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Item Adiponectin pathway activation dampens inflammation and enhances alveolar macrophage fungal killing via LC3-associated phagocytosis(bioRxiv, 2024-08-24) Goli, Sri Harshini; Lim, Joo-Yeon; Basaran-Akgul, Nese; Templeton, Steven P.; Microbiology and Immunology, School of MedicineAlthough innate immunity is critical for antifungal host defense against the human opportunistic fungal pathogen Aspergillus fumigatus, potentially damaging inflammation must be controlled. Adiponectin (APN) is an adipokine produced mainly in adipose tissue that exerts anti-inflammatory effects in adipose-distal tissues such as the lung. We observed 100% mortality and increased fungal burden and inflammation in neutropenic mice with invasive aspergillosis (IA) that lack APN or the APN receptors AdipoR1 or AdipoR2. Alveolar macrophages (AMs), early immune sentinels that detect and respond to lung infection, express both receptors, and APN−/− AMs exhibited an inflammatory/M1 phenotype that was associated with decreased fungal killing. Pharmacological stimulation of AMs with AdipoR agonist AdipoRon partially rescued deficient killing in APN−/− AMs that was dependent on both receptors. Finally, APN-enhanced fungal killing was associated with increased activation of the non-canonical LC3 pathway of autophagy. Thus, our study identifies a novel role for APN in LC3-mediated killing of A. fumigatus.Item PPAR-γ in Macrophages Limits Pulmonary Inflammation and Promotes Host Recovery Following Respiratory Viral Infection(American Society for Microbiology, 2019-05-01) Huang, Su; Zhu, Bibo; Cheon, In Su; Goplen, Nick P.; Jiang, Li; Zhang, Ruixuan; Peebles, R. Stokes; Mack, Matthias; Kaplan, Mark H.; Limper, Andrew H.; Sun, Jie; Pediatrics, School of MedicineAlveolar macrophages (AM) play pivotal roles in modulating host defense, pulmonary inflammation, and tissue injury following respiratory viral infections. However, the transcriptional regulation of AM function during respiratory viral infections is still largely undefined. Here we have screened the expression of 84 transcription factors in AM in response to influenza A virus (IAV) infection. We found that the transcription factor PPAR-γ was downregulated following IAV infection in AM through type I interferon (IFN)-dependent signaling. PPAR-γ expression in AM was critical for the suppression of exaggerated antiviral and inflammatory responses of AM following IAV and respiratory syncytial virus (RSV) infections. Myeloid PPAR-γ deficiency resulted in enhanced host morbidity and increased pulmonary inflammation following both IAV and RSV infections, suggesting that macrophage PPAR-γ is vital for restricting severe host disease development. Using approaches to selectively deplete recruiting monocytes, we demonstrate that PPAR-γ expression in resident AM is likely important in regulating host disease development. Furthermore, we show that PPAR-γ was critical for the expression of wound healing genes in AM. As such, myeloid PPAR-γ deficiency resulted in impaired inflammation resolution and defective tissue repair following IAV infection. Our data suggest a critical role of PPAR-γ expression in lung macrophages in the modulation of pulmonary inflammation, the development of acute host diseases, and the proper restoration of tissue homeostasis following respiratory viral infections.IMPORTANCE Respiratory viral infections, like IAV and respiratory syncytial virus (RSV) infections, impose great challenges to public health. Alveolar macrophages (AM) are lung-resident immune cells that play important roles in protecting the host against IAV and RSV infections. However, the underlying molecular mechanisms by which AM modulate host inflammation, disease development, and tissue recovery are not very well understood. Here we identify that PPAR-γ expression in AM is crucial to suppress pulmonary inflammation and diseases and to promote fast host recovery from IAV and RSV infections. Our data suggest that targeting macrophage PPAR-γ may be a promising therapeutic option in the future to suppress acute inflammation and simultaneously promote recovery from severe diseases associated with respiratory viral infections.Item Regulating the adaptive immune response to respiratory virus infection(Springer Nature, 2012) Braciale, Thomas J.; Sun, Jie; Kim, Taeg S.; Pediatrics, IU School of MedicineRecent years have seen several advances in our understanding of immunity to virus infection of the lower respiratory tract, including to influenza virus infection. Here, we review the cellular targets of viruses and the features of the host immune response that are unique to the lungs. We describe the interplay between innate and adaptive immune cells in the induction, expression and control of antiviral immunity, and discuss the impact of the infected lung milieu on moulding the response of antiviral effector T cells. Recent findings on the mechanisms that underlie the increased frequency of severe pulmonary bacterial infections following respiratory virus infection are also discussed.Item Uncoupling of macrophage inflammation from self-renewal modulates host recovery from respiratory viral infection(Cell Press, 2021) Zhu, Bibo; Wu, Yue; Huang, Su; Zhang, Ruixuan; Son, Young Min; Li, Chaofan; Cheon, In Su; Gao, Xiaochen; Wang, Min; Chen, Yao; Zhou, Xian; Nguyen, Quynh; Phan, Anthony T.; Behl, Supriya; Taketo, M. Mark; Mack, Matthias; Shapiro, Virginia S.; Zeng, Hu; Ebihara, Hideki; Mullon, John J.; Edell, Eric S.; Reisenauer, Janani S.; Demirel, Nadir; Kern, Ryan M.; Chakraborty, Rana; Cui, Weiguo; Kaplan, Mark H.; Zhou, Xiaobo; Goldrath, Ananda W.; Sun, Jie; Microbiology and Immunology, School of MedicineTissue macrophages self-renew during homeostasis and produce inflammatory mediators upon microbial infection. We examined the relationship between proliferative and inflammatory properties of tissue macrophages by defining the impact of the Wnt/β-catenin pathway, a central regulator of self-renewal, in alveolar macrophages (AMs). Activation of β-catenin by Wnt ligand inhibited AM proliferation and stemness, but promoted inflammatory activity. In a murine influenza viral pneumonia model, β-catenin-mediated AM inflammatory activity promoted acute host morbidity; in contrast, AM proliferation enabled repopulation of reparative AMs and tissue recovery following viral clearance. Mechanistically, Wnt treatment promoted β-catenin-HIF-1α interaction and glycolysis-dependent inflammation while suppressing mitochondrial metabolism and thereby, AM proliferation. Differential HIF-1α activities distinguished proliferative and inflammatory AMs in vivo. This β-catenin-HIF-1α axis was conserved in human AMs and enhanced HIF-1α expression associated with macrophage inflammation in COVID-19 patients. Thus, inflammatory and reparative activities of lung macrophages are regulated by β-catenin-HIF-1α signaling, with implications for the treatment of severe respiratory diseases.