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Title: Early infiltration of p40IL12(+)CCR7(+)CD11b(+) cells is critical for fibrosis development
Authors: Braga, Tarcio Teodoro
Correa-Costa, Matheus
Azevedo, Hatylas
Silva, Reinaldo Correia
Cruz, Mario Costa
Soares Almeida, Maira Estanislau
Hiyane, Meire Ioshie
Moreira-Filho, Carlos Alberto
Santos, Marinilce Fagundes
Perez, Katia Regina
Cuccovia, Iolanda Midea
Saraiva Camara, Niels Olsen [UNIFESP]
Keywords: Collagen
pro-inflammatory macrophages
renal fibrosis
Issue Date: 2016
Publisher: Wiley
Citation: Immunity Inflammation And Disease. Hoboken, v. 4, n. 3, p. 300-314, 2016.
Abstract: IntroductionMacrophages are heterogeneous and thus can be correlated with distinct tissue outcomes after injury. Conflicting data have indicated that the M2-related phenotype directly triggers fibrosis. Conversely, we hypothesize here that the inflammatory milieu provided by early infiltration of pro-inflammatory macrophages dictates tissue scarring after injury. Methods and ResultsWe first determined that tissue-localized macrophages exhibit a pro-inflammatory phenotype (p40IL12(+)CCR7(+)CD11b(+)) during the early phase of a chronic injury model, in contrast to a pro-resolving phenotype (Arg1(+)IL10(+)CD206(+)CD11b(+)) at a later stage. Then, we evaluated the effects of injecting macrophages differentiated in vitro in the presence of IFN+LPS or IL4+IL13 or non-differentiated macrophages (hereafter, M0) on promoting inflammation and progression of chronic injury in macrophage-depleted mice. In addition to enhancing the expression of pro-inflammatory cytokines, the injection of M (IFN+LPS), but not M (IL4+IL13) or M0, accentuated fibrosis while augmenting levels of anti-inflammatory molecules, increasing collagen deposition and impairing organ function. We observed a similar profile after injection of sorted CCR7(+)CD11b(+) cells and a more pronounced effect of M (IFN+LPS) cells originated from Stat6(-/-) mice. The injection of M (IFN+LPS) cells was associated with the up-regulation of inflammation- and fibrosis-related proteins (Thbs1, Mmp7, Mmp8, and Mmp13). ConclusionsOur results suggest that pro-inflammatory macrophages promote microenvironmental changes that may lead to fibrogenesis by inducing an inflammatory milieu that alters a network of extracellular-related genes, culminating in tissue fibrosis.
ISSN: 2050-4527
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