Role of the innate immune system in acute kidney injury

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Following the immediate injury to intrinsic kidney cells induced by ischemia/reperfusion, we and others have demonstrated an important role for innate immune cells in both propagation of injury and subsequent recovery. There is an initial renal influx of neutrophils after ischemic injury, followed a few hours later by accumulation of proinflammatory monocytes and activation of resident renal macrophages. Within days after the injury, the majority of renal macrophages shift from a proinflammatory to an anti-inflammatory and pro- resolution phenotype, which is essential for effective repair and resolution of the injury. Meanwhile, with moderate ischemic injury, neutrophil numbers in the injured kidney progressively decrease, and relatively few neutrophils remain after 72 hours. Although neutrophil apoptosis and efferocytosis by macrophages is an important mechanism of neutrophil clearance, in addition, in other tissues, studies have shown that intact neutrophils may also exit the tissue through “reverse migration”. Mechanisms underlying the resolution of inflammation are an area of active investigation. The question of what mediates resolution of inflammation, and specifically what mediates the resolution of the inflammation resulting from ischemic AKI, remains unresolved. Cyclooxygenase (COX) is the rate-limiting enzyme that metabolizes arachidonic acid to prostaglandin G2 and subsequently to prostaglandin H2, thereby serving as the precursor for subsequent metabolism by prostaglandin synthases. More than 20 years ago, Gilroy et al. reported a paradox in sterile inflammation. Pharmacologic COX-2 inhibition at the early phase (2h) accelerated recovery while the same pharmacologic inhibition prevented recovery when applied 24h later, suggesting that COX-2 may have different roles in neutrophils and macrophages in inflammation resolution. We have recently we have reported that COX-2 expression increased in renal macrophages following ischemic injury, and selective deletion of COX-2 or the PGE2 receptor subtype 4 (EP4) with myeloid-specific Cre recombinases delayed recovery, resulting in persistent inflammation in the post-ischemic kidney and subsequent tubulointerstitial fibrosis. In our new preliminary results, we now surprisingly find that selective deletion of neutrophil COX-2 expression results in decreased injury in response to an ischemic insult. We propose that the macrophage COX-2/PGE2 axis promotes recovery from AKI, but the neutrophil COX-2/PGE2 axis has the opposite effect and is important for the initial injury induced by neutrophil infiltration. The goal of our proposed studies is to further our understanding of mechanisms of resolution from AKI by characterizing the disparate roles and mechanisms played by the COX-2/prostaglandin system in neutrophils and macrophages following acute ischemic kidney injury. We have two specific aims: Specific Aim 1 Determine the role of the macrophage COX-2-PGE2-axis in recovery from ischemic AKI Specific Aim 2 Determine the role of COX-2 in neutrophil function in response to ischemic AKI