Fight Aging!

The heart is not a very regenerative organ. Following damage, scarring rather than reconstruction results, leading to reduced function. This contributes to the high mortality resulting from a heart attack. While preventing heart attacks is a much better goal than clearing up the damage afterwards, the research community is nonetheless very interested in understanding how to sabotage this scarring process. Interfering in the activities of immune cells has seemed a promising path forwards. Heart attacks provoke lasting inflammation, and such unresolved inflammation is disruptive of regenerative processes.

In today's research materials, scientists discuss the role of neutrophils in creating an inflammatory feedback loop between bone marrow and heart following heart injury. Suppressing this feedback loop reduces the scarring that takes place following a heart attack in mice. This sort of inappropriate immune activity may be a useful target for approaches to enhance regeneration in other tissues as well.

First-responder cells after heart attack prompt inflammation overdrive

Neutrophils are definitely a key part of the problem. In an earlier study, researchers found that heart-attack patients with higher numbers of neutrophils in their blood upon hospital admission, or even after doctors restored blood flow, had the worst outcomes. However, because neutrophils are vital to all wound healing and infection fighting, their first-responder role in heart repair cannot be bluntly targeted for elimination. Instead, the team has zeroed in on signals sent to the immune response control center - the bone marrow - that trigger ramped-up production of neutrophils.

As part of that investigation, the researchers found that the first wave of neutrophils to arrive at the damaged heart consider the injury so severe that they sacrifice themselves to prevent further damage, releasing their entire contents - including proteins called alarmins. These alarmins in turn activate sensors in a second wave of neutrophils, priming those cells for more intense action. These primed neutrophils then do something unexpected: they reverse migrate from the heart to the bone marrow and release a proinflammatory protein there, which prompts stem cells in the bone marrow to churn out even more neutrophils - all processes that perpetuate inflammation at a time when it's no longer needed for heart repair.

In the most recent paper, experiments in mice using genetic techniques or drugs uncovered at least two potential targets to consider for intervention: limiting the primed neutrophils' reverse migration or suppressing neutrophils' release of the proinflammatory protein in the bone marrow. The studies showed that successful inhibition of either mechanism led to better cardiac outcomes and less scarring in the mice.

Retention of the NLRP3 Inflammasome-Primed Neutrophils in the Bone Marrow Is Essential for Myocardial Infarction-Induced Granulopoiesis

Acute myocardial infarction (MI) results in overzealous production and infiltration of neutrophils to the ischemic heart. Using a combination of time-dependent parabiosis and flow cytometry techniques, we first characterized the migration patterns of different blood cell types across the parabiotic barrier. We next induced MI in parabiotic mice by permanent ligation of the left anterior descending artery and examined the ability of injury-exposed neutrophils to permeate the parabiotic barrier and induce granulopoiesis in noninfarcted parabionts.

MI promoted greater accumulation of the inflammasome-primed neutrophils in the bone marrow. Introducing a time-dependent parabiotic barrier to the free movement of neutrophils inhibited their ability to stimulate granulopoiesis in the noninfarcted parabionts. Our data reveal a new paradigm of how circulatory cells establish a direct communication between organs by delivering signaling molecules (eg, IL-1β) directly at the sites of action rather through systemic release. We suggest that this pathway may exist to limit the off-target effects of systemic IL-1β release.