Early infiltration of p40IL12(+)CCR7(+)CD11b(+) cells is critical for fibrosis development

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Braga, Tarcio Teodoro ^[1] ; Correa-Costa, Matheus ^[1] ; Azevedo, Hatylas ^[2] ; Silva, Reinaldo Correia ^[1] ; Cruz, Mario Costa ^[1] ; Soares Almeida, Maira Estanislau ^[3] ; Hiyane, Meire Ioshie ^[1] ; Moreira-Filho, Carlos Alberto ^[2] ; Santos, Marinilce Fagundes ^[3] ; Perez, Katia Regina ^[4] ; Cuccovia, Iolanda Midea ^[4] ; Saraiva Camara, Niels Olsen ^{[1, 5, 6]}

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Inst Biomed Sci 4, Dept Immunol, Lab Transplantat Immunobiol, Sao Paulo - Brazil

^[2] Univ Sao Paulo, Dept Pediat, Fac Med, FMUSP, Sao Paulo - Brazil

^[3] Univ Sao Paulo, Inst Biomed Sci, Dept Cellular Biol, Sao Paulo - Brazil

^[4] Univ Sao Paulo, Inst Chem, Dept Biochem, Sao Paulo - Brazil

^[5] Fed Univ Sao Paulo UNIFESP, Div Nephrol, Lab Clin & Expt Immunol, Sao Paulo - Brazil

^[6] Univ Sao Paulo, Renal Pathophysiol Lab LIM16, Fac Med, Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: IMMUNITY INFLAMMATION AND DISEASE; v. 4, n. 3, p. 300-314, SEP 2016.
• Citações Web of Science: 1

Resumo

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. (AU)

• Processo FAPESP: 12/02270-2 - Novos mecanismos celulares, moleculares e imunológicos das lesões renais agudas e crônicas: busca por novas estratégias terapêuticas
• Beneficiário: Niels Olsen Saraiva Câmara
• Modalidade de apoio: Auxílio à Pesquisa - Temático