Functional implications of neutrophil metabolism during ischemic tissue repair

Abstract

Immune cell mobilization and their accumulation in the extravascular space is a key consequence of tissue injury. Maladaptive trafficking and immune activation following reperfusion of ischemic tissue can exacerbate tissue repair. After ischemic injury such as myocardial infarction (MI), PMNs are the first cells to arrive at the sites of insult and their response is critical for the sequential progression of ischemia from inflammation to resolution and finally to tissue repair. However, PMN-induced inflammation can also be detrimental to cardiac function and ultimately lead to heart failure. In this review, we highlight the role of PMNs during key cellular and molecular events of ischemic heart failure. We address new research on PMN metabolism, and how this orchestrates diverse functions such as PMN chemotaxis, degranulation, and phagocytosis. Particular focus is given to PMN metabolism regulation by mitochondrial function and mTOR kinase activity.

Figure 1:. Metabolic factors and mitochondrial activity drive PMN migration.

The recognition of chemotactic signals by PMNs is mediated by several surface receptors, including FPR1 GPCRs. Ligand binding to FPRs leads to activation of mTORC2, which is responsible for the uptake of calcium into the mitochondria and activation of mitochondrial respiration. These processes are required for the actin and myosin cytoskeleton motility during initiate PMN migration. During active migration mitochondria-derived ATP fuels the cytoskeletal reorganization, while some ATP escapes into the extracellular space via Pannexin 1 channels to form extracellular ATP gradient. P2Y2 and A3AR receptors on the PMN leading edge sense the ATP gradient and promote mTORC2 activation to direct PMN chemotaxis. Inhibition of mitochondria generation of ATP by FCCP or blockade of mTORC2 signaling by deletion of Rictor will lead to impairment of PMN migration.

Figure 2:. PMN phenotypes in myocardial infarction.

A prominent consequence of MI is accumulation of necrotic cells and the release of DAMPS, which leads to rapid leukocyte recruitment among which PMNs are the first to arrive at the infarct site. It is now well-recognized that PMNs play diverse roles in cardiac pathology and healing. As PMNs enter the tissue they undergo phenotypic and function shifts in response to local inflammatory milieu. Tissue hypoxia and low glucose environment are of the major drivers of PMN phenotypic shifts. Throughout MI resolution acutely recruited PMNs in the first few days post-injury are highly pro-inflammatory featuring degranulation/granule content release and promoting oxidative stress. In the next few days many will become apoptotic while others activate pro-phagocytosis pathways. Both processes will promote initiation of inflammatory resolution (macrophage reprograming during clearance and tissue debridement). During phagocytosis PMNs utilize mTORC1 signaling to shift their metabolic programs to synthesize protein de-novo to fulfill new tissue functions. These PMNs were also shown to upregulate novel markers including, SiglecF and NGAL. Thus, PMNs play important roles in resolution and healing of infarcted regions of the heart after MI.