In the present pilot study, we investigated the iRhom2/TACE/TNF-α-axis as a potentially important regulator of postischemic inflammation in patients with AMI. Similar to previous studies, we observed a significant increase of serum TNF-α levels within the first 3 days following AMI as part of a systemic inflammatory response (further indicated by the increase of CRP between day 1 and 3).25,26 The interaction of iRhom2 with TACE is essential for proper shedding of TNF-α from the cell surface of immune cells.16 Accordingly we found that mRNA expression levels of iRhom2 in circulating monocytes increased in parallel to serum TNF-α levels following AMI. In contrast, TACE and TNF-α mRNA expression in circulating monocytes remained unchanged indicating a central regulatory role of iRhom2 in TNF-α response following AMI. This was further supported by a significant correlation between serum TNF-α levels and iRhom2 expression levels in circulation monocytes on day 3 after AMI. Among monocyte subsets intermediate monocytes are considered the major source of serum TNF-α.27 In fact, we observed a significant correlation between relative levels of circulating intermediate monocytes not only with serum TNF-α levels but also with iRhom2 mRNA expression levels on day 3 following AMI. Taken together these findings strongly suggest a relevant regulatory role of iRhom2 in the augmented shedding of TNF-α from intermediate monocytes in the early phase of AMI.
Given the fact that excess levels of TNF-α are known to impair myocardial recovery and promote postischemic myocardial injury, the observed significant correlation between iRhom2 mRNA expression in circulating monocytes on day 3 following AMI with the extent of LV dysfunction in our patient population appears to be a consistent outcome. These results suggest that modulation of iRhom2 represents a promising novel target to reduce excess TNF-α secretion from immune cells after AMI to attenuate adverse cardiac remodeling. Modulation of iRhom2 is considered a more distinguished strategy compared to non-selective TNF-α blockage as it presumably reduces cardiotoxic effects of TNF-α more selectively while preserving cardioprotective functions of the cytokine.
In the setting of AMI modulation of iRhom2 may potentially prevent an excess and therefore detrimental secretion of soluble TNF-α by reducing transmembrane TNF-α shedding selectively from immune cells.17 Soluble TNF-α primarily binds to TNFR1, which promotes inflammation and apoptosis.28 In contrast, cardioprotective effects of TNFR2 such as tissue healing, angiogenesis, and anti-inflammatory processes which is primarily activated by transmembrane TNF-α would be preserved.28,29
There are some limitations in the present study. First, due to the observational character of this pilot study the results remain descriptive. Secondly, expression analyses of iRhom2 and TACE were limited to mRNA levels. However, in previous in vitro studies with macrophages we observed that iRhom2 mRNA expression levels parallel levels of soluble TNF-α in a concentration-dependent manner after LPS stimulation, thus indicating a strong association between iRhom2 mRNA expression and TNF-α protein levels.17 Thirdly, a longer time-course for the evaluation of the iRhom2/TACE/TNF-α-axis beyond day 3 following AMI was not performed due to the generally intended early hospital discharge of patients after AMI.
In conclusion, the present study suggests that iRhom2 contributes to the regulation of inflammation and is thereby associated with LV systolic dysfunction following AMI. Thus, iRhom2 modulation should be further evaluated as a potential therapeutic strategy in AMI patients to attenuate adverse cardiac remodeling.