGs) and to predict associated pathogenic pathways and networks via the Ingenuity Pathway Analysis database. Through molecular docking, we predicted the mechanism by which TWHF interacts with candidate targets. A total of 351 DEGs were screened from the glomeruli of LN patients and were mainly concentrated in the role of pattern recognition receptors in the recognition of bacteria and viruses and interferon signaling pathways. A total of 130 DEGs were screened from the tubulointerstitium of LN patients, which were concentrated in the interferon signaling pathway. TWHF might be effective in treating LN by hydrogen bonding to regulate the functions of 24 DEGs (including HMOX1, ALB, and CASP1), which are mainly concentrated in the B-cell signaling pathway. The mRNA expression profile of renal tissue from LN patients revealed a large number of DEGs. TWHF has been shown to interact with the DEGs (including HMOX1, ALB and CASP1) through hydrogen bonding to treat LN.

Innate immune response in patients with acute Chikungunya disease.

Chikungunya disease (CHIKD) is an arbovirose that presents with high morbidity, mainly due to arthralgia. Inflammatory mediators including IL-6, IL-1β, GM-CSF and others have been implicated in the pathogenesis of CHIKD, whilst type I interferons can be associated with better outcomes. The role of pattern recognition receptors has been studied incompletely. Here, we evaluated the expression of RNA-specific PRRs, their adaptor molecules and downstream cytokines in acute CHIKD patients. Twenty-eight patients were recruited during the 3rd-5th day after the symptoms onset for clinical examination, peripheral blood collection and qRT-PCR analysis of PBMC to compare to the healthy control group (n = 20). We observed common symptoms of acute CHIKD, with fever, arthralgia, headache and myalgia being the most frequent. Compared with uninfected controls, acute CHIKV infection upregulates the expression of the receptors TLR3, RIG-I and MDA5, and also the adaptor molecule TRIF. Regarding cytokine expression, we found an upregulation of IL-6, IL-12, IFN-α, IFN-β and IFN-γ, which are related directly to the inflammatory or antiviral response. The TLR3-TRIF axis correlated with high expression of IL-6 and IFN-α. Interestingly, greater expression of MDA5, IL-12 and IFN-α was related to lower viral loads in CHIKD acute patients. Together, these findings help to complete the picture of innate immune activation during acute CHIKD, while confirming the induction of strong antiviral responses. Drawing the next steps in the understanding of the immunopathology and virus clearance mechanisms of CHIKD should be of utter importance in the aid of the development of effective treatment to reduce the severity of this debilitating disease.

The role of pattern recognition receptors in crustacean innate immunity

AbstractCrustacean species are among the most valued seafood with socioeconomic and ecological implications in the global fisheries sector. Microbial infections to the farming stock due to continued expansion and aquaculture puts global crustacean production at risk. Understanding and reviewing the complex innate immune system of crustaceans would be pivotal in formulating informed decisions for the control and management of epidemic diseases, thus making the global crustacean aquaculture industry sustainable. Under the purview of innate immunity in crustaceans, pattern recognition receptors (PRRs) represent the sensors capable of discriminating non‐self pathogenic modules and invoking the activation of immune responses. The immunity to infections can be manifested at cellular (via phagocytosis, apoptosis, nodulation and encapsulation) and humoral (effected by prophenoloxidase cascade, lectins, antimicrobial proteins) levels leading to the elimination of pathogens or subversion of the pathogenic implications. In this review, we discuss the participatory role of 12 types of PRRs identified from crustacean species with an exhaustive focus on structural and functional specificities in binding to pathogens and possible execution of the immune activity. Moreover, we have elaborated on the PRRs‐associated or possible signalling cascades (Toll‐NFκB, IMD‐NFκB and JAK‐STAT) in crustacean species that could bridge our understanding of the resistance or susceptibility of the host to varied pathogenic infections thus providing clues to the regulatory mechanisms involved in pathogenesis of infectious diseases and mechanisms of immunity.

The Role of Pattern Recognition Receptor (PRR) in the Body's Defense System: A Narrative Literature Review

Each cell has receptors on the cell surface that specifically bind to solutes (ligands) produced during tissue damage or infection. This review aimed to describe the role of PRR in the human body's defense system. The binding of the ligand to its receptor results in the activation of intracellular signaling pathways and cell activation. The B and T lymphocytes of the adaptive immune system have developed surface receptors (that is, the T-cell receptor, or TCR, and the B-cell receptor, or BCR) that bind a broad spectrum of antigens. The cells involved in innate resistance have developed a distinct set of receptors that recognize a much more limited array of specific molecules. These are called pattern recognition receptor (PRR), and they recognize the molecular patterns in infectious agents or their products (pathogen-associated molecular patterns, or PAMP) or products of cellular damage (necrosis or apoptosis; molecular pattern-associated damage, or DAMPs). In conclusion, the pattern recognition receptor (PRR) is a receptor complex that interacts with various molecules, such as PAMP and DAMPs. PRR bonds with these various molecules and play a role in various actions of innate immunity and adaptive immunity.

The role of Nod-like receptors in modulating the microbiota-gut-brain axis following neonatal bacterial infection

Objective: Pediatric infection with diarrheal pathogens causes cognitive deficits in adulthood via an unknown mechanism. Neonatal infection with a bacterial enteric pathogen disrupts the development of the microbiota-gut-brain (MGB) axis in adult mice. Given the role of pattern recognition receptors, including Nucleotide Oligomerization Domain 1 (Nod1) in innate immune responses to infection, our objective was to establish their role in disrupted MGB axis communication following neonatal enteropathogenic Escherichia coli (EPEC) infection. Hypothesis: Intestinal epithelial cell (IEC) Nod1 modulates disrupted MGB axis communication following neonatal EPEC infection. Methods: C57BL/6 (male/female) IEC Nod1 conditional knockout mice (IEC cKO; Cre+) and wild type (WT) littermate controls (Cre-) were used. Neonatal mice were infected on postnatal day 7 (P7) with EPEC (10 5 CFU; strain e2348/69; orogastric gavage), or vehicle control (Luria broth). Colonization was assessed at P14 and P21 (MacConkey agar plating) and disease monitored via weight loss and ileal inflammation (qPCR). Behavior and neuroinflammation were assessed in adulthood (6-8 weeks). Behavioral tests included the novel object recognition task (NOR) for cognitive function, the light/dark (L/D) box for anxiety-like behavior, and open field test (OFT) for general and locomotor behavior. Results: Neonatally EPEC-infected Nod1 cKO mice demonstrated blunted ileal inflammation, with similar decreased expression of Il6, Tlr2, Tlr4, and Nod2 in cKO vs WT EPEC-infected mice ( P = NS, n = 4-6 ), with no evidence of inflammation in uninfected controls (WT or cKO). In contrast, evidence of hippocampal neuroinflammation was present in EPEC-infected Nod1 cKO mice, with increased expression of Iba1, Il6, and Il22 ( P < 0.0001, n = 4-6), compared to sham-infected Nod1 cKO mice or uninfected control mice. In addition, EPEC-infected Nod1 cKO mice demonstrated decreased hippocampal expression of the neurogenesis marker Bdnf ( P < 0.0001, n ≥ 4) compared to EPEC-infected WT mice, or uninfected mice. With respect to behavior, EPEC-infected WT mice had a lower exploration ratio (49.5 ± 1.7% vs. 54.6 ± 1.7%, P = 0.0035, n ≥ 8), whereas EPEC-infected Nod1 cKO mice displayed normal exploration of a novel object compared to uninfected Nod1 cKO mice ( P = NS, n = 10-12), without impacting anxiety-like behavior ( P = NS, n = 10-12). Conclusions: IEC Nod1 is important for maintaining MGB axis communication following neonatal EPEC infection. We speculate that decreased ileal inflammation due to absence of Nod1 IEC expression prevents cognitive deficits in adulthood, despite the evidence of neuroinflammation and impaired neurogenesis. Inflammation in the gut and brain will be further characterized by immunofluorescence in ongoing studies. NIH R01AT009365; NIH R21MH108154. Olivia Orahood is an active-duty member of the United States Space Force. The views expressed in this article are those of the author and do not reflect the official policy or position of the United States Space Force, United States Air Force, Department of Defense, or the U.S. Government This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

P063 Host-mycobiome interactions during the resolution of inflammation in experimental colitis

Abstract Background Recent studies have documented the complexity of the intestinal fungal community (‘mycobiome’) in mice, and clinical and experimental observations have shown that the mycobiome influences both gut health and disease, e.g., IBD. In fact, prior studies have shown that CD patients, compared to healthy controls, harbor higher levels of intestinal Candida tropicalis (Ct), which is the major fungal species detected in the colons of colitic mice after dextran sodium sulfate (DSS) challenge. Moreover, proteins encoded by genes within IBD susceptibility loci, such as the pattern recognition receptor (PRR), NOD2, are known not only to recognize bacterial components, but also a fungal cell wall element, chitin. In fact, the role of PRRs in regulating immunity against intestinal fungi, and how fungi influence IBD remains poorly defined. Methods We challenged DSS colitic wildtype (WT) and Nod2-/- mice with Ct 2 days before DSS administration and subsequently on day 0, 3 and 6. Bone marrow-derived macrophages (BMDMs) from untreated mice were administered chitin in vitro. Results Our data confirms previous studies that Ct challenge does not exacerbate colitis in DSS-treated C57BL/6 WT mice, however, Ct-infected Nod2-/- mice possess a higher fungal burden and exhibit worse colitis symptoms, such as weight loss, decreased stool consistency, and presence of blood in stools, vs. Ct-infected WT mice, indicating an essential and protective role for NOD2 during colitis recovery after Ct challenge. Our results also show that Ct-infected Nod2-/- mice display a marked reduction in colonic Il22 and Il17, which are cytokines previously reported to be important in maintaining epithelial barrier integrity during DSS colitis. These data were confirmed in colons of Ct infected DSS challenged, ileitis prone SAMP1/YitFc (SAMP) mice NOD2 deficient. Moreover, our in vitro data show, a decrease in Il1ß and Il23 in BMDM from SAMP Nod2-/- mice compared to WT after 2h of exposure to chitin. IL-17+ innate lymphoid cells (ILCs) are also known to control fungal burden during opportunistic fungal infections, and interestingly, our findings indicate that Ct infection of Nod2-/- vs. WT mice results in a decreased frequency of mesenteric lymph node–derived type 3 ILCs (ILC3s), suggesting that delay in fungal clearance and recovery in Nod2-/-mice may be due to the inability to mount protective type 3 immune responses. Conclusion Taken together, the data collected suggests that NOD2 is essential to maintain gut mycobiome homeostasis and drives protective innate immune responses, via a macrophage-mediated ILC3 recruitment and IL-17 mechanism, by preventing the overgrowth of opportunistic fungi that may contribute to chronic intestinal inflammation, such as that observed in CD.

Neuroprotection of Food Bioactives in Neurodegenerative Diseases: Role of the Gut Microbiota and Innate Immune Receptors.

Gut-brain connections may be mediated by an assortment of microbial molecules, which can subsequently traverse intestinal and blood-brain barriers and impact neurological function. Pattern recognition receptors (PRRs) are important innate immune proteins in the gut. Gut microbiota act in concert with the PRRs is a novel target for regulating host-microbe signaling and immune homeostasis, which may involve the pathogenesis of neurodegenerative diseases. Natural food bioactives bestow a protective advantage on neurodegenerative diseases through immunomodulatory effects of the modified gut microbiota or alterations in the landscape of microbiota-produced metabolites via PRRs modulation. In this review, we discuss the effect of natural food bioactives on the gut microbiota and the role of PRRs in the gut-brain crosstalk. We focused on the neuroprotective mechanisms of natural bioactive compounds behind the action of the gut microbiota and PRRs. Research advances in natural food bioactives as antineurodegeneration agents were also presented.

Poxviruses and the immune system: Implications for monkeypox virus.

Poxviruses (PXVs) are mostly known for the variola virus, being the cause of smallpox; however, re-emerging PXVs have also shown a great capacity to develop outbreaks of pox-like infections in humans. The situation is alarming; PXV outbreaks have been involving both endemic and non-endemic areas in recent decades. Stopped smallpox vaccination is a reason offered mainly for this changing epidemiology that implies the protective role of immunity in the pathology of PXV infections. The immune system recognizes PXVs and elicits responses, but PXVs can antagonize these responses. Here, we briefly review the immunology of PXV infections, with emphasis on the role of pattern-recognition receptors, macrophages, and natural killer cells in the early response to PXV infections and PXVs’ strategies influencing these responses, as well as taking a glance at other immune cells, which discussion over them mainly occurs in association with PXV immunization rather than PXV infection. Throughout the review, numerous evasion mechanisms are highlighted, which might have implications for designing specific immunotherapies for PXV in the future.

Pattern recognition receptor signaling and innate immune responses to schistosome infection.

Schistosomiasis remains to be a significant public health problem in tropical and subtropical regions. Despite remarkable progress that has been made in the control of the disease over the past decades, its elimination remains a daunting challenge in many countries. This disease is an inflammatory response-driven, and the positive outcome after infection depends on the regulation of immune responses that efficiently clear worms and allow protective immunity to develop. The innate immune responses play a critical role in host defense against schistosome infection and pathogenesis. Initial pro-inflammatory responses are essential for clearing invading parasites by promoting appropriate cell-mediated and humoral immunity. However, elevated and prolonged inflammatory responses against the eggs trapped in the host tissues contribute to disease progression. A better understanding of the molecular mechanisms of innate immune responses is important for developing effective therapies and vaccines. Here, we update the recent advances in the definitive host innate immune response to schistosome infection, especially highlighting the critical roles of pattern recognition receptors and cytokines. The considerations for further research are also provided.

Role of alarmins in poststroke inflammation and neuronal repair.

Severe loss of cerebral blood flow causes hypoxia and glucose deprivation in the brain tissue, resulting in necrotic cell death in the ischemic brain. Several endogenous molecules, called alarmins or damage-associated molecular patterns (DAMPs), are extracellularly released from the dead cells to activate pattern recognition receptors (PRRs) in immune cells that infiltrate into ischemic brain tissue following the disruption of the blood-brain barrier (BBB) after stroke onset. The activated immune cells produce various inflammatory cytokines and chemokines, triggering sterile cerebral inflammation in the ischemic brain that causes further neuronal cell death. Poststroke inflammation is resolved within several days after stroke onset, and neurological functions are restored to some extent as neural repair occurs around peri-infarct neurons. Clearance of DAMPs from the injured brain is necessary for the resolution of poststroke inflammation. Neurons and glial cells also express PRRs and receive DAMP signaling. Although the role of PRRs in neural cells in the ischemic brain has not yet been clarified, the signaling pathway is likely to be contribute to stroke pathology and neural repair after ischemic stroke. This review describes the molecular dynamics, signaling pathways, and functions of DAMPs in poststroke inflammation and its resolution.

Modern view on the role of pattern-recognition receptors and signaling pathways in the development of innate immunity in viral infections

Features of organization and functioning of pattern-recognizing receptors and signaling pathways in induction of antiviral immune response are considered. The recognition of antigenic structures of the virus is carried out by pathogen-associated molecular patterns of innate immunity cells. These are Toll-like receptors, nucleotide-binding oligomerization domain-like receptors, lectin C-type receptors, and RIG-I-like receptors. The functioning of these receptor structures depends on protein molecules that provide activation signals. These are the adapter proteins of the primary response of myeloid differentiation 88, interleukin-1 receptor-associated kinase, nuclear factor-KB. Interactions of cellular proteins in the activation of signaling pathways are complex and receptor-ligand reactions can lead to different outcomes in a single cell, in most cases leading to a limitation of viral reproduction. An important obstacle to the effective recognition of viruses and the development of an adequate immune response is the close organization of viral antigens and receptor structures of the cell. The role of LGP2 protein molecules is associated with the peculiarities of the development of the immune response, which can be not only positive, but also negative regulators of the transmission of excitation signals from intracellular cytoplasmic helicase receptors. A number of viral proteins inhibit activation signals, which ultimately leads to various options for the development of the immune response. A special role belongs to the transmembrane protein of the endoplasmic reticulum, which increases the expression of interferon a stimulator of interferon genes that provide detection of deoxyribonucleic acid viruses. Maximum activation of this protein, ensures the effective development of a cellular antiviral immune response.

Renal functional, transcriptome, and methylome adaptations in pregnant Sprague Dawley and Brown Norway rats.

Pregnancy induces maternal renal adaptations that include increased glomerular filtration rate and renal blood flow which can be compromised in obstetrical complications such as preeclampsia. Brown Norway (BN) rat pregnancies are characterized by placental insufficiency, maternal hypertension, and proteinuria. We hypothesized that BN pregnancies would show renal functional, anatomical, or molecular features of preeclampsia. We used the Sprague-Dawley (CD) rat as a model of normal pregnancy. Pregnancy increased the glomerular filtration rate by 50% in CD rats and 12.2% in BN rats compared to non-pregnancy, and induced proteinuria only in BN rats. BN pregnancies showed a decrease in maternal plasma calcitriol levels, which correlated with renal downregulation of 1-alpha hydroxylase and upregulation of 24-hydroxylase. RNA sequencing revealed that pregnancy induced 297 differentially expressed genes (DEGs) in CD rats and 174 DEGs in BN rats, indicating a 70% increased response to pregnancy in CD compared to BN rats. Pregnancy induced activation of innate immune pathways such as ‘Role of Pattern Recognition Receptors’, and ‘Interferon signaling’ with interferon regulatory factor 7 as a common upregulated upstream factor in both rat strains. Comparison of rat strain transcriptomic profiles revealed 475 DEGs at non-pregnancy and 569 DEGs at pregnancy with 205 DEGs shared at non-pregnancy (36%), indicating that pregnancy interacted with rat strain in regulating 64% of the DEGs. Pathway analysis revealed that pregnancy induced a switch in renal transcriptomics in BN rats from ‘inhibition of renal damage’ to ‘acute phase reaction’, ‘recruitment of immune cells’ and ‘inhibition of 1,25-(OH)2-vitamin D synthesis’. Key upstream regulators included peroxisome-proliferator-activated receptor alpha (PPARA), platelet-derived growth factor B dimer (PDGF-BB), and NF-kB p65 (RELA). DNA methylome profiling by reduced representation bisulfite sequencing studies revealed that the DEGs did not correlate with changes in promoter methylation. In sum, BN rat kidneys respond to pregnancy-specific signals with an increase in pro-inflammatory gene networks and alteration of metabolic pathways including vitamin D deficiency in association with mild proteinuria and blunted GFR increase. However, the lack of glomerular endotheliosis and mild hypertension/proteinuria in pregnant BN rats limits the relevance of this rat strain for preeclampsia research.

The Fragile X Syndrome‐Related Protein, FMRP, Modulates Innate Immune Gene Expression in Macrophages

Fragile X mental retardation protein (FMRP) is an RNA‐binding protein with a wide range of functions, including mRNA translation, mRNA transport, and mitochondrial organization. Loss of FMRP due to silencing of the FRM1 gene is associated with intellectual disability and has been implicated in viral pathogenesis and cancer risk. However, the contribution of FMRP to innate immunity in response to bacterial infection remains understudied. Given the function of FMRP in post‐transcriptional regulation, we hypothesized that loss of FMRP would impair repression of inflammatory cytokines in response to infection with the bacterial pathogen Listeria monocytogenes. We used RNA‐seq as an unbiased approach to identify global gene expression changes in FMRP‐deficient murine macrophages, both at rest and during infection with Listeria monocytogenes. We identified 22 differentially expressed genes that were upregulated in resting FMRP KO macrophages, including aconitate decarboxylase 1 (ACOD1, IRG1), erythroid differentiation regulator 1 (Erdr1), and Cxcl10, as well as 6 downregulated genes, including microRNA 6236 and mitochondrially encoded ATP synthase 8 (MT‐ATP8). Unbiased canonical pathway analysis of the upregulated genes in resting FMRP KO macrophages revealed significant enrichment of genes related to phagosome maturation and immunity. Within the downregulated genes, unbiased canonical pathway analysis revealed pathways related to EIF2 signaling and BEX2 Signaling. Analysis of L. monocytogenes infected FMRP KO macrophages revealed 31 upregulated genes, including the E3 ubiquitin ligase gene midline 1 (Mid1, Trim18) and the complement genes C1QA and C1QB, as well as 8 downregulated genes including plasminogen activator urokinase (PLAU). Canonical pathway analysis of the downregulated genes included DNA‐damage signaling and role of pattern recognition receptors in recognition of bacteria and viruses. Surprisingly, when comparing differentially enriched genes in infected macrophages to uninfected macrophages, a greater number of innate immune transcripts were upregulated in resting macrophages lacking FMRP. Together, these data suggest that FMRP may also have a role in innate immunity.