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 membrane-bound 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.

Keywords: Airway epithelial cells; Barrier tissues; Complement system; Innate defence; Soluble pattern recognition receptors.

Figure 1

Humoral PRR within the mucosal lining of human airway epithelial cells. Shown are the different sPRRs within the mucus lining of AEC, their trigger factors and their primary mode of immune activation. The long pentraxin PTX3 has opsonic activity with a nonredundant protective role against selected pathogens, such as fungi, bacteria and viruses. Pentraxins are in addition complement activating proteins that lead to increased C3b levels and inflammatory signalling via C3a. The short pentraxins CRP and SAP are considered to bind to phosphorylcholine on pathogens and apoptotic cells, respectively. The collectin MBL is present primarily at mucosal surfaces including the airways and binds to a large array of pathogens, activating the lectin pathway of complement. Ficolins primarily function as opsonins, but can also activate the lectin pathway. SAA is a sPPR for Gram‐negative bacteria and blocks viral entry into cells. sPPRs also interact with and regulate the function of membrane bound PRRs such as Toll‐like receptors and C‐type lectin receptors but can also bind to integrins, Fcγ and scavenger receptors. Allergens might also have C3 convertase activity or might be recognized by C1q (in conjunction with specific antibodies). sPRRS might in addition function as an adjuvant and/or interact directly with environmental inhaled proteins to promote allergic sensitization.

Figure 2

Protein structures, source and roles of sPRRs in the airways. Shown are the functional structures of pentraxins, collectins, ficolins and SAA proteins and their prominent family members. Local production of pentraxins in the lung could be detected in structural and myeloid cells as well as neutrophils. While the lung (type 2 alveolar cells) is the main synthesis site of the collectins SP‐A and SP‐D, MBL is primarily produced by the liver. Ficolins are produced in the liver by hepatocytes and in the lung by type 2 alveolar cells, as well as by neutrophils, macrophages and monocytes. SAA proteins, similar to pentraxins, were long thought to be liver‐derived serum factors but are also produced locally in the lung by type 2 alveolar cells, macrophages and monocytes. sPRRs share overlapping but also nonredundant roles in the first line of defence against microbial intruders through opsonic activity, inhibition of viral entry and the activation of the complement cascade. Some sPRRs play essential roles in the removal of apoptotic bodies, which is crucial for pulmonary immune tolerance and tissue homeostasis. In addition, several sPRRs are involved in leukocyte recruitment to the lung and local proinflammatory cytokine production.