Treatment of Glucocorticoids Inhibited Early Immune Responses and Impaired Cardiac Repair in Adult Zebrafish

Abstract

Myocardial injury, such as myocardial infarction (MI), can lead to drastic heart damage. Zebrafish have the extraordinary ability to regenerate their heart after a severe injury. Upon ventricle resection, fibrin clots seal the wound and serve as a matrix for recruiting myeloid-derived phagocytes. Accumulated neutrophils and macrophages not only reduce the risk of infection but also secrete cytokines and growth factors to promote tissue repair. However, the underlying cellular and molecular mechanisms for how immune responses are regulated during the early stages of cardiac repair are still unclear. We investigated the role and programming of early immune responses during zebrafish heart regeneration. We found that zebrafish treated with an anti-inflammatory glucocorticoid had significantly reduced heart regenerative capacities, consistent with findings in other higher vertebrates. Moreover, inhibiting the inflammatory response led to excessive collagen deposition. A microarray approach was used to assess the differential expression profiles between zebrafish hearts with normal or impaired healing. Combining cytokine profiling and immune-staining, our data revealed that impaired heart regeneration could be due to reduced phagocyte recruitment, leading to diminished angiogenesis and cell proliferation post-cardiac injury. Despite their robust regenerative ability, our study revealed that glucocorticoid treatment could effectively hinder cardiac repair in adult zebrafish by interfering with the inflammatory response. Our findings may help to clarify the initiation of cardiac repair, which could be used to develop a therapeutic intervention that may enhance cardiac repair in humans to compensate for the loss of cardiomyocytes after an MI.

Cell migration during heart regeneration in zebrafish

“…Huang et al found that expression of pro-inflammatory cytokine genes, such as il-1ß , tnf-α , il-8 , and inflammatory markers are upregulated after ventricular resection (Huang et al, 2013b). Treating fish after ventricle resection with anti-inflammatory glucocorticoid or nonsteroidal anti-inflammatory drugs resulted in repression of pro-inflammatory cytokine gene transcript levels and a failure to completely regenerate the heart, which correlated with reduced number of lyz :EGFP positive cells in the injured myocardium.…”

Injury-induced immune responses in Hydra

“…In zebrafish, both fin and cardiac regeneration are impaired when activation of the glucocorticoid receptor (GR) is pharmacologically inhibited [21,22]. As activated GRs transactivate genes encoding pro-inflammatory transcription factors such as AP1, STATs, NF-AT and NF-B [23,24], the negative effect observed upon GR inhibition initially suggested that inflammation was playing an active role during regeneration.…”

Adenosine enhances progenitor cell recruitment and nerve growth via its A2B receptor during adult fin regeneration

“…ATP release participates in the "find me signal," which attracts phagocytes to the lesion site to resolve the wound [28,23]. The infiltration of macrophages is required for blastema formation in newts regenerating their limbs [29], as well as in adult zebrafish regenerating their caudal fin and their heart [30,31]. Within the first 24 hpa, these macrophages release proteases, growth factors, and cytokines that are important for tissue remodelling and the stimulation of proliferation.…”