Macrophage migration inhibitory factor (MIF) controls cytokine release during respiratory syncytial virus infection in macrophages

Abstract

Objective and design Respiratory syncytial virus (RSV) is the major cause of infection in children up to 2 years old and reinfection is very common among patients. Tissue damage in the lung caused by RSV leads to an immune response and infected cells activate multiple signaling pathways and massive production of inflammatory mediators like macrophage migration inhibitory factor (MIF), a pro-inflammatory cytokine. Therefore, we sought to investigate the role of MIF during RSV infection in macrophages. Methods We evaluated MIF expression in BALB/c mice-derived macrophages stimulated with different concentrations of RSV by Western blot and real-time PCR. Additionally, different inhibitors of signaling pathways and ROS were used to evaluate their importance for MIF expression. Furthermore, we used a specific MIF inhibitor, ISO-1, to evaluate the role of MIF in viral clearance and in RSV-induced TNF-α, MCP-1 and IL-10 release from macrophages. Results We showed that RSV induces MIF expression dependently of ROS, 5-LOX, COX and PI3K activation. Moreover, viral replication is necessary for RSV-triggered MIF expression. Differently, p38 MAPK in only partially needed for RSVinduced MIF expression. In addition, MIF is important for the release of TNF-α, MCP-1 and IL-10 triggered by RSV in macrophages. ConclusionsIn conclusion, we demonstrate that MIF is expressed during RSV infection and controls the release of proinflammatory cytokines from macrophages in an in vitro model.

TNF-mediated alveolar macrophage necroptosis drives disease pathogenesis during respiratory syncytial virus infection

“…As macrophage necroptosis triggered by RSV required virus replication, we hypothesized that during RSV replication cycle, the necroptotic machinery was activated indirectly, for example, through the autocrine activity of a virus-induced pro-necroptotic cytokine, such as TNF. Consistent with this assumption, we have recently shown that macrophages respond to RSV infection by secreting TNF [30]. We extended these findings and show that RSV triggers the release of TNF in a concentration-dependent manner and that TNF is released as a result of RSV replication, as UVinactivated RSV is not able to induce TNF secretion from macrophages.…”

“…We have recently shown that macrophages respond to ex vivo RSV infection by releasing TNF [ 30 ]. Because TNF has been extensively studied as a necroptotic trigger [ 31 ], we sought to elucidate the role of TNF in RSV-induced macrophage necroptosis.…”

Evaluation of the relationship between macrophage migration inhibitory factor level and clinical course in patients with COVID‐19 pneumonia

“…MIF increases the production of inflammatory cytokines such as TNF‐α, IL‐1β, IL‐6, and IFN. 6 , 7 It has been shown that the MIF level measured in patients hospitalized with sepsis and acute respiratory failure may be associated with poor prognosis in the early period, and it has also been suggested that the regulation of MIF level can be used in the treatment of these patients. It has also been stated that MIF suppresses glucocorticoid production, which plays an important role in the anti‐inflammatory effects.…”

Immunopathology of RSV: An Updated Review

“…RSV infection mouse or human AMs induces TNFα-mediated necrosis mediated through the RIPK1/3/MLKL expression pathways [117]. RSV replication leads to upregulated macrophage migration inhibitory factor (MIF) expression leading to modified cytokine production by AMs [118]. Interestingly, this pathway is associated with increases in the pro-inflammatory TNFα as well as anti-inflammatory IL-10, suggesting that regulation of these cytokines is pivotal in balancing protection and pathology.…”