In Defense of Homeostasis: Innate Immunity in Cardiac Injury and Repair

Abstract

The ability of the heart to compensate for and adapt to a superimposed environmental stress determines whether the heart will maintain preserved structure and function or decompensate and fail. In mammalian tissues, sterile tissue injury activates a suite of stress-activated programs that integrate cytoprotective stress responses that are tightly coupled with carefully regulated and precisely timed inflammatory signaling, thereby promoting tissue repair while simultaneously limiting collateral damage. Although the terminology for this phenomenon is still evolving, the recently described concept of “disease tolerance” has been proposed to explain tissue-intrinsic cell autonomous molecular programs that couple cytoprotective stress responses with tightly regulated inflammatory signaling that minimizes collateral damage while also activating tissue repair mechanisms. Emerging evidence reviewed here suggests that sterile cardiac injury (e.g., myocardial ischemia or hemodynamic pressure overload) elicits an acquired stress-tolerant state that sustains cytoprotective programs in cardiac myocytes and constrains collateral immune-mediated tissue injury. However, these stress-activated pathways are highly context-dependent and are shaped by the magnitude and duration of the ensuing inflammatory response. When tissue injury-induced inflammation is sustained and/or excessive, it can also lead to unwanted collateral tissue damage and cardiac decompensation.