IL13
Interleukin-13 precursor (IL-13) [NC30]
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A hexanucleotide repeat expansion on chromosome 9 open reading frame 72 (C9orf72) is associated with familial amyotrophic lateral sclerosis (ALS) and a subpopulation of patients with sporadic ALS and frontotemporal dementia. We used inducible pluripotent stem cells from neurotypic and C9orf72 (C9 ) ALS patients to derive neuronal progenitor cells. We demonstrated that C9 and neurotypic neuronal progenitor cells differentiate into neurons. The C9 neurons, however, spontaneously re-expressed cyclin D1 after 12 weeks, suggesting cell cycle re-engagement. Gene profiling revealed significant increases in senescence-associated genes in C9 neurons. Moreover, C9 neurons expressed high levels of mRNA for CXCL8, a chemokine overexpressed by senescent cells, while media from C9 neurons contained significant levels of CXCL8, CXCL1, IL13, IP10, CX3CL1, and reactive oxygen species, which are components of the senescence-associated secretory phenotype. Thus, re-engagement of cell cycle-associated proteins and a senescence-associated secretory phenotype could be fundamental components of neuronal dysfunction in ALS and frontotemporal dementia.
MeSH Terms
- Amyotrophic Lateral Sclerosis
- C9orf72 Protein
- Cell Cycle
- Cells, Cultured
- Cellular Senescence
- DNA Repeat Expansion
- Frontotemporal Dementia
- Gene Expression
- Gene Expression Regulation, Developmental
- Humans
- Induced Pluripotent Stem Cells
- Interleukin-8
- RNA, Messenger
- Stem Cells
Keywords
- Amyotrophic lateral sclerosis
- Cell cycle re-entry
- Frontotemporal dementia
- Senescence
- Senescence-associated secretory phenotype
Atopic dermatitis (AD) shows differential clinical presentation in older compared with younger patients. Nevertheless, changes in the AD molecular profile with age are unknown. We sought to characterize age-related changes in the AD profile. We evaluated age-specific changes in lesional and nonlesional tissues and blood from patients with moderate-to-severe AD (n = 246) and age-matched control subjects (n = 71) using immunohistochemistry, quantitative real-time PCR, and Singulex in a cross-sectional study. Patients were analyzed by age group (18-40, 41-60, and ≥61 years). Although disease severity/SCORAD scores were similar across AD age groups (mean, approximately 60 years; P = .873), dendritic cell infiltrates (CD1b and FcεRI , P < .05) decreased with age. T 2 measures (IL5, IL13, CCL13, CCL18, and CCL26) significantly decreased with age in patients with AD, despite increasing with age in control subjects. Consistent with T 2 axis decreases, serum IgE levels and eosinophil counts negatively correlated with age in patients with AD (r = -0.24 and r = -0.23, respectively; P < .05). T 22-secreted IL22 expression levels also decreased with age uniquely in patients with AD (P < .05). Expression of T 1-related (IFNG, IL12/23p40, STAT1, and CXCL9; P < .05 for CXCL9) and T 17-related (IL17A and IL20; P < .05 for IL20) markers increased with age in both patients with AD and control subjects. Expression of terminal differentiation measures significantly increased in older patients with AD (loricrin [LOR] and filaggrin [FLG], P < .05), whereas expression of S100As (S100A8, P < .01) and hyperplasia markers (epidermal thickness, keratin 16, and Ki67; P < .05 for keratin 16) decreased. Serum trends in AD mimicked skin findings, with T 2 downregulation (CCL26; r = -0.32, P < .1) and T 1 upregulation (IFN-γ; r = 0.48, P < .01) with age. The adult AD profile varies with age. Although T 1/T 17 skewing increases in both patients with AD and control subjects, patients with AD show unique decreases in T 2/T 22 polarization and normalization of epithelial abnormalities. Thus age-specific treatment approaches might be beneficial for AD.
MeSH Terms
- Adolescent
- Adult
- Aged
- Aged, 80 and over
- Aging
- Cytokines
- Dermatitis, Atopic
- Female
- Gene Expression
- Humans
- Male
- Middle Aged
- Phenotype
- Severity of Illness Index
- Skin
- Young Adult
Keywords
- Atopic dermatitis
- T(H)1
- T(H)17
- T(H)2
- T(H)22
- aging
- biomarker
- filaggrin
- hyperplasia
- loricrin
- skin
Macrophage dysfunction plays a pivotal role during neovascular proliferation in diseases of ageing including cancers, atherosclerosis and blinding eye disease. In the eye, choroidal neovascularization (CNV) causes blindness in patients with age-related macular degeneration (AMD). Here we report that increased IL10, not IL4 or IL13, in senescent eyes activates STAT3 signalling that induces the alternative activation of macrophages and vascular proliferation. Targeted inhibition of both IL10 receptor-mediated signalling and STAT3 activation in macrophages reverses the ageing phenotype. In addition, adoptive transfer of STAT3-deficient macrophages into eyes of old mice significantly reduces the amount of CNV. Systemic and CD163( ) eye macrophages obtained from AMD patients also demonstrate STAT3 activation. Our studies demonstrate that impaired SOCS3 feedback leads to permissive IL10/STAT3 signalling that promotes alternative macrophage activation and pathological neovascularization. These findings have significant implications for our understanding of the pathobiology of age-associated diseases and may guide targeted immunotherapy.
MeSH Terms
- Aged
- Aged, 80 and over
- Aging
- Animals
- Eye
- Female
- Humans
- Interleukin-10
- Macrophages
- Macular Degeneration
- Male
- Mice
- Mice, Inbred C57BL
- Middle Aged
- Neovascularization, Pathologic
- Porphyrins
- RAW 264.7 Cells
- Receptors, Interleukin-10
- STAT3 Transcription Factor
- Suppressor of Cytokine Signaling 3 Protein
- Suppressor of Cytokine Signaling Proteins