Neutrophil-epithelial microRNA shuttling in acute lung injury (ALI)
Final Report Abstract
The focus of the project has been extended towards studying neutrophil and platelet responses during acute organ dysfunction, including respiratory failure, myocardial infarction, and sepsis. Coordinated immune activation is essential for pathogen defense and healing; however, excessive cytokine release causes collateral tissue damage and organ injury. In a time and context-dependent manner, immune cells, such as leukocytes and platelets, can have pro- as well as anti-inflammatory functions. Fine-tuning of the inflammatory response therefore is key for therapeutic development to improve patient outcomes. In the lung, we found that the metalloprotease-disintegrin 8 (ADAM8) drives neutrophil migration and disease severity during acute inflammation. Both, genetic deletion and pharmacological inhibition of ADAM8 reduced neutrophilic lung inflammation, while notably, microbe clearance was improved. Mechanistically, blocking ADAM8 limited neutrophil motility by reducing intracellular interactions of ADAM8 with the actin-based motor molecule Myosin1f. These data favor ADAM8 as a promising therapeutic target. Additionally, we analyzed the proteolytic activities in lung fluids from patients with pneumonia and found that increased ADAM8 activity indicated severe disease. We conclude that proteolytic signatures could be a rapid tool for early recognition and stratification of patients with acute respiratory distress syndrome (ARDS) in a critical care setting. In myocardial infarction (MI), we described a protective function of neutrophils in mice by attenuating ischemia-reperfusion injury through netrin-1 release and purinergic signaling. Netrin-1 levels were increased in the blood of patients and mice with MI, and we identified neutrophils as main source for elevated blood netrin-1. In mouse sepsis models, we described that severe systemic inflammatory states can lead to changes in the sites of platelet production and phenotypes, resulting in a protective platelet population with mainly immunomodulatory functions. These findings could inform precision therapy for sepsis through a cellular approach of transfusing platelets that are preprogrammed for immune functions. Together, our findings advance the mechanistic understanding of organ dysfunction and uncover novel druggable approaches that may be impactful to develop therapies for patients with organ failure.
Publications
- Disease Mechanisms of Perioperative Organ Injury. Anesth Analg 131(6):1730-1750. 2021
Conrad C, Eltzschig HK
(See online at https://doi.org/10.1213/ane.0000000000005191) - PMN-derived netrin-1 attenuates cardiac ischemia-reperfusion injury via myeloid ADORA2B signaling. J Exp Med 218(6):e2021000, 2021
Li J, Conrad C, Mills TW, Berg NK, Kim B, Ruan W, Lee JW, Zhang X, Yuan X, Eltzschig HK
(See online at https://doi.org/10.1084/jem.20210008) - ADAM8 signaling drives neutrophil migration and ARDS severity. JCI Insight 7(3):e149870, 2022
Conrad C, Yildiz D, Cleary SJ, Margraf A, Cook L, Schlomann U, Panaretou B, Bowser JL, Karmouty-Quintana H, Li J, Berg NK, Martin SC, Aljohmani A, Moussavi-Harami SF, Wang KM, Tian JJ, Magnen M, Valet C, Qiu L, Singer JP, Eltzschig HK, CapSys Study Group, Bertrams W, Herold S, Suttorp N, Schmeck B, Ball ZT, Zarbock A, Looney MR, Bartsch JW
(See online at https://doi.org/10.1172/jci.insight.149870) - Is neutrophilic inflammation treatable in COVID-19? Lancet Respir Med; 10(12): 1100–1101, 2022
Conrad C, Looney MR
(See online at https://doi.org/10.1016/s2213-2600(22)00293-4) - Sepsis promotes splenic production of a protective platelet pool with high CD40 ligand expression. J Clin Invest 132(7):e153920, 2022
Valet C, Magnen M, Qiu L, Cleary SJ, Wang KM, Ranucci S, Grockowiak E, Boudra R, Conrad C, Seo Y, Calabrese DR, Greenland JR, Leavitt AD, Passegué E, Méndez-Ferrer S, Swirski FK, Looney, MR
(See online at https://doi.org/10.1172/jci153920)
