Soluble pattern recognition molecules: Guardians and regulators of homeostasis at airway mucosal surfaces

Abstract

Maintenance of homeostasis at body barriers that are constantly challenged by microbes, toxins and potentially bioactive (macro)molecules requires complex, highly orchestrated mechanisms of protection. Recent discoveries in respiratory research have shed light on the unprecedented role of airway epithelial cells (AEC), which, besides immune cells homing to the lung, also significantly contribute to host defence by expressing membranebound and soluble pattern recognition receptors (sPRR). Recent evidence suggests that distinct, evolutionary ancient, sPRR secreted by AEC might become activated by usually innocuous proteins, commonly referred to as allergens. We here provide a systematic overview on sPRR detectable in the mucus lining of AEC. Some of them become actively produced and secreted by AECs (like the pentraxins C-reactive protein and pentraxin 3; the collectins mannose binding protein and surfactant proteins A and D; H-ficolin; serum amyloid A; and the complement components C3 and C5). Others are elaborated by innate and adaptive immune cells such as monocytes/macrophages and T cells (like the pentraxins C-reactive protein and pentraxin 3; L-ficolin; serum amyloid A; and the complement components C3 and C5). Herein we discuss how sPRRs may contribute to homeostasis but sometimes also to overt disease (e.g. airway hyperreactivity and asthma) at the alveolar-air interface.

Structural Basis for Vital Function and Malfunction of Serum Amyloid A: an Acute-Phase Protein that Wears Hydrophobicity on Its Sleeve

“…Although some discrepancies stem from bacterial contaminations and amino acid substitutions in commercial preparations of recombinant hSAA1 [ 50 •], others reflect structural and functional differences between lipid-free and lipid-bound protein [ 38 , 40 ] as well as isoform-specific and context-dependent effects. Overall, SAA has emerged as a homeostatic regulator of inflammation (reviewed in [ 1 , 51 ]).…”

“…Remarkably for an intrinsically disordered protein, x-ray crystal structures of SAA have been determined to nearly 2 Å resolution by two independent teams. Four different crystal structures have been reported to date: two of human SAA1 (hSAA1) [ 68 ••] and two of murine SAA3 (mSAA3) [ 51 , 52 •]. In these crystals, the protein molecules are packed as a dimer, a dimer of dimers, a trimer, or a hexamer, forming different lattice contacts in different unit cells.…”

“…In these crystals, the protein molecules are packed as a dimer, a dimer of dimers, a trimer, or a hexamer, forming different lattice contacts in different unit cells. Nevertheless, all structures showed a very similar monomer fold, suggesting that this fold has been evolutionally conserved [ 51 ] (Fig. 1 ).…”

“…SAA monomer folds into a Y-shaped helix bundle containing α-helices h1–h4, followed by a 3/10 helix h’ and stabilized by a flexible C-terminal tail [ 51 , 68 ••] (Fig. 1A ).…”

“…These bundles readily open to expose the hydrophobic helical faces for binding lipids. In contrast, the SAA helix bundle has a hydrophilic interior partially filled with water [ 51 ] and a large hydrophobic surface approximately 1 nm × 4 nm (Fig. 1C , in yellow).…”