Lung-derived HMGB1 is detrimental for vascular remodeling of metabolically imbalanced arterial macrophages

Ludovic Boytard,Glenn Jacobowitz,Michele Silvestro,Lior Zangi,Dornazsadat Alebrahim,Chiara Bellini,Jean-Sébastien Silvestre,Jessica Oakes,Rayan Sleiman,Tarik Hadi,Hengdong Qu,Francesco Boccalatte,Bruce E Gelb,George Miller,Annanina Corsica,Andrew Kumpfbeck,Bhama Ramkhelawon,Matthias Kugler,Kissinger Hyppolite Fils

doi:10.1038/s41467-020-18088-2

Abstract

Pulmonary disease increases the risk of developing abdominal aortic aneurysms (AAA). However, the mechanism underlying the pathological dialogue between the lungs and aorta is undefined. Here, we find that inflicting acute lung injury (ALI) to mice doubles their incidence of AAA and accelerates macrophage-driven proteolytic damage of the aortic wall. ALI-induced HMGB1 leaks and is captured by arterial macrophages thereby altering their mitochondrial metabolism through RIPK3. RIPK3 promotes mitochondrial fission leading to elevated oxidative stress via DRP1. This triggers MMP12 to lyse arterial matrix, thereby stimulating AAA. Administration of recombinant HMGB1 to WT, but not Ripk3−/− mice, recapitulates ALI-induced proteolytic collapse of arterial architecture. Deletion of RIPK3 in myeloid cells, DRP1 or MMP12 suppression in ALI-inflicted mice repress arterial stress and brake MMP12 release by transmural macrophages thereby maintaining a strengthened arterial framework refractory to AAA. Our results establish an inter-organ circuitry that alerts arterial macrophages to regulate vascular remodeling.

Highlights

Pulmonary disease increases the risk of developing abdominal aortic aneurysms (AAA)
Data collected from 632 patients presenting with AAA revealed that ~25% of the cohort studied suffered from chronic obstructive pulmonary disease (COPD) at the time of AAA diagnosis (Fig. 1a)
We directly addressed this knowledge gap by assessing the incidence of AAA in mice modeled through the subcutaneous infusion of angiotensin II (Ang II)[29], and nasal instillation of LPS, as a prototypical model of acute lung injury (ALI) that recapitulates the inflammatory phases that manifest in COPD

Summary

Introduction

Pulmonary disease increases the risk of developing abdominal aortic aneurysms (AAA). the mechanism underlying the pathological dialogue between the lungs and aorta is undefined. To circumvent the direct effects of cigarette smoke on the aorta and evaluate the role of inflammatory lung damage on AAA, we subjected mice to acute lung injury mimicked by intranasal lipopolysaccharide (LPS) instillation[18] Under such conditions where the alveolar gasexchange surfaces are destroyed, we hypothesized that macrophages residing in the artery could serve as cellular sensors of exogenous DAMPs that escape from the diseased lungs thereby remotely stimulating arterial injury. The absence of RIPK3 in macrophages, DRP1 inhibition or MMP12 deficiency in mice subjected to ALI reduce mitochondrial oxidative stress and MMP12 expression, thereby protecting the abdominal artery wall from proteolytic damage and refraining AAA development

Methods

Results

Conclusion