Interleukin-1 Receptor-Like 2: One Receptor, Three Agonists, and Many Implications

Manzanares-Meza, Laura D; Valle‐Rios, Ricardo; Medina-Contreras, Óscar

doi:10.1089/jir.2021.0173

Cited by 4 publications

(5 citation statements)

References 85 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We also found that elevation of 1‐stearoyl‐2‐oleoyl‐GPE (18:0 / 18:1) in female AD is positively associated with IL1RL2 (

\rho

= 0.33) and p21 activated kinase 1 ( PAK1 ,

\rho

= 0.33) gene expression. IL1RL2 plays crucial roles in interleukin 1 (IL‐1) family signaling, 57,58 while PAK1 is involved in both the C‐type lectin receptors 59 (CLRs) pathway and Toll ‐like receptor (TLR) signaling 60,61 . An elevated level of GPC correlates with IL17RB expression (

\rho

= 0.55) 62 and RAF1 expression (

\rho

= 0.53), potentially regulating IL‐17 signaling and the CLR pathways in male AD.…”

Section: Resultsmentioning

confidence: 99%

“…We also found that elevation of 1-stearoyl-2-oleoyl-GPE (18:0 / 18:1) in female AD is positively associated with IL1RL2 (𝜌 = 0.33) and p21 activated kinase 1 (PAK1, 𝜌 = 0.33) gene expression. IL1RL2 plays crucial roles in interleukin 1 (IL-1) family signaling, 57,58 while PAK1 is involved in both the C-type lectin receptors 59 (CLRs) pathway F I G U R E 3 Sex-specific metabolite-gene association network in AD. Spearman's rank correlation coefficient (ρ) was used to create the metabolite-gene association network.…”

Section: Differential Immunometabolism Between Males and Females With Admentioning

confidence: 99%

See 1 more Smart Citation

Microglial immunometabolism endophenotypes contribute to sex difference in Alzheimer's disease

Hou,

Caldwell,

Lathia

et al. 2023

Alzheimer's & Dementia

View full text Add to dashboard Cite

IntroductionThe molecular mechanisms that contribute to sex differences, in particular female predominance, in Alzheimer's disease (AD) prevalence, symptomology, and pathology, are incompletely understood.MethodsTo address this problem, we investigated cellular metabolism and immune responses (“immunometabolism endophenotype”) across AD individuals as a function of sex with diverse clinical diagnosis of cognitive status at death (cogdx), Braak staging, and Consortium to Establish a Registry for AD (CERAD) scores using human cortex metabolomics and transcriptomics data from the Religious Orders Study / Memory and Aging Project (ROSMAP) cohort.ResultsWe identified sex‐specific metabolites, immune and metabolic genes, and pathways associated with the AD diagnosis and progression. We identified female‐specific elevation in glycerophosphorylcholine and N‐acetylglutamate, which are AD inflammatory metabolites involved in interleukin (IL)‐17 signaling, C‐type lectin receptor, interferon signaling, and Toll‐like receptor pathways. We pinpointed distinct microglia‐specific immunometabolism endophenotypes (i.e., lipid‐ and amino acid‐specific IL‐10 and IL‐17 signaling pathways) between female and male AD subjects. In addition, female AD subjects showed evidence of diminished excitatory neuron and microglia communications via glutamate‐mediated immunometabolism.DiscussionOur results point to new understanding of the molecular basis for female predominance in AD, and warrant future independent validations with ethnically diverse patient cohorts to establish a likely causal relationship of microglial immunometabolism in the sex differences in AD.HIGHLIGHTS Sex‐specific immune metabolites, gene networks and pathways, are associated with Alzheimer's disease pathogenesis and disease progression. Female AD subjects exhibit microglial immunometabolism endophenotypes characterized by decreased glutamate metabolism and elevated interleukin‐10 pathway activity. Female AD subjects showed a shift in glutamate‐mediated cell‐cell communications between excitatory neurons to microglia and astrocyte.

show abstract

“…We also found that elevation of 1‐stearoyl‐2‐oleoyl‐GPE (18:0 / 18:1) in female AD is positively associated with IL1RL2 (

\rho

= 0.33) and p21 activated kinase 1 ( PAK1 ,

\rho

\rho

= 0.55) 62 and RAF1 expression (

\rho

= 0.53), potentially regulating IL‐17 signaling and the CLR pathways in male AD.…”

Section: Resultsmentioning

confidence: 99%

Section: Differential Immunometabolism Between Males and Females With Admentioning

confidence: 99%

Microglial immunometabolism endophenotypes contribute to sex difference in Alzheimer's disease

Hou,

Caldwell,

Lathia

et al. 2023

Alzheimer's & Dementia

View full text Add to dashboard Cite

show abstract

“…IL-1, IL-6, and TNF are pivotal pro-inflammatory cytokines involved in the dynamics of cytokine storms. IL-1 binds to the IL-1 receptor (IL-1R) and activates a cascade of NF-κB pro-inflammatory signaling pathways[ 56 , 57 ]. IL-6, another inflammatory cytokine, binds to the membrane-bound IL-6 receptor (IL-6R) and creates a physiological immune balance.…”

Section: Discussionmentioning

confidence: 99%

Protective effects of Jing-Si-herbal-tea in inflammatory cytokines-induced cell injury on normal human lung fibroblast via multiomic platform analysis

Wang,

Yang,

Chen

et al. 2024

Tzu Chi Medical Journal

View full text Add to dashboard Cite

Objectives: The protective effects and related mechanisms of Jing-Si herbal tea (JSHT) were investigated in cellular damage mediated by pro-inflammatory cytokines, including interleukin (IL)-1β, IL-6, and tumor necrosis factor-α, on normal human lung fibroblast by multiomic platform analysis. Materials and Methods: The in silico high-throughput target was analyzed using pharmacophore models by BIOVIA Discovery Studio 2022 with ingenuity pathway analysis software. To assess cell viability, the study utilized the MTT assay technique. In addition, the IncuCyte S3 ZOOM System was implemented for the continuous monitoring of cell confluence of JSHT-treated cytokine-injured HEL 299 cells. Cytokine concentrations were determined using a Quantibody Human Inflammation Array. Gene expression and signaling pathways were determined using next-generation sequencing. Results: In silico high-throughput target analysis of JSHT revealed ingenuity in canonical pathways and their networks. Glucocorticoid receptor signaling is a potential signaling of JSHT. The results revealed protective effects against the inflammatory cytokines on JSHT-treated HEL 299 cells. Transcriptome and network analyses revealed that induction of helper T lymphocytes, TNFSF12, NFKB1-mediated relaxin signaling, and G-protein coupled receptor signaling play important roles in immune regulatory on JSHT-treated cytokine-injured HEL 299 cells. Conclusion: The findings from our research indicate that JSHT holds promise as a therapeutic agent, potentially offering advantageous outcomes in treating virus infections through various mechanisms. Furthermore, the primary bioactive components in JSHT justify extended research in antiviral drug development, especially in the context of addressing coronavirus.

show abstract

“…In addition to the central role of IL-36 receptor signaling in the pathogenesis of GPP, evidence suggests that IL-36 may have a role in the pathogenesis of other diseases (115,116); including inflammatory bowel disease (117,118), hidradenitis suppurativa (119,120), arthritis (121)(122)(123), systemic lupus erythematosus (124,125), pyoderma gangrenosum (126), and Netherton syndrome (127). Phase 2 clinical trials of spesolimab in the treatment of hidradenitis suppurativa are active (NCT04876391), or recently completed (NCT04762277 (128), and a Phase 2/3 clinical trial of spesolimab in the treatment of Netherton syndrome is in progress (NCT05856526).…”

Section: Unmet Needs In Gpp and The Future Of Il-36 Pathway Modulationmentioning

confidence: 99%

“…However, a recent Phase 2b randomized placebocontrolled trial of spesolimab in patients with PPP did not meet its primary endpoint (110). Investigations are also underway into the possible role of IL-36 cytokines in fibrotic disorders (115) and malignancy (129-131).…”

Section: Unmet Needs In Gpp and The Future Of Il-36 Pathway Modulationmentioning

confidence: 99%

The role of the interleukin-36 axis in generalized pustular psoriasis: a review of the mechanism of action of spesolimab

Hawkes,

Visvanathan,

Krueger

2023

Front. Immunol.

View full text Add to dashboard Cite

Generalized pustular psoriasis (GPP) is a rare, chronic, inflammatory skin disorder characterized by recurrent flares associated with skin erythema, desquamation, and widespread superficial sterile pustules, which may be severe (“lakes of pus”). Systemic symptoms are often present, including malaise, fever, and skin pain. In GPP, innate immune responses are driven by abnormal activation of the interleukin (IL)-36-chemokine-neutrophil axis and excessive neutrophil infiltration. This review highlights the IL-36 pathway in the context of the IL-1 superfamily and describes how unopposed IL-36 signaling can lead to the development of GPP. Targeted inhibition of the IL-36 receptor (IL-36R) is an attractive therapeutic strategy in the treatment of GPP, including flare prevention and sustained disease control. Spesolimab is a first-in-class, humanized, monoclonal antibody that binds specifically to the IL-36R and antagonizes IL-36 signaling. Spesolimab was approved by the US Food and Drug Administration in September 2022 to treat GPP flares in adults and was subsequently approved for GPP flare treatment in other countries across the world. Anti-IL-36R therapy, such as spesolimab, can mitigate flares and address flare prevention in GPP, presumably through rebalancing IL-36 signaling and modulating the pro-inflammatory response of the downstream effectors.

show abstract

Interleukin-1 Receptor-Like 2: One Receptor, Three Agonists, and Many Implications

Cited by 4 publications

References 85 publications

Microglial immunometabolism endophenotypes contribute to sex difference in Alzheimer's disease

Microglial immunometabolism endophenotypes contribute to sex difference in Alzheimer's disease

Protective effects of Jing-Si-herbal-tea in inflammatory cytokines-induced cell injury on normal human lung fibroblast via multiomic platform analysis

The role of the interleukin-36 axis in generalized pustular psoriasis: a review of the mechanism of action of spesolimab

Contact Info

Product

Resources

About