IL-1R1 signaling in TBI: assessing chronic impacts and neuroinflammatory dynamics in a mouse model of mild closed-head injury.

Neuroinflammation contributes to secondary injury cascades following traumatic brain injury (TBI), with alternating waves of inflammation and resolution. Interleukin-1 (IL-1), a critical neuroinflammatory mediator originating from brain endothelial cells, microglia, astrocytes, and peripheral immune cells, is acutely overexpressed after TBI, propagating secondary injury and tissue damage. IL-1 affects blood-brain barrier permeability, immune cell activation, and neural plasticity. Despite the complexity of cytokine signaling post-TBI, we hypothesize that IL-1 signaling specifically regulates neuroinflammatory response components. Using a closed-head injury (CHI) TBI model, we investigated IL-1's role in the neuroinflammatory cascade with a new global knock-out (gKO) mouse model of the IL-1 receptor (IL-1R1), which efficiently eliminates all IL-1 signaling. We found that IL-1R1 gKO attenuated behavioral impairments 14 weeks post-injury and reduced reactive microglia and astrocyte staining in the neocortex, corpus callosum, and hippocampus. We then examined whether IL-1R1 loss altered acute neuroinflammatory dynamics, measuring gene expression changes in the neocortex at 3, 9, 24, and 72 h post-CHI using the NanoString Neuroinflammatory panel. Of 757 analyzed genes, IL-1R1 signaling showed temporal specificity in neuroinflammatory gene regulation, with major effects at 9 h post-CHI. IL-1R1 signaling specifically affected astrocyte-related genes, selectively upregulating chemokines like Ccl2, Ccl3, and Ccl4, while having limited impact on cytokine regulation, such as Tnfα. This study provides further insight into IL-1R1 function in amplifying the neuroinflammatory cascade following CHI in mice and demonstrates that suppression of IL-1R1 signaling offers long-term protective effects on brain health.

A paracrine circuit of IL-1ß/IL-1R1 between myeloid and tumor cells drives genotype-dependent glioblastoma progression.

Monocytes and monocyte-derived macrophages (MDMs) from blood circulation infiltrate glioblastoma (GBM) and promote growth. Here, we show that PDGFB-driven GBM cells induce the expression of the potent proinflammatory cytokine IL-1ß in MDM, which engages IL-1R1 in tumor cells, activates the NF-κB pathway, and subsequently leads to induction of monocyte chemoattractant proteins (MCPs). Thus, a feedforward paracrine circuit of IL-1ß/IL-1R1 between tumors and MDM creates an interdependence driving PDGFB-driven GBM progression. Genetic loss or locally antagonizing IL-1ß/IL-1R1 leads to reduced MDM infiltration, diminished tumor growth, and reduced exhausted CD8+ T cells and thereby extends the survival of tumor-bearing mice. In contrast to IL-1ß, IL-1α exhibits antitumor effects. Genetic deletion of Il1a/b is associated with decreased recruitment of lymphoid cells and loss-of-interferon signaling in various immune populations and subsets of malignant cells and is associated with decreased survival time of PDGFB-driven tumor-bearing mice. In contrast to PDGFB-driven GBM, Nf1-silenced tumors have a constitutively active NF-κB pathway, which drives the expression of MCPs to recruit monocytes into tumors. These results indicate local antagonism of IL-1ß could be considered as an effective therapy specifically for proneural GBM.

The expression profiling and clinical significance of a chronic pain-related gene IL1R1.

Chronic pain is a disease that existed during cancer treatment for a long time. It has been reported that interleukin (IL)-1 is involved in the inflammatory response during tumor development. IL1R1 and IL1R2 are members of the IL-1 receptor family of cytokine receptors. However, few studies have reported the role of chronic pain-related genes, IL1R1, in pan-cancer. In this study, 8 lumbar disc prolapse (LDP) patients and 8 controls with differentially expressed genes were investigated to find chronic pain-related genes. Then, IL1R1 was analyzed using the TCGA database. The clinical survival data from TCGA were used to analyze the prognostic value of IL1R1. This study further evaluated the relationship between IL1R1 and immune checkpoints, immune-activating genes, immunosuppressive genes, chemokines, and chemokine receptors. IL1R1 was expressed in varying degrees in most TCGA tumor types, indicating a better survival status. The expression of IL1R1 is closely related to T cell infiltration, immune checkpoints, immune-activating genes, immunosuppressive genes, chemokines, and chemokine receptors. The results show that IL1R1 is a kind of potential cancer biomarker. Coordination with other immune checkpoints IL1R1k may adjust the immune microenvironment, immunotherapy can be applied to the development of new targeted drugs.

IL1R1+ cancer-associated fibroblasts drive tumor development and immunosuppression in colorectal cancer.

Fibroblasts have a considerable functional and molecular heterogeneity and can play various roles in the tumor microenvironment. Here we identify a pro-tumorigenic IL1R1+, IL-1-high-signaling subtype of fibroblasts, using multiple colorectal cancer (CRC) patient single cell sequencing datasets. This subtype of fibroblasts is linked to T cell and macrophage suppression and leads to increased cancer cell growth in 3D co-culture assays. Furthermore, both a fibroblast-specific IL1R1 knockout and IL-1 receptor antagonist Anakinra administration reduce tumor growth in vivo. This is accompanied by reduced intratumoral Th17 cell infiltration. Accordingly, CRC patients who present with IL1R1-expressing cancer-associated-fibroblasts (CAFs), also display elevated levels of immune exhaustion markers, as well as an increased Th17 score and an overall worse survival. Altogether, this study underlines the therapeutic value of targeting IL1R1-expressing CAFs in the context of CRC.

Cumulus Cells Accelerate Postovulatory Oocyte Aging through IL1-IL1R1 Interaction in Mice.

The oocytes of female mammals will undergo aging after ovulation, also known as postovulatory oocyte aging (POA). Until now, the mechanisms of POA have not been fully understood. Although studies have shown that cumulus cells accelerate POA over time, the exact relationship between the two is still unclear. In the study, by employing the methods of mouse cumulus cells and oocytes transcriptome sequencing and experimental verification, we revealed the unique characteristics of cumulus cells and oocytes through ligand-receptor interactions. The results indicate that cumulus cells activated NF-κB signaling in oocytes through the IL1-IL1R1 interaction. Furthermore, it promoted mitochondrial dysfunction, excessive ROS accumulation, and increased early apoptosis, ultimately leading to a decline in the oocyte quality and the appearance of POA. Our results indicate that cumulus cells have a role in accelerating POA, and this result lays a foundation for an in-depth understanding of the molecular mechanism of POA. Moreover, it provides clues for exploring the relationship between cumulus cells and oocytes.

Interleukin-1 contributes to clonal expansion and progression of bone marrow fibrosis in JAK2V617F-induced myeloproliferative neoplasm.

Chronic inflammation is frequently associated with myeloproliferative neoplasms (MPN), but the role of inflammation in the pathogenesis of MPN remains unclear. Expression of the proinflammatory cytokine interleukin-1 (IL-1) is elevated in patients with MPN as well as in Jak2V617F knock-in mice. Here, we show that genetic deletion of IL-1 receptor 1 (IL-1R1) normalizes peripheral blood counts, reduces splenomegaly and ameliorates bone marrow fibrosis in homozygous Jak2V617F mouse model of myelofibrosis. Deletion of IL-1R1 also significantly reduces Jak2V617F mutant hematopoietic stem/progenitor cells. Exogenous administration of IL-1ß enhances myeloid cell expansion and accelerates the development of bone marrow fibrosis in heterozygous Jak2V617F mice. Furthermore, treatment with anti-IL-1R1 antibodies significantly reduces leukocytosis and splenomegaly, and ameliorates bone marrow fibrosis in homozygous Jak2V617F mice. Collectively, these results suggest that IL-1 signaling plays a pathogenic role in MPN disease progression, and targeting of IL-1R1 could be a useful strategy for the treatment of myelofibrosis.

IL-1R1 blockade attenuates liver injury through inhibiting the recruitment of myeloid-derived suppressor cells in sepsis.

Myeloid-derived suppressor cells (MDSCs) mobilize and migrate from bone marrow to peripheral tissues or immune organs, which is associated with poor prognosis in sepsis. Intervention of MDSCs might be a potential target for the effective treatment of sepsis. In the present study, we demonstrated that IL-1R1 blockade with either recombinant human IL-1R antagonist Anakinra or IL-1R1 deficiency had a protective effect on the liver injury in septic mice. The possible mechanism was that Anakinra treatment and IL-1R1 knockout inhibited the migration of MDSCs to the liver in sepsis, thus attenuating the immune suppression of MDSCs on effector T cells characterized with the decrease in proportion of CD4+ and CD8+ T cells. Furthermore, the switch from pro-inflammatory M1 macrophage to anti-inflammatory M2 phenotype and the ability of bacterial clearance in the liver of septic mice were enhanced obviously by Anakinra and IL-1R1 deficiency, which contributes to the attenuated liver injury. Taken together, these findings provide new ideas for revealing the relationship between IL-1R1 and MDSCs in sepsis, thereby providing a potentially effective target for ameliorating septic liver injury.

IL-1R8 silencing improves the anti-tumor function of freshly isolated human NK cells.

The inhibitory receptor interleukin-1 receptor 8 (IL-1R8) has been recently recognized to be expressed also by human natural killer (NK) cells. This study was aimed to design and optimize IL-1R8 silencing conditions in human NK cells to precisely establish the activity of such receptor in these cells. Electroporation of freshly isolated or IL-2-cultured NK cells with small interfering RNA (siRNA), resulted in a marked, even though variable, IL-1R8-silencing. Although the expression profile revealed downregulation of most genes involved in several intracellular pathways, some genes related to proliferation, expression of some chemokine receptors, antibody-dependent cell cytotoxicity and cytotoxic activity were upregulated in IL-1R8-silenced NK cells. Furthermore, upon IL-15 activation, the majority of genes involved in NK cell function were upregulated in IL-1R8-siRNA-compared with control-siRNA-transfected NK cells. More importantly, in agreement with these findings, the reduction of IL-1R8 gene expression levels resulted in enhanced expression of NK cell activation markers, production of cytokines and chemokines, and cytotoxic activity against several NK cell targets with different susceptibility to NK-mediated lysis. Similar results were obtained following stimulation with IL-18. All together these data, deeply impacting on the main effector functions of human NK cells, can lead to a better understanding of IL-1R8-mediated regulation on these cells and to the design of new strategies for improving NK cell-mediated anti-tumor responses.

Early alveolar macrophage response and IL-1R-dependent T cell priming determine transmissibility of Mycobacterium tuberculosis strains.

Mechanisms underlying variability in transmission of Mycobacterium tuberculosis strains remain undefined. By characterizing high and low transmission strains of M.tuberculosis in mice, we show here that high transmission M.tuberculosis strain induce rapid IL-1R-dependent alveolar macrophage migration from the alveolar space into the interstitium and that this action is key to subsequent temporal events of early dissemination of bacteria to the lymph nodes, Th1 priming, granulomatous response and bacterial control. In contrast, IL-1R-dependent alveolar macrophage migration and early dissemination of bacteria to lymph nodes is significantly impeded in infection with low transmission M.tuberculosis strain; these events promote the development of Th17 immunity, fostering neutrophilic inflammation and increased bacterial replication. Our results suggest that by inducing granulomas with the potential to develop into cavitary lesions that aids bacterial escape into the airways, high transmission M.tuberculosis strain is poised for greater transmissibility. These findings implicate bacterial heterogeneity as an important modifier of TB disease manifestations and transmission.

The Therapeutic Prospects of Targeting IL-1R1 for the Modulation of Neuroinflammation in Central Nervous System Disorders.

The interleukin-1 receptor type 1 (IL-1R1) holds pivotal roles in the immune system, as it is positioned at the "epicenter" of the inflammatory signaling networks. Increased levels of the cytokine IL-1 are a recognized feature of the immune response in the central nervous system (CNS) during injury and disease, i.e., neuroinflammation. Despite IL-1/IL-1R1 signaling within the CNS having been the subject of several studies, the roles of IL-1R1 in the CNS cellular milieu still cause controversy. Without much doubt, however, the persistent activation of the IL-1/IL-1R1 signaling pathway is intimately linked with the pathogenesis of a plethora of CNS disease states, ranging from Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS), all the way to schizophrenia and prion diseases. Importantly, a growing body of evidence is showing that blocking IL-1R1 signaling via pharmacological or genetic means in different experimental models of said CNS diseases leads to reduced neuroinflammation and delayed disease progression. The aim of this paper is to review the recent progress in the study of the biological roles of IL-1R1, as well as to highlight key aspects that render IL-1R1 a promising target for the development of novel disease-modifying treatments for multiple CNS indications.

Intratumoral IL-1R1 expression delineates a distinctive molecular subset with therapeutic resistance in patients with gastric cancer.

BACKGROUND: With the essential role of interleukin-1 signaling in cancer-related inflammation, IL-1R1, the main receptor for both IL-1α and IL-1ß, demonstrated therapeutic potential in several types of cancer, which has been put into clinical trials. However, the expression profile and critical role of IL-1R1 in gastric cancer (GC) remain obscure. This study aimed to investigate the prognostic significance of IL-1R1 expression and its predictive value for chemotherapy and immunotherapy in GC. METHODS: The study enrolled three cohorts, consisting of 409 tumor microarray specimens of GC patients from Zhongshan Hospital, 341 transcriptional data from The Cancer Genome Atlas, and 45 transcriptional data from patients treated with pembrolizumab. IL-1R1 mRNA expression was directly acquired from public datasets, and we also detected IL-1R1 protein expression on tumor microarray by immunohistochemistry. Finally, the associations of IL-1R1 expression with clinical outcomes, immune contexture, and genomic features were analyzed. RESULTS: High IL-1R1 expression predicted poor prognosis and inferior responsiveness to both 5-fluorouracil-based adjuvant chemotherapy (ACT) and immune checkpoint blockade (ICB). IL-1R1 fostered an immunosuppressive microenvironment characterized by upregulated M2 macrophages and exhausted CD8+ T cells infiltration. Moreover, the expression of IL-1R1 was intrinsically linked to genomic alterations associated with targeted therapies in GC. CONCLUSIONS: IL-1R1 served as an independent prognosticator and predictive biomarker for ACT and ICB in GC. Furthermore, IL-1R1 antagonists could be a novel agent alone or combined with current therapeutic strategies in GC.

Why are the phenotypes of TRAF6 knock-in and TRAF6 knock-out mice so different?

The expression of TNF-Receptor Associated Factor 6 (TRAF6) is essential for many physiological processes. Here we studied the phenotype of TRAF6[L74H] knock-in mice which are devoid of TRAF6 E3 ligase activity in every cell of the body, but express normal levels of the TRAF6 protein. Remarkably, TRAF6[L74H] mice have none of the phenotypes seen in TRAF6 KO mice. Instead TRAF6[L74H] mice display an entirely different phenotype, exhibiting autoimmunity, and severe inflammation of the skin and modest inflammation of the liver and lungs. Similar to mice with a Treg-specific knockout of TRAF6, or mice devoid of TRAF6 in all T cells, the CD4+ and CD8+ T cells in the spleen and lymph nodes displayed an activated effector memory phenotype with CD44high/CD62Llow expression on the cell surface. In contrast, T cells from WT mice exhibited the CD44low/CD62Lhigh phenotype characteristic of naïve T cells. The onset of autoimmunity and autoinflammation in TRAF6[L74H] mice (two weeks) was much faster than in mice with a Treg-specific knockout of TRAF6 or lacking TRAF6 expression in all T cells (2-3 months) and we discuss whether this may be caused by secondary inflammation of other tissues. The distinct phenotypes of mice lacking TRAF6 expression in all cells appears to be explained by their inability to signal via TNF Receptor Superfamily members, which does not seem to be impaired significantly in TRAF6[L74H] mice.

IL1R1 gene variants associate with disease susceptibility to IgG4-related periaortitis/periarteritis in IgG4-related disease.

BACKGROUND: IgG4-related disease (IgG4-RD) is an immune-mediated disorder characterized by high serum IgG4 concentration and IgG4-bearing plasma cell infiltration in affected organs. IgG4-related periaortitis/periarteritis is a recently identified disease entity in IgG4-RD that affects the cardiovascular system. Since the genetic factors related to disease onset are unclear, we examined the genetic associations with IgG4-related periaortitis/periarteritis susceptibility. METHODS: A small scale of genome-wide association analysis identified that interleukin 1 receptor type 1 (IL1R1) gene variants were correlated with the development of IgG4-related periaortitis/periarteritis in 75 patients with IgG4-RD. Accordingly, 8 single nucleotide polymorphisms (SNPs) in the IL1R1 gene were selected and genotyped in 124 patients with IgG4-RD (43 with periaortitis/periarteritis and 81 without periaortitis/periarteritis) and 344 healthy subjects. RESULTS: The minor allele frequencies of 6 SNPs (rs2287049, rs3917273, rs2160227, rs951192, rs3917318, rs7582198) were significantly increased in IgG4-related periaortitis/periarteritis patients compared with those without periaortitis/periarteritis (corrected P < 0.05). In addition, the frequency of the AGAAA haplotype, comprised of 5 SNPs (rs3917273, rs2160227, rs951192, rs3917318, rs7582198), was significantly higher in patients with periaortitis/periarteritis (OR = 2.41, 95% CI:1.42-4.10). CONCLUSION: Our findings indicated that IL1R1 genetic polymorphisms contributed to IgG4-related periaortitis/periarteritis and the possibility of certain genetic factors influencing the risk of specific IgG4-RD manifestations.

Expression of obesity- and type-2 diabetes-associated genes in omental adipose tissue of individuals with obesity.

AIMS: Obesity and type 2 diabetes mellitus are two pathologies that share metabolic abnormalities in most of the cases; however, there are differences as well. Some studies have reported that approximately 30% of obese patients have normal glucose and lipid levels in blood despite an accumulation of abdominal adipose tissue. Here, we compare the gene expression in adipose tissue of several genes associated with obesity and/or diabetes between obese patients without T2D and obese patients with T2D. METHODS: Omental adipose tissue was collected during the patients elective bariatric surgery. Gene expression was determined by real-time PCR. Phenotypic variables were correlated with gene expression and 2^-ΔΔCt relative expression analysis between groups was performed. RESULTS: The stronger correlations in the obese without T2D or reference group was between ICAM1 and HbA1c; HP and TC and LDL while in the obese with diabetes or case group the correlation occurred between CSF1 and BMI. A correlation between HP and TC was found in the case group as well. The expression of VEGFA, CCND2, IL1R1 and PTEN was downregulated in the obese with T2D group. CONCLUSIONS: This study identified genes whose expression is different between obese subjects with and without diabetes. Those genes are related to inflammation, cholesterol transport, adipocyte differentiation/expansion and browning.

The interleukin-1 receptor type I promotes the development of aging-associated cardiomyopathy in mice.

BACKGROUND: Aging is associated with metabolic and structural changes causing heart failure with preserved ejection fraction (HFpEF). Interleukin-1 (IL-1) is a pro-inflammatory cytokine involved in aging-related inflammation. OBJECTIVE: We sought to determine whether IL-1 mediates aging-related changes in the heart, as seen in HFpEF. METHODS: We studied age-matched young (4-month-old), middle-aged (14-month-old), and old (23-month-old) wild-type (WT) C57BL/6J and IL-1 receptor type I deficient (IL1RI-KO) male mice. Echocardiography was used to evaluate left ventricular (LV) dimensions and systolic/diastolic function, and a pressure transducer was used to measure the LV end-diastolic pressure. Picrosirius red stain was used to assess for myocardial interstitial fibrosis (MIF) at pathology. RESULTS: WT and IL-1RIKO mice showed a normal cardiac phenotype at young age, without any differences between the two groups. With aging, the WT mice developed LV concentric hypertrophy (as measured by a significant increase in LV mass [+42%, P < 0.01] and relative wall thickness [+34%, P < 0.01]), whereas the aging IL-1RI-KO mice did not. With aging, the WT mice also developed diastolic dysfunction (as measured by a significant increase in isovolumetric relaxation time [+148%, P < 0.01] and a significantly higher LV end-diastolic pressure [+174%, P < 0.01]), whereas the aging IL1RI-KO did not. Aged WT mice showed a significant increase in MIF (+124%, P < 0.01) at cardiac pathology, whereas the aging IL-1RI-KO did not. CONCLUSIONS: Genetically-modified mice lacking the IL-1RI receptor, not responsive to IL-1, are protected from aging-related LV hypertrophy, fibrosis, and diastolic dysfunction. These data support a central role of IL-1 in the pathophysiology of aging-related HFpEF.

Subfornical organ interleukin 1 receptor: A novel regulator of spontaneous and conditioned fear associated behaviors in mice.

Impaired threat responding and fear regulation is a hallmark of psychiatric conditions such as post-traumatic stress disorder (PTSD) and Panic Disorder (PD). Most studies have focused on external psychogenic threats to study fear, however, accumulating evidence suggests a primary role of homeostatic perturbations and interoception in regulating emotional behaviors. Heightened reactivity to interoceptive threat carbon dioxide (CO2) inhalation associates with increased risk for developing PD and PTSD, however, contributory mechanisms and molecular targets are not well understood. Previous studies from our group suggested a potential role of interleukin 1 receptor (IL-1R1) signaling within BBB-devoid sensory circumventricular organ, the subfornical organ (SFO) in CO2-evoked fear. However, the necessity of SFO-IL-1R1 in regulating CO2-associated spontaneous fear as well as, long-term fear potentiation relevant to PD/PTSD has not been investigated. The current study tested male mice with SFO-targeted microinfusion of the IL-1R1 antagonist (IL-1RA) or vehicle in a recently developed CO2-startle-fear conditioning-extinction paradigm. Consistent with our hypothesis, SFO IL-1RA treatment elicited significant attenuation of freezing and increased rearing during CO2 inhalation suggesting SFO-IL1R1 regulation of spontaneous fear to CO2. Intriguingly, SFO IL-1RA treatment normalized CO2-associated potentiation of conditioned fear and impaired extinction a week later suggesting modulation of long-term fear by SFO-IL-1R1 signaling. Post behavior FosB mapping revealed recruitment of prefrontal cortex-amygdala-periaqueductal gray (PAG) areas in SFO-IL-1RA mediated effects. Additionally, we localized cellular IL-1R1 expression within the SFO to blood vessel endothelial cells and observed CO2-induced alterations in IL-1ß/IL-1R1 expression in peripheral mononuclear cells and SFO. Lastly, CO2-evoked microglial activation was attenuated in SFO-IL-1RA treated mice. These observations suggest a peripheral monocyte-endothelial-microglia interplay in SFO-IL-1R1 modulation of CO2-associated spontaneous fear and delayed fear memory. Collectively, our data highlight a novel, "bottom-up" neuroimmune mechanism that integrates interoceptive and exteroceptive threat processing of relevance to fear-related pathologies.

IL-1 receptor signaling in podocytes limits susceptibility to glomerular damage.

Interleukin (IL)-1 receptor type 1 (IL-1R1) activation triggers a proinflammatory signaling cascade that can exacerbate kidney injury. However, the functions of podocyte IL-1R1 in glomerular disease remain unclear. To study the role of IL-1R1 signaling in podocytes, we selectively ablated podocyte IL-1R1 in mice (PKO mice). We then subjected PKO mice and wild-type controls to two glomerular injury models: nephrotoxic serum (NTS)- and adriamycin-induced nephropathy. Surprisingly, we found that IL-1R1 activation in podocytes limited albuminuria and podocyte injury during NTS- and adriamycin-induced nephropathy. Moreover, deletion of IL-1R1 in podocytes drove podocyte apoptosis and glomerular injury through diminishing Akt activation. Activation of Akt signaling abrogated the differences in albuminuria and podocyte injury between wild-type and PKO mice during NTS. Thus, IL-1R1 signaling in podocytes limits susceptibility to glomerular injury via an Akt-dependent signaling pathway. These data identify an unexpected protective role for IL-1R1 signaling in podocytes in the pathogenesis of glomerular disease.NEW & NOTEWORTHY The present study establishes that activation of the receptor for interleukin-1 limits susceptibility to damage to the kidney glomerulus in preclinical mouse models by stimulating Akt signaling cascades inside the podocyte.

Association of IL1R1 gene (SNP rs2071374) with the risk of preeclampsia.

BACKGROUND: Association of IL1R1rs2071374 with the risk of preeclampsia compared with normotensive pregnant women. METHODOLOGY: The study was a case-control study with 304 pregnant women comprising of preeclampsia (n = 152) and normotensive pregnancies (n = 152). And SNP rs2071374 was genotyped by PCR-RFLP method. RESULTS: The presence of IL1R1rs2071374G allele was associated with the increased risk of preeclampsia P = 0.01741, odds ratio = 0.7006 (95% CI: 0.5023-0.9759). CONCLUSION: The results indicated that there was an association in IL1R1 rs2071374SNP with preeclampsia compared to non-preeclampsia women. It is the first study to evaluate that IL1R1 polymorphism is correlated with preeclampsia pathogenesis in the Population in India.

Glycan-mediated functional assembly of IL-1RI: structural insights into completion of the current description for immune response.

Interleukin 1 Receptor type I (IL-1RI) is a multi-domain transmembrane receptor that triggers the inflammatory response. Understanding its detailed mechanism of action is crucial for treating immune disorders. IL-1RI is activated upon formation of its functional assembly that occurs by binding of the IL-1 cytokine and the accessory protein (Il-1RAcP) to it. X-ray crystallography, small-Angle X-ray Scattering and molecular dynamics simulation studies showed that IL-1RI adopts two types of 'compact' and 'extended' conformational states in its dynamical pattern. Furthermore, glycosylation has shown to play a critical role in its activation process. Here, classical and accelerated atomistic molecular dynamics were carried out to examine the role of full glycosylation of IL-1RI and IL-1RAcP in arrangement of the functional assembly. Simulations showed that the 'compact' and 'extended' IL-1RI form two types of 'cytokine-inaccessible-non-signaling' and 'cytokine-accessible-signaling' assemblies with the IL-1RacP, respectively that are both abiding in the presence of glycans. Suggesting that the cytokine binding to IL-1RI is not required for the formation of IL-1RI-IL-1RAcP complex and the 'compact' complex could act as a down-regulatory mechanism. The 'extended' complex is maintained by formation of several persistent hydrogen bonds between the IL-1RI-IL-1RAcP inter-connected glycans. Taken together, it was shown that full glycosylation regulates formation of the IL-1RI functional assembly and play critical role in cytokine biding and triggering the IL-1RI involved downstream pathways in the cell.Communicated by Ramaswamy H. Sarma.