S-nitrosylation of surfactant protein D as a modulator of pulmonary inflammation

Abstract

Background Surfactant protein D (SP-D) is a member of the family of proteins termed collagen-like lectins “collectins” that play a role in non-antibody-mediated innate immune responses [1]. The primary function of SP-D is the modulation of host defense and inflammation [2]. Scope of Review This review will discuss recent findings on the physiological importance of SP-D S-nitrosylation in biological systems and potential mechanisms that govern SP-D mediated signaling. Major Conclusions SP-D appears to have both pro- and anti-inflammatory signaling functions. SP-D multimerization is a critical feature of its function and plays an important role in efficient innate host defense. Under baseline conditions, SP-D forms a multimer in which the N-termini are hidden in the center and the C-termini are on the surface. This multimeric form of SP-D is limited in its ability to activate inflammation. However, NO can modify key cysteine residues in the hydrophobic tail domain of SP-D resulting in a dissociation of SP-D multimers into trimers, exposing the S-nitrosylated N-termini. The exposed S-nitrosylated tail domain binds to the calreticulin/CD91 receptor complex and initiates a pro-inflammatory response through phosphorylation of p38 and NF-κB activation [3,4]. In addition, the disassembled SP-D loses its ability to block TLR4, which also results in activation of NF-κB. General Significance Recent studies have highlighted the capability of NO to modify SP-D through S-nitrosylation, causing the activation of a pro-inflammatory role for SP-D [3]. This represents a novel mechanism both for the regulation of SP- D function and NO’s role in innate immunity, but also demonstrates the S-nitrosylation can control protein function by regulating quaternary structure.

Eosinophil-Associated Lung Diseases. A Cry for Surfactant Proteins A and D Help?

“…For example, NO, produced locally by airway epithelial cells and increased in asthma (114), has been shown to S-nitrosylate two free Cys thiols in the N-terminus of dodecameric SP-D (Cys- [15][16][17][18][19][20] and to affect dissociation into SP-D trimers (115). Consequences of this structural perturbation include the activation of SP-D proinflammatory chemoattractant function and the loss of control TLR4 blockade (39). Tyrosine nitration of SP-A and SP-D and Tyr-Tyr crosslinking of SP-D have been also found in protein exposed in vitro to peroxynitrite (116)(117)(118)(119) and in inflammatory lung diseases (120).…”

“…These altered oligomers limit the SP ability to bind carbohydrates and agglutinate bacteria. In addition, reactive oxygen and nitrogen species may also affect posttranslational modifications of SP-D that alter its structure and function at sites of inflammation (39,113). For example, NO, produced locally by airway epithelial cells and increased in asthma (114), has been shown to S-nitrosylate two free Cys thiols in the N-terminus of dodecameric SP-D (Cys- [15][16][17][18][19][20] and to affect dissociation into SP-D trimers (115).…”

Influence of Concomitant Arterial Hypertension on Activity of Inflammatory Process in Patients With Community-Acquired Pneumonia

“…The SP-D concentration gradient thus allows leakage into the bloodstream SP-D with acute and chronic lung injury, as confirmed in experimental studies in mice [11]. Inter- [7,8]. In recent years, it has been shown that SP-D has different antimicrobial and anti-inflammatory effects, affects lipid metabolism and shows pro-inflammatory effects in the walls of vessels, which increases the risk of atherosclerosis.…”

“…The presence of SP-D in the systemic circulation can contribute to the development of cardiovascular disease and mortality in patients with CAP, as its role in the development of endothelial dysfunction is known [6]. It is also important that in the vascular wall SP-D can perform the same anti-inflammatory function as in the lungs or vice versa, leading to a pro-inflammatory reaction [7].…”

Nitrosothiols in the Immune System: Signaling and Protection

“…(6). This modification disassembles the dodecamer into trimers, producing macrophage chemotaxis and triggering a proinflammatory response by activating calreticulin/CD91-dependent p38 (57).…”