| (Postmortem) | (Ising, 2019 #1896) cortex, ihc (but no quantification) | cortex, WB | |||
| (Brosseron, 2022 #2016) DELCODE and F.ACE cohorts, (아마 MCI), ↑ MIF (NLRP3/CASP/ASC/IL-1b/IL-18등은 안 봄) | |||||
| CSF | (Rui, 2021 #2026) | ||||
| plasma | (Rui, 2021 #2026) | ||||
| PBMC | (Rui, 2021 #2026) | ||||
| limitation | |||||
| mice | Tau22 mice | (Ising, 2019 #1896) | (Ising, 2019 #1896) | ||
| In vitro | |||||
| In vitro | human iPSC-derived microglia | Correction | |||
| human primary microglia] | |||||
| mouse primary microglia | |||||
| Co-culture | |||||
| Mice | (Ising, 2019 #1896) | (Ising, 2019 #1896) | (Ising, 2019 #1896) |
-1β
iv) Size
a. The molecular weight of the proteolytically processed IL-1β is 17.5 kDa.
v) amino acid sequence:
a. APVRSLNCTL RDSQQKSLVM SGPYELKALH LQGQDMEQQV VFSMSFVQGE ESNDKIPVAL GLKEKNLYLS CVLKDDKPTL QLESVDPKNY PKKKMEKRFV FNKIEINNKL EFESAQFPNW YISTSQAENM PVFLGGTKGG QDITDFTMQF VSS
vi) Expression
a. {Kaneko, 2019 #1831} IL-1α and IL-1β are expressed in a wide range of tissues and a variety of cells, especially in macrophages in lymphoid organs including the thymus, spleen, lymph nodes, Peyer’s patches, and bone marrow.
b. In non-lymphoid organs, IL-1α and IL-1β are expressed in tissue macrophages in the lung, digestive tract, and liver. They are also expressed in cellular subepithelial endometrial tissue of the uterus, in the glomeruli, in outer cortical areas of the kidney, and in various specialized cell types, including neutrophils, keratinocytes, epithelial and endothelial cells, lymphocytes, smooth muscle cells, and fibroblasts [74, 75].
IL-1 Receptors
vii) Expression
a. {Kaneko, 2019 #1831} There are two cell surface IL-1 receptors,
i. IL-1R1
IL-1 binds to IL-1R1, which requires the formation of a heterodimer with the IL-1 type 3 receptor (IL-1R3) (also known as IL-1RAcP) accompanied by adaptor IL-1 receptor-associated kinase (IRAK) and myeloid differentiation primary response protein 88 (MyD88) [76]
ii. IL-1 type 2 receptor (IL-1R2), a decoy receptor.
b. IL-1R1 initiates inflammatory responses when binding to the ligands IL-1α and IL-1β and has been reported to be expressed by T-lymphocytes, fibroblasts, epithelial cells, and endothelial cells. IL-1R2, which does not initiate signal transduction,
c. is expressed in a variety of hematopoietic cells, especially in B-lymphocytes, mononuclear phagocytes, polymorphonuclear leukocytes, and bone marrow cells. Notably, expression levels of IL-1R1 and IL-1R2 are different among the cell types; for example, neutrophils predominantly express IL-1R2. As a result, much higher concentrations of IL-1β are required to activate neutrophils, whereas low concentrations of IL-1β are required to activate endothelial cells. The IL-1R1-mediated signaling pathways also differ according to the cell types [77, 78]. IL-1R3 is a co-receptor for IL-1R1, responsible for signaling after binding ligands IL-1α and IL-1β, and has been reported to be ubiquitously expressed by all cells responsive to IL-1. IL-1R3b is a brain-specific isoform of IL-1R3 generated by alternative splicing, and it has been reported to be expressed in the brain, cerebellum, and spinal cord [79].
Toxicity
| (very important) anakinra emea assessment report | in the brain, the interleukin is also involved in hippocampal-dependent memory process (Goshen et al 2007, Yirmiya et al 2002). Goshen et al (2007) state "IL-1β, IL-1Ra and IL-1 receptor are present during neonatal development in mouse embryos (Kruessel et al 1997), and their proteins are detectable starting at the 2 cell stage and throughout human embryonic development (De los Santos et al 1996) as well as human newborns (Pillay et al 1993). Specifically, IL-1β was found to increase with time in human forebrain cells during the first trimester." In the rat, IL-1 levels are increased immediately before birth and remain elevated until the end of the first post natal week (Giulian et al 1988) which is a period of neurodevelopment (Kaffman and Meaney 2007). |
| Goshen et al (2007) found that prenatal IL-1 blockade in mice have developmental consequences that results in memory deficiency in adulthood and state that this is consistent with previous reports on the neurodevelopment role of IL-1. Moreover, transgenic mice overexpressing the human soluble IL-1ra have smaller brains and poorer results in hippocampal-dependent learning tests than wild-type animals, and the difference is consistent in young (1 month old) and adult (12 month old) mice (Spulber et al 2011). there appears to be a narrow physiological range of IL-1 required for optimal brain development and both too little and too much IL-1 is detrimental to the normal (and optimal) brain development (Spulber et al 2011). But, it appeared that hippocampal memory is only detrimentally affected when the foetus is subjected to chronic and complete blockade of IL-1 signalling or pathologically elevated IL-1 levels. |
NLRP3 Structure
ii) NLRP3 is composed of N-terminal PYD (js: should be pyrin domain), central NACHT domain, and C-terminal LRR domain (Figure 1A).
a. The structure of the PYD domain of human NLRP3 (NLRP3PYD) was determined by X-ray crystallography and solution-state NMR (Figure 1B,C)
[111,112].
b. The crystal structure of NLRP3PYD reveals the presence of a symmetric dimer, whereas NMR, MALS (Multiangle light scattering), and SEC (Size-exclusion chromatography) show the coexistence of monomeric with higher-order oligomeric forms of NLRP3PYD in solution.
c. The existence of monomer or dimer depends on the concentrations of NLRP3PYD and salt, as well as pH [111,112].
Uncertain Spans
| location | transcription | uncertainty |
|---|---|---|
| Brain (Postmortem) row, “Ising 2019 #1896 cortex, WB” | inline box-plot panel | Box-plot data points and y-axis values are not legible at this resolution. |
| Brain row, Brosseron 2022 #2016 inline table | numeric cells under con / MCI / AD / FTD | Some values appear faint (e.g. “0.8” in con column for AD); preserved as best-effort. |
| CSF / plasma / PBMC rows | inline scatter and bar charts (Rui, 2021 #2026) | Group labels under each chart are too small to confirm token-by-token. |
| Page heading at very top “(Postmortem)“ | leftmost cell label | Only “(Postmortem)” reads cleanly; column-header row above it is cut off in this capture. |
| NLRP3PYD figure labels | ”PYD / NBD / HD1 / WHD / HD2 / LRR” with positions | The schematic and the Hochheiser 2021 ribbon are kept as evidence; intermediate tick labels (e.g. between 91 and 216) are not transcribed. |