In schistosomiasis and other diseases associated with type-2 immunity, the pathology resulting from chronic infection or chronic allergen exposure is predominantly induced by the host immune response. The chronic type-2 immune response eventually triggers significant fibrosis, which is the primary cause of morbidity and mortality in many chronic infectious and inflammatory diseasese. Our work is focused on elucidating the mechanisms of granulomatous inflammation, fibrosis, portal hypertension, and death following infection with S. mansoni and to devise novel strategies to slow or reverse the progression of liver fibrosis. Progress was made in the following areas: Type 2 cytokine responses are important drivers of tissue remodeling and fibrosis in many diseases, including asthma, ulcerative colitis, and chronic helminth infections. In all these diseases, the affected organs accumulate a heterogeneous population of macrophages derived from recruited monocytes and activated tissue residents whose phenotype shifts as the inflammatory response progresses. Many recent studies have cumulated in two key conclusions: that the origins and homeostatic signals for resident tissue macrophages and monocyte-derived macrophages differ fundamentally, and that monocytes are capable of developing multiple distinct phenotypes and functions when entering tissues. Macrophage depletion studies have identified no defects in systemic initiation of type 2 cytokine responses during helminth infection. However, their overall role in maintaining or resolving established interleukin 13 (IL-13)-driven inflammation and fibrosis was unclear. To dissect the role of macrophages in type 2 immunity in the lung, we examined three models of T helper type 2 (Th2)-associated disease, and rather than targeting a single signaling pathway or putative effector gene, we transiently depleted macrophages using CD11b-diphtheria toxin receptor (CD11b-DTR) transgenic mice treated with diphtheria toxin (DTX). This well-established model offered the advantage of selectively depleting monocytes, monocyte descendants, and most tissue macrophages independently of their phagocytic activity and without impacting CD11b+ eosinophils, neutrophils, or other innate populations. Our primary model was intravenous (IV) challenge of antigen-primed mice with Schistosoma mansoni eggs, creating eosinophil-rich fibrotic granulomas in the lung that progress through characteristic stages. We also employed acute house dust mite (HDM)-induced allergic airway inflammation and infection with Nippostrongylus brasiliensis, a hookworm parasite that migrates destructively through the lung and resides in the small intestine before being expelled by IL-13-dependent mechanisms. Unexpectedly, the combined data from all three models revealed a striking decrease in type 2-dependent inflammation and fibrosis in the lung, without impaired IL-13 responses in draining lymph nodes, regardless of when macrophages were depleted. In contrast to previous studies based on chemical or surgical injury suggesting macrophage switch from pro- to anti-fibrotic roles between the initiation and resolution phases of liver fibrosis, we showed that macrophages exhibit pro-fibrotic activity at all stages of the IL-13-driven inflammatory response in the lung. Mechanistically, we found that macrophages play a critical role in recruiting and activating effector CD4+ Th2 cells in the affected tissues, likely explaining why depleting macrophages rapidly decrease IL-13-dependent lung fibrosis. An important implication of these findings is that IL-13-driven tissue inflammation and fibrosis can resolve rapidly if macrophages are rendered incapable of recruiting T cells and actively maintaining tissue-localized immune responses. Therefore, therapeutic strategies that deactivate macrophages or reverse their accumulation in inflamed tissues could emerge as viable targets to ameliorate progressive IL-13-driven fibrosis and other diseases associated with persistent overproduction of type 2 cytokines.
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