Neutrophil-Macrophage Imbalance Drives the Development of Renal Scarring during Experimental Pyelonephritis
Authors: Ruiz-Rosado Juan de Dios , Robledo-Avila Frank , Cortado Hanna , Rangel-Moreno Javier , Justice Sheryl S. , Yang Ching , Spencer John David , Becknell Brian , Partida-Sanchez Santiago 
Published: November 2020

Significance Statement
More than a half of urinary tract infections in infants spread from the bladder to the kidneys and cause acute pyelonephritis, which may lead to renal scarring, hypertension, and subsequent loss of kidney function. However, the cellular mechanisms underlying permanent renal damage after an acute pyelonephritis episode are unknown. In this study, the authors used a preclinical rodent model of acute pyelonephritis–mediated renal scarring to evaluate the contribution of immune phagocytes to resolution of the condition. The data demonstrated that neutrophils are required to control bacterial ascent and to prevent aberrant macrophage-dependent inflammatory responses in the infected kidney. These findings suggest a delicate balance between neutrophil and macrophage immune responses is required to effectively control acute pyelonephritis and prevent impairment of kidney function.

Background
In children, the acute pyelonephritis that can result from urinary tract infections (UTIs), which commonly ascend from the bladder to the kidney, is a growing concern because it poses a risk of renal scarring and irreversible loss of kidney function. To date, the cellular mechanisms underlying acute pyelonephritis–driven renal scarring remain unknown.

Methods
We used a preclinical model of uropathogenic Escherichia coli–induced acute pyelonephritis to determine the contribution of neutrophils and monocytes to resolution of the condition and the subsequent development of kidney fibrosis. We used cell-specific monoclonal antibodies to eliminate neutrophils, monocytes, or both. Bacterial ascent and the cell dynamics of phagocytic cells were assessed by biophotonic imaging and flow cytometry, respectively. We used quantitative RT-PCR and histopathologic analyses to evaluate inflammation and renal scarring.

Results
We found that neutrophils are critical to control bacterial ascent, which is in line with previous studies suggesting a protective role for neutrophils during a UTI, whereas monocyte-derived macrophages orchestrate a strong, but ineffective, inflammatory response against uropathogenic, E. coli–induced, acute pyelonephritis. Experimental neutropenia during acute pyelonephritis resulted in a compensatory increase in the number of monocytes and heightened macrophage-dependent inflammation in the kidney. Exacerbated macrophage-mediated inflammatory responses promoted renal scarring and compromised renal function, as indicated by elevated serum creatinine, BUN, and potassium.

Conclusions
These findings reveal a previously unappreciated outcome for neutrophil-macrophage imbalance in promoting host susceptibility to acute pyelonephritis and the development of permanent renal damage. This suggests targeting dysregulated macrophage responses might be a therapeutic tool to prevent renal scarring during acute pyelonephritis.