Kidney Dendritic Cells Induce Innate Immunity against Bacterial Pyelonephritis

Abstract

Dendritic cells (DCs) are the most abundant immune cells in the kidney and form an intricate network in the tubulointerstitium, suggesting that they may play an important role in interstitial infections such as pyelonephritis. Here, we optimized a murine pyelonephritis model by instilling uropathogenic Escherichia coli two times at a 3-hour interval, which produced an infection rate of 84%. By 3 hours after the second instillation, resident kidney DCs began secreting the chemokine CXCL2, which recruits neutrophilic granulocytes. During the time studied, DCs remained responsible for most of the CXCL2 production. Neutrophils began infiltrating the kidney 3 hours after the second instillation and phagocytozed bacteria. Macrophages followed 3 hours later and contributed much less to both CXCL2 production and bacterial phagocytosis. To investigate whether DCs recruit neutrophils into the kidney for antibacterial defense, we used CD11c.DTR mice allowing conditional depletion of CD11c(+) dendritic cells. The absence of CD11c(+) DCs markedly delayed neutrophil recruitment and bacterial clearance. In conclusion, these findings suggest that the tubulointerstitial dendritic cell network serves an innate immune sentinel function against bacterial pyelonephritis.

Dendritic Cells and Macrophages

“…The DCs in the renal medulla are particularly potent at recruiting neutrophils (40), perhaps because they are the first to encounter the ascending bacteria and/or because of microenvironmental cues that cause them to specialize at anti-infectious functions. Notably, kidney macrophages contributed to neither the chemokine production nor the phagocytosis of uropathogenic E. coli (55). By contrast, another study reported that renal macrophages are critical for the defense against candida (56), which preferentially infect murine kidneys.…”

The Renal Mononuclear Phagocytic System

“…rMoPh resident at steady state are induced to rapidly produce proinflammatory innate cytokines (TNF, IL-6, and IL-1) and chemokines (CCL2, CCL5, CXCL10, and CXCL2) depending on environmental cues. 40,70,74,76 As a result, Ly6C + monocytes and other leukocytes are recruited into the kidney, providing a secondary and major source of innate mediators. 35,40,74 This innate phase, evident during either glomerular or tubulointerstitial inflammation, shapes subsequent adaptive immune responses by rMoPh, although this progression has been more clearly described for interstitial compared with glomerular rMoPh.…”

CX3CR1 Reduces Kidney Fibrosis by Inhibiting Local Proliferation of Profibrotic Macrophages

“…Furthermore, CD11c + kidney cells possess a transcriptome that resembles that of DCs but not of macrophages (8,9). Although kidney DCs have been shown to perform sentinel and regulatory functions in inflammation and infection (10), macrophages contributed to host protection from infection and maintained tissue homeostasis (1,11,12). In contrast, inappropriate macrophage functions promoted fibrosis in various organs (13,14).…”