Inflammation in the hippocampus affects IGF1 receptor signaling and contributes to neurological sequelae in rheumatoid arthritis

Andersson, Karin; Wasén, Caroline; Juzokaite, Lina; Leifsdottir, L.; Erlandsson, Malin C.; Silfverswärd, Sofia Töyrä; Stokowska, Anna; Pekna, Marcela; Pekny, Milos; Olmarker, Kjell; Heckemann, Rolf A.; Kalm, Marie; Bokarewa, Maria

doi:10.1073/pnas.1810553115

Cited by 44 publications

(40 citation statements)

References 74 publications

(95 reference statements)

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“…The unsupervised clustering of the IGF1-related proteins proposed the high CVR signature, which combined the low expression of IGF1, IRS1, and IRS2 with high serum IL6, insulin and plasma glucose and emphasized the functional role of serum IGF1 in the development of early CVD in RA. These findings are in line with our recent report in experimental arthritis, which puts forward the role of excessive inhibitory phosphorylation in IRS1 to create a condition of insulin/IGF1 resistance [35]. The situation seems more complex in patients, where low IGF1 is concurrent with high IGF1R and low adaptors IRS1/2.…”

Section: Discussionsupporting

confidence: 90%

“…It contributes to joint inflammation and affects homeostasis in chondrocytes, leukocytes and synovial fibroblasts [31–33]. It has been shown that inflammation is directly related to high expression of IGF1R in leukocytes [34], which might be responsible for higher pain perception in RA [33, 35]. In a study combining two independent RA cohorts, we demonstrated that smoking and inflammation had additive suppressive effects on serum IGF1 levels [36].…”

Section: Introductionmentioning

confidence: 95%

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Low serum IGF1 is associated with hypertension and predicts early cardiovascular events in women with rheumatoid arthritis

Erlandsson

Lyngfelt

Åberg

et al. 2019

BMC Med

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Objectives Since low insulin-like growth factor (IGF) 1 is often linked to inflammation, we analyze whether serum levels of IGF1 are associated with cardiovascular disease (CVD) in rheumatoid arthritis (RA) in a longitudinal observational study. Methods A CVD risk was estimated (eCVR) in 184 female RA patients (mean age 52 years) and in 132 female patients after ischemic stroke (mean age 56 years) with no rheumatic disease, using the Framingham algorithm. The median level of IGF1 divided the cohorts in IGF1 high and IGF1 low groups. A 5-year prospective follow-up for new CVD events was completed in all RA patients. The Mantel-Cox analysis and event-free survival curves were prepared. Unsupervised clustering of proteins within the IGF1 signaling pathway was employed to identify their association with eCVR. Results Low IGF1 resulted in a higher eCVR in RA patients (7.2% and 3.3%, p = 0.0063) and in stroke (9.3% and 7.1%, p = 0.033). RA had higher rate for new CVD events at prospective follow-up (OR 4.96, p = 0.028). Hypertension was the major risk factor associated with low IGF1 in RA and stroke. In hypertension, IGF1 was no longer responsible for intracellular activation and lost its correlation to IRS1/2 adaptor proteins. The clustering analysis confirmed that combination of low IGF1 and IRS1/2 with high IL6, insulin, and glucose predisposed to high eCVR and emphasized the functional role of serum IGF1. Conclusions Low serum IGF1 precedes and predicts development of early CVD events in female RA patients. Hypertension and aberrant IGF1 receptor signaling are highlighted as the important contributors to IGF1-related CVD events.

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Section: Discussionsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 95%

Low serum IGF1 is associated with hypertension and predicts early cardiovascular events in women with rheumatoid arthritis

Erlandsson

Lyngfelt

Åberg

et al. 2019

BMC Med

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“…In conjunction with its glycoprotein receptor (IGF-1R), IGF-1 is a phylogenetically ancient neurotrophic hormone and plays crucial roles in central nervous system development and maturation (Dyer et al, 2016). In astrocyte from mice, two previous studies demonstrated that cognition is influenced by IGF-1 by exhibiting expression of IGF-1R (Logan et al, 2018; Chen et al, 2019), as supported by both in animal and in clinical experiments (Baker et al, 2012; Andersson et al, 2018).…”

Section: Discussionmentioning

confidence: 65%

Three Novel Loci for Infant Head Circumference Identified by a Joint Association Analysis

Yang

Zhang

et al. 2019

Front. Genet.

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As an important trait at birth, infant head circumference (HC) is associated with a variety of intelligence- and mental-related conditions. Despite being dominated by genetics, the mechanism underlying the variation of HC is poorly understood. Aiming to uncover the genetic basis of HC, we performed a genome-wide joint association analysis by integrating the genome-wide association summary statistics of HC with that of its two related traits, birth length and birth weight, using a recently developed integrative method, multitrait analysis of genome-wide association (MTAG), and performed in silico replication in an independent sample of intracranial volume (N = 26,577). We then conducted a series of bioinformatic investigations on the identified loci. Combining the evidence from both the MTAG analysis and the in silico replication, we identified three novel loci at the genome-wide significance level (α = 5.0 × 10−8): 3q23 [lead single nucleotide polymorphism (SNP) rs9846396, p MTAG = 3.35 × 10−8, p replication = 0.01], 7p15.3 (rs12534093, p MTAG = 2.00 × 10−8, p replication = 0.004), and 9q33.3 (rs7048271 p MTAG = 9.23 × 10−10, p replication = 1.14 × 10−4). Each of the three lead SNPs was associated with at least one of eight brain-related traits including intelligence and educational attainment. Credible risk variants, defined as those SNPs located within 500 kb of the lead SNP and with p values within two orders of magnitude of the lead SNP, were enriched in DNase I hypersensitive site region in brain. Nine candidate genes were prioritized at the three novel loci using multiple sources of information. Gene set enrichment analysis identified one associated pathway GO:0048009, which participates in the development of nervous system. Our findings provide useful insights into the genetic basis of HC and the relationship between brain growth and mental health.

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“…In AIA, a slight increase in the proliferation of neural progenitor cells and the number of surviving newly generated neurons were described (71,72). In contrast, Andersson et al recently showed reduced adult hippocampal neurogenesis and smaller hippocampal volume in mice with CIA (61). Impaired adult hippocampal neurogenesis was mediated by inflammation-induced insulin-like growth factor 1 receptor (IGF1R) signaling.…”

Section: Structural Alterations and Neuronal Dysfunction In Ramentioning

confidence: 99%

The Joint-Brain Axis: Insights From Rheumatoid Arthritis on the Crosstalk Between Chronic Peripheral Inflammation and the Brain

et al. 2020

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Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by erosive polyarthritis. Beyond joint pathology, RA is associated with neuropsychiatric comorbidity including depression, anxiety, and an increased risk to develop neurodegenerative diseases in later life. Studies investigating the central nervous system (CNS) in preclinical models of RA have leveraged the understanding of the intimate crosstalk between peripheral and central immune responses. This mini review summarizes the current knowledge of CNS comorbidity in RA patients and known underlying cellular mechanisms. We focus on the differential regulation of CNS myeloid and glial cells in different mouse models of RA reflecting different patterns of peripheral immune activation. Moreover, we address CNS responses to anti-inflammatory treatment in human RA patients and mice. Finally, to illustrate the bidirectional communication between the CNS and chronic peripheral inflammation, we present the current knowledge about the impact of the CNS on arthritis. A comprehensive understanding of the crosstalk between the CNS and chronic peripheral inflammation will help to identify RA patients at risk of developing CNS comorbidity, setting the path for future therapeutic approaches in both RA and neuropsychiatric diseases.

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Inflammation in the hippocampus affects IGF1 receptor signaling and contributes to neurological sequelae in rheumatoid arthritis

Cited by 44 publications

References 74 publications

Low serum IGF1 is associated with hypertension and predicts early cardiovascular events in women with rheumatoid arthritis

Low serum IGF1 is associated with hypertension and predicts early cardiovascular events in women with rheumatoid arthritis

Three Novel Loci for Infant Head Circumference Identified by a Joint Association Analysis

The Joint-Brain Axis: Insights From Rheumatoid Arthritis on the Crosstalk Between Chronic Peripheral Inflammation and the Brain

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