Human anterior chamber angle development without cell death or macrophage involvement
Ophthalmology; Biochemistry & Molecular Biology; light; aqueous outflow system; human eye; human trabecular meshwork; iridocorneal angle
Purpose: The iridocorneal angle in the mammalian eye including the trabecular meshwork (TM) develops from undifferentiated mesenchyme/neural crest between the iris root and cornea. The precise mechanisms underlying anterior angle development are unclear, and the contribution of cell death and phagocytic resorption by macrophages in angle development is controversial. In this study, we examined the human anterior chamber angle during various stages of development for evidence of cell death and phagocytic resorption. Methods: Eyes from the human fetus (F) of 7, 8, 9, 10, 11, 13, 15, 18, 19, 21, 22, 23, and 27 weeks as well as eyes from 5-and 11-month-old children and donors 24, 48, and 67 years of age were obtained. Formalin-fixed and paraffin-embedded sections were examined by hematoxylin and eosin (H&E) staining. Immunohistochemistry was performed using polyclonal antibodies against CD68. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) labeling was also performed to evaluate cell death. Results: By light microscopy, the development of human angle structures appeared to progress as previously described. Histological evidence of cellular death or resorption by macrophages was not observed. Furthermore, the chamber angle tissues did not stain with CD68 at any stage of development. Few CD68 positive cells were observed in the iris stroma and the anterior ciliary body between fetal weeks 10 and 18 (F10w and F18w). TUNEL labeled nuclei were not detected in the anterior chamber angle in any fetal or infant eyes. By contrast, TUNEL positive nuclei in TM cells were observed in the examined adult donor specimens. Conclusions: The results suggest that at the time points examined, neither cell death nor phagocytic resorption with macrophages appear to play a role in the development of the human anterior chamber angle.
Meghpara B; Li X; Nakamura H; Khan A; Bejjani B A; Lin S; Edward D P
Molecular Vision
2008
2008-12
Journal Article or Conference Abstract Publication
n/a
IL-1 induces mitochondrial translocation of IRAK2 to suppress oxidative metabolism in adipocytes.
Chronic inflammation is a common feature of obesity, with elevated cytokines such as interleukin-1 (IL-1) in the circulation and tissues. Here, we report an unconventional IL-1R-MyD88-IRAK2-PHB/OPA1 signaling axis that reprograms mitochondrial metabolism in adipocytes to exacerbate obesity. IL-1 induced recruitment of IRAK2 Myddosome to mitochondria outer membranes via recognition by TOM20, followed by TIMM50-guided translocation of IRAK2 into mitochondria inner membranes, to suppress oxidative phosphorylation and fatty acid oxidation, thereby attenuating energy expenditure. Adipocyte-specific MyD88 or IRAK2 deficiency reduced high-fat-diet-induced weight gain, increased energy expenditure and ameliorated insulin resistance, associated with a smaller adipocyte size and increased cristae formation. IRAK2 kinase inactivation also reduced high-fat diet-induced metabolic diseases. Mechanistically, IRAK2 suppressed respiratory super-complex formation via interaction with PHB1 and OPA1 upon stimulation of IL-1. Taken together, our results suggest that the IRAK2 Myddosome functions as a critical link between inflammation and metabolism, representing a novel therapeutic target for patients with obesity.
Zhou H; Wang H; Yu M; Schugar RC; Qian W; Tang F; Liu W; Yang H; McDowell RE; Zhao J; Gao J; Dongre A; Carman JA; Yin M; Drazba JA; Dent R; Hine C; Chen Y; Smith JD; Fox PL; Brown JM; Li X
Nature Immunology
2020
2020-08-10
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<a href="http://doi.org/10.1038/s41590-020-0750-1" target="_blank" rel="noreferrer noopener">10.1038/s41590-020-0750-1</a>