RSV infection-elicited high MMP-12–producing macrophages exacerbate allergic airway inflammation with neutrophil infiltration

Abstract

Summary Respiratory syncytial virus (RSV) infection often exacerbates bronchial asthma, but there is no licensed RSV vaccine or specific treatments. Here we show that RSV-induced alveolar macrophages, which produce high levels of matrix metalloproteinase-12 (MMP-12), exacerbate allergic airway inflammation with increased neutrophil infiltration. When mice subjected to allergic airway inflammation via exposure to the house dust mite antigen (HDM) were infected with RSV (HDM/RSV), MMP-12 expression, viral load, neutrophil infiltration, and airway hyperresponsiveness (AHR) were increased compared to those in the HDM and RSV groups. These exacerbations in the HDM/RSV group were attenuated in MMP-12-deficient mice and mice treated with MMP408, a selective MMP-12 inhibitor, but not in mice treated with dexamethasone. Finally, M2-like macrophages produced MMP-12, and its production was promoted by increase of IFN-β-induced IL-4 receptor expression with RSV infection. Thus, targeting MMP-12 represents a potentially novel therapeutic strategy for the exacerbation of asthma.

Gammaherpesvirus Alters Alveolar Macrophages According to the Host Genetic Background and Promotes Beneficial Inflammatory Control over Pneumovirus Infection

“…Our results confirm previous publication suggesting that memory AMs, but not other macrophage subsets, in the lung of viral-exposed animals mediate antibacterial trained immunity via similar enhanced neutrophil chemokine production [29]. Additionally, in mock-primed mice, the degree of neutrophilic infiltration and the increased expression of chemokines and neutrophil activators, especially CXCL1 and CXCL2, into the lungs following PVM inoculation has been positively correlated with the severity of hRSV-induced bronchiolitis [65][66][67][68][69]. As the more rapid attenuation of CXCL1 and CXCL2 cytokine production in MuHV-4-primed mice likely plays a role in the drastic decrease in neutrophil infiltration in the lungs measured 6 days p.i.…”

Airway Administration of Bacterial Lysate OM-85 Protects Mice Against Respiratory Syncytial Virus Infection

“…Our study showed that OM–85 treatment used as preventive measure consistently maintained AM population in the lungs, while RSV–infected untreated animals presented a pronounced reduction in these cells. This decrease in AM population can be partially explained by previous evidence demonstrating that RSV elicits MMP–12–producing macrophages over AM ( 72 ). OM–85 prevents this shift contributing to controlled RSV–induced disease.…”

Molecular Clustering Analysis of Blood Biomarkers in World Trade Center Exposed Community Members with Persistent Lower Respiratory Symptoms

“…Alternatively, it is possible that the WTC exposure led to de novo development of aberrant inflammatory responses, such as an increase in allergic and asthmatic responses described in children exposed to WTC dust [85], in WTC rescue and clean-up workers [86], and suggested in children exposed to outdoor air pollution [87]. Some of the bio-markers that we found to be increased in the WTC categorical variables of more intense exposures, include markers that can be associated with T helper 2 (type 2) responses, for example CCL17/TARC, CCL11/eotaxin [88], MMP12 [89], or VCAM1 [90]. Other markers, like RAGE [89], TREM1 [91], or angiogenin (and also VCAM1 [92]), can be associated with Th17 (type 17) responses.…”