Fibrosis is regulated by Th2 and Th17 responses and by dynamic interactions between fibroblasts and macrophages

Abstract

Dysregulated wound healing leads to fibrosis, whereby fibroblasts synthesize excess extracellular matrix and scarring impairs proper organ function. Although fibrotic diseases arise from diverse causes and display heterogeneous features, fibrosis commonly associates with chronic inflammation. Recent discoveries reinforce the idea that communication between fibroblasts, macrophages, and CD4 T cells integrates the processes of wound healing and host defense. Signals between macrophages and fibroblasts can exacerbate, suppress, or reverse fibrosis. Fibroblasts and macrophages are activated by T cells, but their activation also engages negative feedback loops that reduce fibrosis by restraining the immune response, particularly when the Th2 cytokine IL-13 contributes to pathology. Thus the interactions among fibroblasts, macrophages, and CD4 T cells likely play general and critical roles in initiating, perpetuating, and resolving fibrosis in both experimental and clinical conditions.

Fig. 1.

Model of the initiation and perpetuation of fibrosis. Injuries and infections activate macrophages and fibroblasts, which move together, enabling macrophages to simulate fibroblasts with TGF-β, PDGF, IL-1β, and other factors. Macrophages also promote inflammation by recruiting and activating monocytes and neutrophils, present antigens to CD4 T cells, and modulate T cell responses with costimulation and cytokines. Fibroblasts also influence T cells. CD4 T cells coordinate the immune response with cytokines, enhancing neutrophil recruitment with IL-17A, activating macrophages with IL-4 and IL-13 or IFN-γ, and inducing collagen production by fibroblasts with IL-4, IL-13, and possibly TGF-β. The combination of activating signals from the inflammatory environment, macrophages, and CD4 T cells stimulate fibroblasts to proliferate and synthesize collagens, matrix metalloproteinases (MMPs), and tissue inhibitors of metalloproteinases (TIMPs) that construct and remodel extracellular matrix and lead to fibrosis.

Fig. 2.

Model of the resolution of fibrosis. The immune response eliminates infections, with phagocytosis by macrophages clearing dead cells, microbes, and debris that would otherwise activate myofibroblasts. Macrophages also reverse myofibroblast activation with IL-10, by stopping production of TGF-β, PDGF, and IL-1β, and by acting in negative feedback loops that reduce immune-mediated fibrosis. IL-4- and IL-13-stimulated alternatively activated macrophages restrain the CD4 T cell response with arginase-1, RELM-α, and IL-10, whereas IFN-γ-stimulated classically activated macrophages reduce fibrosis by producing nitric oxide. Fibroblasts produce IL-13Rα2, a decoy receptor for IL-13, and contract to seal lesions. Fibrosis resolves as activated fibroblasts die or return to a quiescent state and cease adding to the extracellular matrix and as macrophages degrade excess extracellular matrix (ECM) with MMPs.