The NLRP3 Inflammasome Promotes Renal Inflammation and Contributes to CKD

Abstract

Inflammation significantly contributes to the progression of chronic kidney disease (CKD). Inflammasome-dependent cytokines, such as IL-1␤ and IL-18, play a role in CKD, but their regulation during renal injury is unknown. Here, we analyzed the processing of caspase-1, IL-1␤, and IL-18 after unilateral ureteral obstruction (UUO) in mice, which suggested activation of the Nlrp3 inflammasome during renal injury. Compared with wild-type mice, Nlrp3 Ϫ/Ϫ mice had less tubular injury, inflammation, and fibrosis after UUO, associated with a reduction in caspase-1 activation and maturation of IL-1␤ and IL-18; these data confirm that the Nlrp3 inflammasome upregulates these cytokines in the kidney during injury. Bone marrow chimeras revealed that Nlrp3 mediates the injurious/inflammatory processes in both hematopoietic and nonhematopoietic cellular compartments. In tissue from human renal biopsies, a wide variety of nondiabetic kidney diseases exhibited increased expression of NLRP3 mRNA, which correlated with renal function. Taken together, these results strongly support a role for NLRP3 in renal injury and identify the inflammasome as a possible therapeutic target in the treatment of patients with progressive CKD.

A Tissue-Specific Role for Nlrp3 in Tubular Epithelial Repair after Renal Ischemia/Reperfusion

“…This observation is consistent with articles demonstrating that Nlrp3 enhances renal epithelial-mesenchymal transition 27 and fibrosis in a model of unilateral ureteral obstruction. 19 In addition, mice that lack Nlrp3 in renal cells show increased levels of KC and MCP-1, suggesting a prolonged inflammatory phase that could be introduced by a reduced responsiveness to transforming growth factor-b. 27 On the basis of these findings and the results of our study, we speculate that epithelial Nlrp3 is an important regulator of proliferation versus fibrosis during repair.…”

“…Our data suggest Nlrp3 as a negative regulator of resident tubular cell proliferation in addition to its detrimental role in renal fibrosis and inflammation. 14,19 Materials and Methods…”

NLRP3 regulates a non-canonical platform for caspase-8 activation during epithelial cell apoptosis

“…Inflammasome genes such as NLRP3 and ASC are expressed in both gut and kidney epithelia. 3,[19][20][21] We and others have demonstrated primarily non-canonical and inflammasome-independent roles for NLRP3 in the kidney epithelium and during experimental kidney injury in vivo. [20][21][22][23] For example, Nlrp3 − / − mice undergoing renal ischemia/reperfusion or unilateral ureteric obstruction (UUO) display reduced epithelial apoptosis and tubular injury independent of a canonical inflammasome or caspase-1.…”

“…3,[19][20][21] We and others have demonstrated primarily non-canonical and inflammasome-independent roles for NLRP3 in the kidney epithelium and during experimental kidney injury in vivo. [20][21][22][23] For example, Nlrp3 − / − mice undergoing renal ischemia/reperfusion or unilateral ureteric obstruction (UUO) display reduced epithelial apoptosis and tubular injury independent of a canonical inflammasome or caspase-1. [20][21][22][23] In the intestinal tract, non-canonical NLRP3 regulates IL-18 maturation as well as epithelial cell shedding in response to Salmonella infection.…”

“…[20][21][22][23] For example, Nlrp3 − / − mice undergoing renal ischemia/reperfusion or unilateral ureteric obstruction (UUO) display reduced epithelial apoptosis and tubular injury independent of a canonical inflammasome or caspase-1. [20][21][22][23] In the intestinal tract, non-canonical NLRP3 regulates IL-18 maturation as well as epithelial cell shedding in response to Salmonella infection. 3 Despite these studies, the biology of NLRP3 and other inflammasomerelated genes in epithelial cells has yet to be fully elucidated.…”