Early infiltration of p40IL12+CCR7+CD11b+ cells is critical for fibrosis development. Issue 3 (21st July 2016)

• Record Type: Journal Article
• Authors: Braga, Tarcio Teodoro; Correa‐Costa, Matheus; Azevedo, Hatylas; Silva, Reinaldo Correia; Cruz, Mario Costa; Almeida, Maira Estanislau Soares; Hiyane, Meire Ioshie; Moreira‐Filho, Carlos Alberto; Santos, Marinilce Fagundes; Perez, Katia Regina; Cuccovia, Iolanda Midea; Camara, Niels Olsen Saraiva
• Is Part Of: Immunity, inflammation and disease. Volume 4:Issue 3(2016)
• Page Start: 300
• Page End: 314
• Publication Date: 2016-07-21
• Subjects: Collagen -- pro‐inflammatory macrophages -- renal fibrosis; Immunology -- Periodicals; Immunity -- Periodicals; Inflammation -- Periodicals; 616.079
• DOI: 10.1002/iid3.114
• Languages: English
• ISSNs: 2050-4527

Abstract

Abstract: Introduction: Macrophages 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 Results: We 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 IFNγ + 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 (IFNγ + 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 (IFNγ + LPS) cells originated from Stat6 −/− mice. The injection of M (IFNγ + LPS) cells was associated with the up‐regulation of inflammation‐ and fibrosis‐related proteins (Thbs1, Mmp7, Mmp8, and Mmp13). Conclusions: Our 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. Abstract : p40IL12 + CCR7 + CD11b + cells and renal fibrosis.