ObjectiveKawasaki disease (KD) is the most common cause of acquired pediatric heart disease in the developed world. 10% of KD patients are resistant to front-line therapy, and no interventions exist to address secondary complications such as myocardial fibrosis. We sought to identify proteins and pathways associated with disease and anti-IL-1 treatment in a mouse model of KD.MethodsVasculitis was induced via Lactobacillus casei cell wall extract (LCWE) injection in 5-week-old male mice. Groups of mice were injected with LCWE alone, LCWE and IL-1 receptor antagonist anakinra, or saline for controls. Upper heart tissue was assessed by quantitative mass spectrometry analysis. Expression and activation of STAT3 was assessed by immunohistochemistry, immunofluorescence and Western blot, and IL-6 expression by RNA-seq and ELISA. A STAT3 small molecular inhibitor and anti-IL-6R antibody were used to evaluate the role of STAT3 and IL-6 in disease development.ResultsSTAT3 was highly expressed and phosphorylated in cardiac tissue of LCWE-injected mice, and reduced following anakinra treatment. Il6 and Stat3 gene expression was enhanced in abdominal aorta of LCWE-injected mice and reduced with Anakinra treatment. IL-6 serum levels were enhanced in LCWE-injected mice and normalized by anakinra. However, neither inhibition of STAT3 nor blockade of IL-6 altered disease development.ConclusionProteomic analysis of cardiac tissues demonstrates differential protein expression between KD-like, control and anakinra treated cardiac tissue. STAT3 and IL-6 were highly upregulated with LCWE and normalized by anakinra treatment. However, both STAT3 and IL-6 were dispensable for disease development indicating they may be bystanders of inflammation.
There is a critical need in MS to develop biomarkers to improve early diagnosis, predict imminent disease relapses, and optimize treatment responses. In MS, central nervous system (CNS) inflammation results in damage to neuronal tissues and disruption of blood-brain barrier integrity, and ultimately to leakage of CNS-specific proteins (CSPs) into serum. Therefore, altered serum levels of CSPs could be promising biomarkers of MS. Based on our previous discovery of CSP expression waves in brain tissue of mice with experimental autoimmune encephalomyelitis (EAE), a preclinical model for human MS, we investigated a subset of CSPs which have human-homologs in longitudinal serum specimens from individual mice in this model. Herein, we establish a pre-onset serum CSP expression wave that enabled prediction of clinical onset of EAE and stratification of subjects into diseased versus healthy. Importantly, we demonstrate that the pre-onset serum CSP wave was not affected by adjuvants and microbial infection, thereby has high sensitivity and specificity for a neuroinflammatory disease. Moreover, we identify differences in serum protein expression between active and passive immunization of EAE revealing hitherto not appreciated differences for disease induction mechanisms. The results provide proof of concept for the development serum CSP waves as biomarkers of MS, specifically for early detection and prediction of the onset of clinical relapse.
Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine elevated in multiple conditions. MIF is also elevated in autoimmune myocarditis (AM), a condition in which the immune system aberrantly attacks the heart muscle. AM can be induced by antigenic mimicry, autoimmune stimulation, genetic defects, issues with regulatory T cells, dysregulation of immune effector cells. AM also has the possibility to progress to the fatal disease dilated cardiomyopathy (DCM) through chronic inflammation, the deposition and crosslinking of collagen, proliferation by fibroblasts, and differentiation into myofibroblasts. Our lab has previously shown that MIF and OPN synergize to enhance the progression of disease to DCM, by affecting cardiac fibrosis and the deposition of collagen. Glucocorticoids (GCs) are given to suppress the inflammation caused by immune reactions and therefore are prescribed as treatment for autoimmune myocarditis. However, GCs are unable prevent the progression of AM to DCM. Our lab investigated the role of GCs for promoting the actions of MIF by enhancing the OPN-dependent deposition of collagen in the myocardium by gene expression of extracellular matrix proteins affected by AM through qPCR and their protein concentration by ELISA. Establishing a pathway for collagen deposition in AM will allow for the development of more effective treatment and prevention of the progression to DCM.
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