The Maresin 1–LGR6 axis decreases respiratory syncytial virus-induced lung inflammation

Abstract

The resolution of infection is an active process with specific molecular and cellular mechanisms that temper inflammation and enhance pathogen clearance. Here, the specialized pro-resolving mediator (SPM) Maresin 1 (MaR1) inhibited respiratory syncytial virus (RSV)-induced inflammation. inlerleukin-13 production from type 2 innate lymphoid cells (ILC) and CD4 T helper type 2 cells was decreased by exogenous MaR1. In addition, MaR1 increased amphiregulin production and decreased RSV viral transcripts to promote resolution. MaR1 also promoted interferon-β production in mouse lung tissues and also in pediatric lung slices. MaR1 significantly inhibited the RSV-triggered aberrant inflammatory phenotype in FoxP3-expressing Tregs. The receptor for MaR1, leucine-rich repeat-containing G protein-coupled receptor 6 (LGR6), was constitutively expressed on Tregs. Following RSV infection, mice lacking Lgr6 had exacerbated type 2 immune responses with an increased viral burden and blunted responses to MaR1. Together, these findings have uncovered a multi-pronged protective signaling axis for MaR1–Lgr6, improving Tregs’s suppressive function and upregulating host antiviral genes resulting in decreased viral burden and pathogen-mediated inflammation, ultimately promoting restoration of airway mucosal homeostasis.

Respiratory viral infection and resolution of inflammation: Roles for specialized pro-resolving mediators

“…63 Of interest, RSV disrupts the immunosuppressive function of Tregs, converting them to pathological pro-inflammatory effectors. 64,65 Tregs are another target for SPMs to enhance resolution from viral pathogen-evoked inflammation. 65…”

“…64,65 Tregs are another target for SPMs to enhance resolution from viral pathogen-evoked inflammation. 65…”

“…Together, these host-directed mechanisms for Mar1 enhanced the resilience of the lung to infection with RSV. 65 Of interest, a comprehensive feeding study of pregnant mothers with omega-3 fatty acids led to decreased risk for respiratory tract of their infants over five years of follow-up. 96…”

“…63 Of interest, RSV disrupts the immunosuppressive function of Tregs, converting them to pathological pro-inflammatory effectors. 64,65 Tregs are another target for SPMs to enhance resolution from viral pathogen-evoked inflammation. 65 In summary, a well-balanced self-limited inflammatory response is crucial in controlling pathogen replication and promoting the development of adaptive immune responses.…”

“…64,65 Tregs are another target for SPMs to enhance resolution from viral pathogen-evoked inflammation. 65 In summary, a well-balanced self-limited inflammatory response is crucial in controlling pathogen replication and promoting the development of adaptive immune responses. Nevertheless, in severe respiratory viral infections, this equilibrium is disrupted, resulting in an overactivation of various inflammatory pathways that contribute to tissue damage, pulmonary dysfunction, and even death.…”