The role of GCN2 in type-2 mucosal inflammation within the lung (IRM7P.483)

Abstract

Abstract Infection with the parasitic roundworm Nippostrongylus brasiliensis causes lung damage associated with an inflammatory response dominated by alternative (type-2) inflammation. Macrophages are requisite mediators of lung inflammation and pathology resolution in the N. brasiliensis infection model. Metabolic stress resulting from enzymatic consumption of amino acids engages the GCN2 arm of the integrated stress response, which profoundly alters the inflammatory potential of antigen presenting cells, causing them to suppress type-1 cytokine expression and promote type-2 cytokine expression. Thus, we hypothesized that GCN2 activation, as a result of infection driven nutrient stress, may be a key mechanism promoting M2 macrophage differentiation and type-2 inflammatory processes. When we examined cytokine expression in the lungs of GCN2KO mice infected with N. brasiliensis, we found significantly decreased levels of IL-10 relative to WT controls. This was associated with increased lung infiltration of macrophages that expressed reduced expression of FIZZ1 and YM-1, indicative of a skewing towards an M1 phenotype. Moreover, we observed dramatic increases in lung pathology associated with increased cellular infiltrate and fibrosis in infected GCN2KO mice suggestive of severe helminth-driven lung inflammation. Thus, our findings suggest a novel regulatory role for GCN2 kinase during type-2 inflammatory processes in the lung.