Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2017 Oct 13:8:546.
doi: 10.3389/fneur.2017.00546. eCollection 2017.

Inflammatory Gene Expression in Whole Peripheral Blood at Early Stages of Sporadic Amyotrophic Lateral Sclerosis

Pol Andrés-Benito  1   2 , Jesús Moreno  2 , Raúl Domínguez  3 , Ester Aso  1   2 , Mónica Povedano  2   3 , Isidro Ferrer  1   2   4   5
Affiliations

Inflammatory Gene Expression in Whole Peripheral Blood at Early Stages of Sporadic Amyotrophic Lateral Sclerosis

Pol Andrés-Benito et al. Front Neurol. .

Abstract

Objective: Characterization of altered expression of selected transcripts linked to inflammation in the peripheral blood of sporadic amyotrophic lateral sclerosis (sALS) patients at early stage of disease to increase knowledge about peripheral inflammatory response in sALS.

Methods: RNA expression levels of 45 genes were assessed by RT-qPCR in 22 sALS cases in parallel with 13 age-matched controls. Clinical and serum parameters were assessed at the same time.

Results: Upregulation of genes coding for factors involved in leukocyte extravasation (ITGB2, INPP5D, SELL, and ICAM1) and extracellular matrix remodeling (MMP9 and TIMP2), as well as downregulation of certain chemokines (CCL5 and CXC5R), anti-inflammatory cytokines (IL10, TGFB2, and IL10RA), pro-inflammatory cytokines (IL-6), and T-cell regulators (CD2 and TRBC1) was found in sALS cases independently of gender, clinical symptoms at onset (spinal, respiratory, or bulbar), progression, peripheral leukocyte number, and integrity of RNA. MMP9 levels positively correlated with age, whereas CCR5, CCL5, and TRBC1 negatively correlated with age in sALS but not in controls. Relatively higher TNFA expression levels correlate with higher creatinine kinase protein levels in plasma.

Conclusion: Present findings show early inflammatory responses characterized by upregulation of factors enabling extravasation of leukocytes and extracellular matrix remodeling in blood in sALS cases, in addition to increased TNFA levels paralleling skeletal muscle damage.

Keywords: amyotrophic lateral sclerosis; blood; cytokines; extracellular matrix; leukocyte extravasation.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Gene expression of anti-inflammatory cytokines (A), chemokines (B), cytokine modulators (C), extracellular matrix remodeling-related factors (D), molecules involved in extravasation mechanisms (E), oxidative stress markers (F), pro-inflammatory cytokines (G), and T-cell markers (H), as revealed by RT-qPCR, in blood from control and sporadic amyotrophic lateral sclerosis (sALS) cases. All data were expressed as the mean ± SEM. Statistical comparisons were performed using unpaired t-test; significance level was set at *p < 0.05, **p < 0.01 and ***p < 0.001, and tendencies at #<0.1. A total of 13 healthy samples and 22 sALS samples were included in RT-qPCR analysis.
Figure 2
Figure 2
(A) Positive correlation between MMP9 and age at sampling, and negative correlation between age at sampling and CCL5, CCR5, and TRBC1 in sporadic amyotrophic lateral sclerosis (sALS) (right graphs), but not in control cases (left graphs). (B) Relation between TNFA mRNA expression levels in blood and creatine kinase (CK) protein levels in serum in sALS (nCK, normal CK levels; hCK, high/out of range CK levels) using Student’s t-test. Gene expression values correspond to fold change values of ΔΔCT.
See this image and copyright information in PMC

References

    1. Graves MC, Fiala M, Dinglasan LA, Liu NQ, Sayre J, Chiappelli F, et al. Inflammation in amyotrophic lateral sclerosis spinal cord and brain is mediated by activated macrophages, mast cells and T cells. Amyotroph Lateral Scler Other Motor Neuron Disord (2004) 5:213–9.10.1080/14660820410020286 - DOI - PubMed
    1. Henkel JS, Engelhardt JI, Siklós L, Simpson EP, Kim SH, Pan T, et al. Presence of dendritic cells, MCP-1, and activated microglia/macrophages in amyotrophic lateral sclerosis spinal cord tissue. Ann Neurol (2004) 55:221–35.10.1002/ana.10805 - DOI - PubMed
    1. Johann S, Heitzer M, Kanagaratnam M, Goswami A, Rizo T, Weis J, et al. NLRP3 inflammasome is expressed by astrocytes in the SOD1 mouse model of ALS and in human sporadic ALS patients. Glia (2015) 63:2260–73.10.1002/glia.22891 - DOI - PubMed
    1. Casula M, Iyer AM, Spliet WG, Anink JJ, Steentjes K, Sta M, et al. Toll-like receptor signaling in amyotrophic lateral sclerosis spinal cord tissue. Neuroscience (2011) 179:233–43.10.1016/j.neuroscience.2011.02.001 - DOI - PubMed
    1. Sta M, Sylva-Steenland RM, Casula M, de Jong JM, Troost D, Aronica E, et al. Innate and adaptive immunity in amyotrophic lateral sclerosis: evidence of complement activation. Neurobiol Dis (2011) 42:211–20.10.1016/j.nbd.2011.01.002 - DOI - PubMed