RESUMO
The urothelium of the urinary bladder represents the first line of defense. However, uropathogenic E. coli (UPEC) damage the urothelium and cause acute bacterial infection. Here, we demonstrate the crosstalk between macrophages and the urothelium stimulating macrophage migration into the urothelium. Using spatial proteomics by MALDI-MSI and LC-MS/MS, a novel algorithm revealed the spatial activation and migration of macrophages. Analysis of the spatial proteome unravelled the coexpression of Myo9b and F4/80 in the infected urothelium, indicating that macrophages have entered the urothelium upon infection. Immunofluorescence microscopy additionally indicated that intraurothelial macrophages phagocytosed UPEC and eliminated neutrophils. Further analysis of the spatial proteome by MALDI-MSI showed strong expression of IL-6 in the urothelium and local inhibition of this molecule reduced macrophage migration into the urothelium and aggravated the infection. After IL-6 inhibition, the expression of matrix metalloproteinases and chemokines, such as CX3CL1 was reduced in the urothelium. Accordingly, macrophage migration into the urothelium was diminished in the absence of CX3CL1 signaling in Cx3cr1gfp/gfp mice. Conclusively, this study describes the crosstalk between the infected urothelium and macrophages through IL-6-induced CX3CL1 expression. Such crosstalk facilitates the relocation of macrophages into the urothelium and reduces bacterial burden in the urinary bladder.
Assuntos
Comunicação Celular , Quimiocina CX3CL1/metabolismo , Interleucina-6/metabolismo , Macrófagos/metabolismo , Proteômica , Urotélio/imunologia , Urotélio/metabolismo , Animais , Modelos Animais de Doenças , Suscetibilidade a Doenças , Imunofluorescência , Imuno-Histoquímica , Macrófagos/imunologia , Camundongos , Proteômica/métodos , Bexiga Urinária/imunologia , Bexiga Urinária/metabolismo , Bexiga Urinária/microbiologia , Infecções Urinárias/etiologia , Infecções Urinárias/metabolismo , Infecções Urinárias/patologia , Urotélio/microbiologiaRESUMO
Discussion on remote activation of Th17 cells by lung myeloid cells during EAE.
Assuntos
Sistema Nervoso Central/imunologia , Encefalomielite Autoimune Experimental/imunologia , Pulmão/imunologia , Células Supressoras Mieloides/imunologia , Células Th17/imunologia , Animais , Linhagem da Célula/genética , Linhagem da Célula/imunologia , Movimento Celular , Sistema Nervoso Central/patologia , Citocinas/genética , Citocinas/imunologia , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/genética , Encefalomielite Autoimune Experimental/patologia , Expressão Gênica , Humanos , Pulmão/patologia , Camundongos Endogâmicos C57BL , Esclerose Múltipla/genética , Esclerose Múltipla/imunologia , Esclerose Múltipla/patologia , Células Supressoras Mieloides/patologia , Transdução de Sinais/imunologia , Células Th17/patologiaRESUMO
The antibacterial defense against infections depends on the cooperation between distinct phagocytes of the innate immune system, namely macrophages and neutrophils. However, the mechanisms driving this cooperation are incompletely understood. In this study we describe the crosstalk between Ly6C⺠and Ly6C(-) macrophage-subtypes and neutrophils in the context of urinary tract infection (UTI) with uropathogenic E. coli (UPEC). Ly6C(-) macrophages acted as tissue resident sentinels and attracted circulating phagocytes by chemokines. Ly6C⺠macrophages produced tumor necrosis factor (TNF) that licensed Ly6C(-) macrophages to release preformed CXCL2, which in turn caused matrix metalloproteinases (MMP-9) secretion by neutrophils to enable transepithelial migration.
