To understand the pathogenesis of chronic inflammatory disease, we analyzed an experimental mouse model of a chronic lung disease that resembles asthma and chronic obstructive pulmonary disease (COPD) in humans. In this model, chronic lung disease develops after infection with a common type of respiratory virus is cleared to trace levels of noninfectious virus. Unexpectedly, the chronic inflammatory disease arises independently of an adaptive immune response and is driven by IL-13 produced by macrophages stimulated by CD1d-dependent TCR-invariant NKT cells. This innate immune axis is also activated in the lungs of humans with chronic airway disease due to asthma or COPD. These findings provide new insight into the pathogenesis of chronic inflammatory disease with the discovery that the transition from respiratory viral infection into chronic lung disease requires persistent activation of a novel NKT cell-macrophage innate immune axis. It has been widely speculated that infections are linked to the development of chronic inflammatory diseases. Although the connection between infection and chronic disease is uncertain, it likely depends on an aberrant immune response. In particular, it is believed that the innate immune system mediates the acute response to an infectious agent 1 , while an atypical adaptive immune response may cause chronic inflammation 2. Furthermore, infectioninduced alterations in the adaptive immune response that produce T cell or antibody-mediated

Graphical Abstract Highlights d Atlas of 512,595 cis-regulatory elements active in 86 immunologic cell types d Two classes of loci, controlled by either promoter-or enhancer-driven logic d Inference of enhancer elements that activate each gene across differentiation d Context-specificity of enhancer activation by transcription factors Pile-up traces of ATAC-seq signals in Itgax locus. Blue bars in the first row indicate the positions of identified peaks (Pval % 0.05) and the graph in the 2 nd row conservation score among vertebrates. RNA expression for Itgax (Cd11c) gene are indicated by barplots with * where RNA-seq data was not acquired.

Invariant natural killer T cells (iNKT cells) play a prominent role during infection and other inflammatory processes, and these cells can be activated through their T cell receptors by microbial lipid antigens. However, increasing evidence shows that they are also activated in situations where no foreign lipid antigens are present, suggesting a role for lipid self-antigen. We now demonstrate that an abundant endogenous lipid, β-D-glucopyranosylceramide (β-GlcCer), is a potent iNKT cell self-antigen in mouse and human, and that its activity depends on N-acyl chain composition. Furthermore, β-GlcCer accumulates during infection and in response to Toll-like receptor agonists, contributing to iNKT cell activation. Thus, we propose that recognition of β-GlcCer by the invariant TCR translates innate danger signals into iNKT cell activation.

Host defense against viruses probably depends on targeted death of infected host cells and then clearance of cellular corpses by macrophages. For this process to be effective, the macrophage must presumably avoid its own virus-induced death. Here we identify one such mechanism. We show that mice lacking the chemokine Ccl5 are immune compromised to the point of delayed viral clearance, excessive airway inflammation and respiratory death after mouse parainfluenza or human influenza virus infection. Virus-inducible levels of Ccl5 are required to prevent apoptosis of virus-infected mouse macrophages in vivo and mouse and human macrophages ex vivo. The protective effect of Ccl5 requires activation of the Ccr5 chemokine receptor and consequent bilateral activation of G(alphai)-PI3K-AKT and G(alphai)-MEK-ERK signaling pathways. The antiapoptotic action of chemokine signaling may therefore allow scavengers to finally stop the host cell-to-cell infectious process.