Rationale: Recently, models of macrophage activation have been revised. Macrophages stimulated with Th2 cytokines have been classified as alternatively activated. Objectives: This article examines the expression and regulation of CC chemokine ligand 18 (CCL18), a marker of alternative activation, by human alveolar macrophages (AMs). Methods: AM were obtained from bronchoalveolar lavage (BAL) fluid of patients with idiopathic pulmonary fibrosis, sarcoidosis, or hypersensitivity pneumonitis (n = 69) and healthy volunteers (n = 22). Expression of CCL18 was determined by quantitative reverse transcriptase–polymerase chain reaction, in situ hybridization, flow cytometry, and immunohistochemistry, respectively. Measurements and Main Results: Spontaneous CCL18 production by BAL-derived cells was markedly increased in patients with pulmonary fibrosis and correlated negatively with pulmonary function test parameters. CCL18 gene expression and protein production were up-regulated in normal AMs after Th2 cytokine stimulation and/or coculture with human lung fibroblasts. Native collagen significantly up-regulated CCL18 expression in normal AMs activated with Th2 cytokines via a mechanism mediated by β2-integrin/ scavenger receptor(s). Culture supernatants of AMs from patients with idiopathic pulmonary fibrosis increased collagen production by normal lung fibroblasts partly mediated via CCL18. Conclusions: Our findings suggest that AMs from patients with pulmonary fibrosis disclose a phenotype of alternative activation and might be a part of a positive feedback loop with lung fibroblasts perpetuating fibrotic processes.

Macrophages are a diverse group of phagocytic cells acting in host protection against stress, injury, and pathogens. Here, we show that the scavenger receptor SR-A6 is an entry receptor for human adenoviruses in murine alveolar macrophage-like MPI cells, and important for production of type I interferon. Scavenger receptors contribute to the clearance of endogenous proteins, lipoproteins and pathogens. Knockout of SR-A6 in MPI cells, anti-SR-A6 antibody or the soluble extracellular SR-A6 domain reduced adenovirus type-C5 (HAdV-C5) binding and transduction. Expression of murine SR-A6, and to a lower extent human SR-A6 boosted virion binding to human cells and transduction. Virion clustering by soluble SR-A6 and proximity localization with SR-A6 on MPI cells suggested direct adenovirus interaction with SR-A6. Deletion of the negatively charged hypervariable region 1 (HVR1) of hexon reduced HAdV-C5 binding and transduction, implying that the viral ligand for SR-A6 is hexon. SR-A6 facilitated macrophage entry of HAdV-B35 and HAdV-D26, two important vectors for transduction of hematopoietic cells and human vaccination. The study highlights the importance of scavenger receptors in innate immunity against human viruses. Macrophages are a diverse group of phagocytic cells acting in host protection against stress, injury, and pathogens. They phenotypically and functionally adapt to their local environment, for example, peritoneal macrophages are distinct from brain-resident microglia, from liver-resident Kupffer cells or lung macrophages in the lung. Airway macrophages are among the first cells to encounter human respiratory viruses, such as adenoviruses. They release pro-inflammatory cytokines, kill pathogens, present antigens, and restore tissues. Yet, interactions of viruses with lung macrophages are poorly understood, and it is unclear, how they lead to infection or virus clearance. Here we identified the murine scavenger receptor SR-A6 as a receptor for a subset of human adenoviruses on alveolar macrophage-like cells, so-called MPI cells. Scavenger receptors comprise a large family of trans-membrane proteins, and contribute to the clearance of endogenous proteins, lipoproteins and pathogens. In a series of robust experimentation, we show that adenoviruses use SR-A6 as an entry receptor for infection of MPI cells, and production of type I interferon. MPI cells are non-transformed, self-renewing macrophages derived from fetal murine liver, and closely resemble adult alveolar macrophages. The results demonstrate that SR-A6 binds virions on the surface of alveolar macrophage-like cells, and leads to infection.