Fibrosis is a pathological feature of most chronic inflammatory diseases. Fibrosis, or scarring, is defined by the accumulation of excess extracellular matrix components. If highly progressive, the fibrotic process eventually leads to organ malfunction and death. Fibrosis affects nearly every tissue in the body. Here we discuss how key components of the innate and adaptive immune response contribute to the pathogenesis of fibrosis. We also describe how cell-intrinsic changes in important structural cells can perpetuate the fibrotic response by regulating the differentiation, recruitment, proliferation and activation of extracellular matrix–producing myofibroblasts. Finally, we highlight some of the key mechanisms and pathways of fibrosis that are being targeted as potential therapies for a variety of important human diseases.

Complexes of the heat shock protein gp96 and antigenic peptides are taken up by antigen-presenting cells and presented by MHC class I molecules. In order to explain the unusual efficiency of this process, the uptake of gp96 had been postulated to occur through a receptor, identified recently as CD91. We show here that complexes of peptides with heat shock proteins hsp90, calreticulin, and hsp70 are also taken up by macrophages and dendritic cells and re-presented by MHC class I molecules. All heat shock proteins utilize the CD91 receptor, even though some of the proteins have no homology with each other. Postuptake processing of gp96-chaperoned peptides requires proteasomes and the transporters associated with antigen processing, utilizing the classical endogenous antigen presentation pathway.

Macrophage-specific expression of Arginase-1 is commonly believed to promote inflammation, fibrosis, and wound healing by enhancing L-proline, polyamine, and Th2 cytokine production. Here, however, we show that macrophage-specific Arg1 functions as an inhibitor of inflammation and fibrosis following infection with the Th2-inducing pathogen Schistosoma mansoni. Although susceptibility to infection was not affected by the conditional deletion of Arg1 in macrophages, Arg1 −/flox ;LysMcre mice died at an accelerated rate. The mortality was not due to acute Th1/NOS2-mediated hepatotoxicity or endotoxemia. Instead, granulomatous inflammation, liver fibrosis, and portal hypertension increased in infected Arg1 −/flox ;LysMcre mice. Similar findings were obtained with Arg1 flox/flox ;Tie2cre mice, which delete Arg1 in all macrophage populations. Production of Th2 cytokines increased in the infected Arg1 −/flox ;LysMcre mice, and unlike alternatively activated wild-type macrophages, Arg1 −/flox ;LysMcre macrophages failed to inhibit T cell proliferation in vitro, providing an underlying mechanism for the exacerbated Th2 pathology. The suppressive activity of Arg1-expressing macrophages was independent of IL-10 and TGF-β1. However, when exogenous L-arginine was provided, T cell proliferation was restored, suggesting that Arg1-expressing macrophages deplete arginine, which is required to sustain CD4+ T cell responses. These data identify Arg1 as the essential suppressive mediator of alternatively activated macrophages (AAM) and demonstrate that Arg1-expressing macrophages function as suppressors rather than inducers of Th2-dependent inflammation and fibrosis.