New immune pathways from chronic post-viral lung disease

Abstract

To better understand the immunopathogenesis of chronic inflammatory lung disease, we established a mouse model of disease that develops after respiratory viral infection. The disease that develops in this model is similar to chronic obstructive lung disease in humans. Using this model we have characterized two distinct phases in the chronic disease process. The first phase appears at three weeks after viral infection and depends on type I interferon-dependent expression and then subsequent activation of the high-affinity IgE receptor (FcepsilonRI) on conventional lung dendritic cells, which in turn recruit IL-13-producing CD4+ T cells to the lower airways. The second phase becomes maximal at seven weeks after infection and depends on invariant natural killer T (iNKT) cells and lung macrophages. Cellular cross-talk relies on interactions between the semi-invariant Valpha14Jalpha18 T-cell receptor on lung iNKT cells and CD1d on macrophages as well as iNKT cell-derived IL-13 and IL-13 receptor on macrophages. These interactions drive macrophages to a pattern of alternative activation and overproduction of IL-13. This innate immune axis is also activated in patients with chronic obstructive lung disease, as evidenced by increased numbers of iNKT cells and IL-13-producing alternatively activated macrophages marked by chitinase 1 production. Together the findings identify two new immune pathways responsible for early and late phases of chronic inflammatory lung disease in experimental and clinical settings. These findings extend our understanding of the complex mechanisms that underlie chronic obstructive lung disease and provide useful targets for diagnosis and therapy of this common disorder.

Figure 1

Cellular and molecular scheme for immune pathways leading to chronic lung disease after viral infection. (A) For the first phase of chronic disease, viruses cause airway epithelial cell (AEC) and plasmacytoid dendritic cell (pDC) production of type I interferon (IFN). Subsequent type I IFN receptor(IFNAR) signaling leads to upregulation of FcɛRI expression on resident lung conventional (c)DCs. In turn, FcɛRI activation by viral antigen and antiviral IgE leads to production of CCL28 and recruitment of CCR10‐expressing IL‐13‐producing T helper (Th)2 cells to the lung. The actions of IL‐13 drive differentiation of airway epithelial cell precursors toward mucous cells (mucous cell metaplasia) and airway smooth muscle cells to become more reactive to contractile agonists (airway hyper‐reactivity [AHR]). (B) For the second phase of chronic disease, viral remnants activate antigen‐presenting cells (APCs) and thereby facilitate CD1d‐dependent antigen presentation and consequent activation of invariant CD4⁻ natural killer T (NKT) cells. NKT cells then interact directly with lung macrophages via IL‐13 production and binding to the IL‐13 receptor (IL‐13R) as well as contact between invariant Va14 T‐cell receptor (TCR) and glycolipid‐loaded CD1d. This interaction leads to increased expression of IL‐13R and production of IL‐13 that drives a positive feedback loop to amplify IL‐13 production and alternative activation of macrophages, including Chi3l3/4, Fizz1, Mmp12, Arg1, and Alox12e gene expression in mice and Chit1, Arg1, and Alox15 in humans.