Figure 4.

Surfactant protein innate immunoprotective responses in atherosclerotic lesions. [1] SP-D can be synthesized by endothelial cells and released into plasma and arterial intima, and circulatory SP-D inhibits circulatory IL-6 and tumor necrosis factor-α (TNF-α) and the transport of oxidized low-density lipoprotein (OxLDL) from the artery lumen to the subendothelial space; SP-D bound to CD305 (leukocyte-associated immunoglobulin-like receptor 1, LAIR1) reduces generation of reactive oxygen species (ROS) in foam cells (right and center in 1, and lower right in 5). SP-D bound to CD305 reduces ROS generation in circulating monocytes, and reduced ROS impedes oxidation of LDL (center in 1). Circulating native C-reactive protein (nCRP) bound to cellular or microparticle lysophosphatidylcholine (LPC) generated by phospholipase A₂ (PLA₂), or to phosphorylcholine (PC) can be dissociated to monomeric CRP (mCRP) with intermediate formation of non-native CRP (nnCRP), and mCRP can bind lipid rafts and increase ROS formation (left in 1). [2] SP-D reduces T-cell proliferation and interferon-γ (IFN-γ) and TNF-α release (top in 2). [3] [SP-D and SP-A facilitate intimal severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) virus removal by macrophages through CRT/CD91Rs (center in 3). SP-D binding to osteoclast-associated immunoglobulin-like receptor (OSCAR) in macrophages and foam cells enhances TNF-α release that stimulates SP-D production by smooth muscle (SMC) cells. SP-D also lowers SMC IL-8 (right in 3). [4] Pattern recognition proteins surfactant protein (SP)-A, SP-D, mannose binding lectin (MBL) and complement component 1q (C1q) facilitate macrophage uptake of apoptotic cells in atherosclerotic plaques through calreticulin (CRT)/CD91 receptors (Rs) (bottom in 4). [5] Immunoglobulin M (IgM) anti-oxidation-specific natural antibodies (OSE NAbs) in the arterial intima facilitate macrophage/foam cell uptake of apoptotic cells through Fcα/μRs (lower left in 5). Low-density lipoproteins (LDL) are taken by macrophages/foam cells through LDLRs (center in 5). Reduced foam cell ROS disallows LDL oxidation in the intima (lower left in 5). SP-D binding of CRT/CD91Rs leads to reduced inflammation characterized by reduced secretion of TNF-α in macrophages/foam cells; reduced nuclear factor κB (NFκB) activation and reduced macrophage recruitment and apoptosis; reduced expression of TNF-α receptor 1 (TNFR1) with concomitant reduction of foam cell TNF-α binding and reduced inducible nitric oxide synthase (iNOS), complement C1r protein, IL-6 and monocyte chemoattractant protein-1 (MCP-1) (upper left in 5). Native CRP (nCRP) facilitates clearance of oxidized/modified LDL through FcγRs and CD36 (upper right in 5); and IgM anti-OSE helps with clearance of oxidized/modified LDL through Fcα/μRs (upper right in 5), and by inhibiting their uptake through scavenger receptors lectin-like oxidized low-density lipoprotein (LDL) receptor-1 (LOX-1), scavenger receptor class B type 1 (SR-BI), scavenger receptor A1 (SR-A1) and CD36 (right in 5); all leading to reduced foam cell formation.