Toll-Like Receptor 4–Induced IL-22 Accelerates Kidney Regeneration

Abstract

AKI involves early Toll-like receptor (TLR)-driven immunopathology, and resolution of inflammation is needed for rapid regeneration of injured tubule cells. Notably, activation of TLRs also has been implicated in epithelial repair. We hypothesized that TLR signaling drives tubule regeneration after acute injury through the induction of certain ILs. Systematic screening in vitro identified IL-22 as a candidate proregeneratory factor in primary tubular cell recovery, and IL-22 deficiency or IL-22 blockade impaired postischemic tubular recovery after AKI in mice. Interstitial mononuclear cells, such as dendritic cells and macrophages, were the predominant source of IL-22 secretion, whereas IL-22 receptor was expressed by tubular epithelial cells exclusively. Depleting IL-22-producing cells during the healing phase impaired epithelial recovery, which could be rescued entirely by reconstituting mice with IL-22. In vitro, necrotic tubular cells and oxidative stress induced IL-22 secretion selectively through TLR4. Although TLR4 blockade during the early injury phase prevented tubular necrosis and AKI, TLR4 blockade during the healing phase suppressed IL-22 production and impaired kidney regeneration. Taken together, these results suggest that necrotic cell-derived TLR4 agonists activate intrarenal mononuclear cells to secrete IL-22, which accelerates tubular regeneration and recovery in AKI.

Inflammation in AKI

“…[20][21][22] Among the most striking advances in knowledge of the past decade is the recognition that many of the same triggers and cellular mediators that are responsible for initial organ damage are also key players in a subsequent phase of repair and regeneration. 7,23,24 In the experimental setting, this phase has been shown to be essential for optimal recovery of renal function after AKI and result from programmed transitions in the phenotype of immune effector cells (especially mononuclear phagocytes) involving specific alternative intracellular signaling pathways and soluble mediators. 6,11,[23][24][25] The recent progress in understanding these inherent restorative mechanisms has led to a new emphasis on harnessing them to actively promote repair and regeneration after established acute organ injury, including AKI.…”

“…7,23,24 In the experimental setting, this phase has been shown to be essential for optimal recovery of renal function after AKI and result from programmed transitions in the phenotype of immune effector cells (especially mononuclear phagocytes) involving specific alternative intracellular signaling pathways and soluble mediators. 6,11,[23][24][25] The recent progress in understanding these inherent restorative mechanisms has led to a new emphasis on harnessing them to actively promote repair and regeneration after established acute organ injury, including AKI. 7,26,27 However, interventions that target earlier phases of inflammation during AKI may bring unintended negative consequences by disrupting the role played by the same mediators in the transition from proinflammatory to prorepair mechanisms ( Figure 2).…”

Targeting Endogenous Repair Pathways after AKI

“…Damage-associated molecular patterns also can activate a set of pattern recognition receptors, such as Toll-like receptors (TLRs), on renal parenchymal as well as in the interstitium. 28 A recent study 29 examined the role of TLR4 and IL-22 secretion in renal repair. TLR4 blockade during the early phase suppressed IL-22 production, but also, TLR4 blockade during the healing phase suppressed IL-22 production and impaired kidney regeneration.…”

Dendritic Cells and Macrophages

“…After acute injury, both DCs and CSF-1-dependent macrophages orchestrated tissue repair by producing mediators like IL-22 (67,68), suggesting novel therapeutic avenues in both transplantation and acute tubular necrosis.…”