RSV-induced M2 macrophage differentiation: role of TLR4/PPARg/RXR signaling axis (80)

项目总结/文摘

PROJECT SUMMARY/ABSTRACT Monocytes and macrophages (Mf) sense the presence of pathogens, tissue damage, and host-derived mediators in their environment and respond by differentiating into distinct functional phenotypes that mediate host innate immune responses. For example, “classically activated” (M1) macrophages are highly microbicidal, yet their production of inflammatory mediators may also damage host tissue. At the other end of a functional spectrum, “alternatively activated” (M2) macrophages, induced by IL-4 and IL-13, mediate “wound healing” through elimination of damaged tissue and other anti-inflammatory mechanisms. The Blanco and Vogel laboratories have worked closely together to study the host response to Respiratory Syncytial Virus (RSV), the most significant cause of severe lower respiratory tract infection in infants, the elderly, and immunosuppressed individuals. In wild-type (WT) mice, RSV infection elicits an early, transient M1 Mf re- sponse in the lung that is followed by a more sustained period of M2 Mf predominance and resolution of inflam- matory lung pathology. We reported that IL-4Ra-/- mice, that fail to respond to RSV infection with the development of M2 Mf, exhibit greatly enhanced lung pathology that can be overcome by adoptive transfer of WT Mf that differentiate into M2 Mf upon RSV infection. Importantly, RSV-induced TLR4 signaling was shown to be a pre- requisite for induction of the transcription factor peroxisome proliferator-activated receptor gamma (PPARg). PPARg forms heterodimers with retinoid X receptor (RXR) that bind to M2 Mf gene promoters and activate tran- scription of M2 Mf genes. Our primary objective in this R21 application is to define in greater detail mechanisms governing the TLR4-induced PPARg/RXR signaling axis and the consequences of M2 Mf in the resolution of RSV infection. The overarching hypothesis to be tested is that the balance of M1 and M2 Mf during RSV infection dictates the extent of RSV disease. By comparing the responses of WT mice and mice with PPARg-deficient Mf in vivo and in vitro, we will determine the role of TLR4-induced PPARg/RXR axis in the regulation of M2 Mf development in RSV (Specific Aim 1). In Specific Aim 2, Targeting the TLR4-induced PPARg/RXR signal- ing axis in the cotton rat model of RSV, we will extend our findings using cotton rats, the gold standard for development of RSV therapies, to test the hypothesis that therapeutic administration of PPARg and RXR agonists to infected cotton rats will result in synergistic M2 Mf differentiation that, in turn, will mitigate inflammatory lung damage normally caused by RSV infection. These two aims are based on our strong published and preliminary data, and support the concept that the balance between M1 Mf-mediated inflammatory lung damage and PPARg/RXR-driven transcription of M2 Mf genes, leading to tissue repair, dictates the ultimate outcome. At the conclusion of these exploratory studies, key processes that lead to changes in Mf activation will have been defined that, in turn, are expected to translate into reasonable and practical therapeutic approaches for counter- acting inflammatory lung damage induced by RSV, and possibly other agents (e.g., influenza, SARS-CoV-2).