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Scavenger receptor BI attenuates oxidized phospholipid-induced pulmonary inflammation
Katelyn Dunigan-Russell1, Michael J Yaeger1, Myles X Hodge2
1Pulmonary, Critical Care and Sleep Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, United States.
Abstract:
Damage associated molecular patterns (DAMPs) are molecules released from dead/dying cells following toxicant and/or environmental exposures that activate the immune response through binding of pattern recognition receptors (PRRs). Excessive production of DAMPs or failed clearance leads to chronic inflammation and delayed inflammation resolution. One category of DAMPs are oxidized phospholipids (oxPLs) produced upon exposure to high levels of oxidative stress, such as following ozone (O3) induced inflammation. OxPLs are bound by multiple classes of PRRs that include scavenger receptors (SRs) such as SR class B-1 (SR-BI) and toll-like receptors (TLRs). Interactions between oxPLs and PRRs appear to regulate inflammation; however, the role of SR-BI in oxPL-induced lung inflammation has not been defined. Therefore, we hypothesize that SR-BI is critical in protecting the lung from oxPL-induced pulmonary inflammation/injury. To test this hypothesis, C57BL/6J (WT) female mice were dosed with oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphatidylcholine (oxPAPC) by oropharyngeal aspiration which increased pulmonary SR-BI expression. Following oxPAPC exposure, SR-BI deficient (SR-BI-/-) mice exhibited increased lung pathology and inflammatory cytokine/chemokine production. Lipidomic analysis revealed that SR-BI-/- mice had an altered pulmonary lipidome prior to and following oxPAPC exposure, which correlated with increased oxidized phosphatidylcholines (PCs). Finally, we characterized TLR4-mediated activation of NF-κB following oxPAPC exposure and discovered that SR-BI-/- mice had increased TLR4 mRNA expression in lung tissue and macrophages, increased nuclear p65, and decreased cytoplasmic IκBα. Overall, we conclude that SR-BI is required for limiting oxPAPC-induced lung pathology by maintaining lipid homeostasis, reducing oxidized PCs, and attenuating TLR4-NF-κB activation, thereby preventing excessive and persistent inflammation.
Insights
Scavenger receptor SR-BI protects lungs from inflammation caused by oxidized phospholipids. SR-BI deficiency worsens lung injury and inflammation by altering lipid profiles and increasing TLR4-NF-κB activation.
Area of Science:
- Immunology
- Toxicology
- Cell Biology
Background:
- Damage associated molecular patterns (DAMPs) trigger immune responses.
- Oxidized phospholipids (oxPLs) are DAMPs implicated in inflammation.
- Scavenger Receptor class B-1 (SR-BI) role in oxPL-induced lung inflammation is unclear.
Purpose of the Study:
- Investigate the role of SR-BI in protecting the lung from oxidized phospholipid-induced inflammation.
- Hypothesize SR-BI is critical in mitigating pulmonary inflammation and injury.
Main Methods:
- Oropharyngeal aspiration of oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphatidylcholine (oxPAPC) in wild-type and SR-BI deficient mice.
- Assessment of lung pathology, inflammatory cytokine/chemokine production.
- Lipidomic analysis and evaluation of TLR4-NF-κB pathway activation.
Main Results:
- SR-BI deficient mice showed increased lung pathology and inflammation post-oxPAPC exposure.
- Altered pulmonary lipidome and increased oxidized phosphatidylcholines (PCs) in SR-BI deficient mice.
- Enhanced TLR4 mRNA expression, nuclear p65, and decreased IκBα in SR-BI deficient mice.
Conclusions:
- SR-BI is essential for limiting lung pathology induced by oxPAPC.
- SR-BI maintains lipid homeostasis and reduces oxidized PCs.
- SR-BI attenuates TLR4-NF-κB activation, preventing excessive lung inflammation.
