Investigating Strategies to Modulate Macrophage Function to Prevent the Progression of Fibrotic Lung Disease

Abstract

Tissue fibrosis occurs in the advanced stages of various chronic diseases and can account for 45% of all deaths related to chronic diseases worldwide. The extracellular matrix (ECM) components comprising the fibrotic scar are primarily derived from myofibroblasts, which are contractile fibroblasts arising from the trans-differentiation of several cellular progenitors. Disturbances in immune cell infiltration and function could lead to the uncontrolled production of pro/anti-inflammatory mediators, which may alter the phenotype, state, and function of myofibroblasts progenitors, leading to aberrant wound repair and pathological fibrosis. A great deal of knowledge has implicated macrophages in the pathogenesis and exacerbation of the fibrotic process. Nonetheless, much remains to be elucidated on the potential mechanisms regulating macrophage accumulation and pro-fibrotic polarization, and whether these mechanisms can be further investigated to modulate tissue repair. The Endoplasmic reticulum (ER) stress has recently been implicated as a key mechanism that propagates the pathogenesis of the fibrotic process. How ER stress precisely impacts the fibrotic process is still unclear. This thesis partly explored how modulating the outcome of ER stress – the unfolded protein response (UPR), would affect the severity of lung fibrosis and addressed the role of IL-6 signalling in macrophages during fibrosis. The data demonstrated that UPR activation in pro-fibrotic macrophages and partial deficiency of Grp78, the master regulator of the UPR, abrogated pulmonary fibrotic changes and reduced the accumulation of pro-fibrotic (M2-like) macrophages. These findings were later associated with high TUNEL levels, 7AAD positive cells, Chop and cleaved caspase 3 levels, which are suggestive of GRP78 mediated apoptosis in this population. On the contrary, mice lacking a terminal UPR mediator of apoptosis, called Chop, had increased ECM deposition and greater persistence of non-apoptotic macrophages. These findings suggest that UPR-mediated macrophage polarization and apoptosis may alter lung wound repair processes. As IL-6 synergized the effect of IL-4 to promote a hyper M2 macrophage state, it provided a unique and compelling model to study the dynamics of macrophage alternative programming, which has set the stage to investigate whether the UPR was implicated in the generation of a hyper pro-fibrotic macrophage phenotype. This hyper M2 macrophage model led to the identification of ER expansion program and the IRE1-XBP1 arm of the UPR in pro-fibrotic macrophage polarization, and suggested an unprecedented in vivo role of IL-6 in priming macrophages in the injured lungs to possibly potentiate pathological wound repair. Looking forward, many questions remain to be answered in order to precisely identify the vital UPR axis regulating ER expansion in macrophages during pathological wound repair and to get closer to the understanding of whether the UPR modulates the pro-fibrotic/pro-resolving capacity of macrophages. Insights on these mechanisms may facilitate the development of therapeutics that better manage chronic fibrotic diseases which pose fatal consequences and increase public concern.