SALSA: A Regulator of the Early Steps of Complement Activation on Mucosal Surfaces

Abstract

Complement is present mainly in blood. However, following mechanical damage or inflammation, serous exudates enter the mucosal surfaces. Here, the complement proteins interact with other endogenous molecules to keep microbes from entering the parenteral tissues. One of the mucosal proteins known to interact with the early complement components of both the classical and the lectin pathway is the salivary scavenger and agglutinin (SALSA). SALSA is also known as deleted in malignant brain tumors 1 and gp340. It is found both attached to the epithelium and secreted into the surrounding fluids of most mucosal surfaces. SALSA has been shown to bind directly to C1q, mannose-binding lectin, and the ficolins. Through these interactions SALSA regulates activation of the complement system. In addition, SALSA interacts with surfactant proteins A and D, secretory IgA, and lactoferrin. Ulcerative colitis and Crohn's disease are examples of diseases, where complement activation in mucosal tissues may occur. This review describes the latest advances in our understanding of how the early complement components interact with the SALSA molecule. Furthermore, we discuss how these interactions may affect disease propagation on mucosal surfaces in immunological and inflammatory diseases.

Keywords: C1q; Crohn’s disease; DMBT1; IBD; MBL; ficolins; gp340; ulcerative colitis.

Figure 1

Function and structure of SALSA at the mucosal surfaces. (A) At the mucosal surfaces, the SALSA protein is mainly found associated with the epithelium and secreted into the surrounding fluids. The known features and functions of SALSA are presented in four panels (I–IV). (I) SALSA is present on the epithelial cell surface and deposited in the extracellular matrix, where it is involved in maintaining epithelial homeostasis. (II) Fluid-phase SALSA binds a broad array of microbes. It has been shown to agglutinate viruses, as well as both Gram-positive and Gram-negative bacteria thus preventing them from invading the parenteral spaces. (III) SALSA interacts with other endogenous molecules present at the mucosal surfaces, such as surfactant proteins SpA and SpD as well as IgA. It is believed that these molecules cooperate in antimicrobial defense. (IV) In the case of epithelial damage, cells and molecules from the tissue become mixed with the luminal contents. In this context, SALSA may bind the complement sensor molecules C1q, MBL, and the ficolins, thereby SALSA could initiate complement activation against distinct microbes or participate in the clearance of injured tissue components. (B) In its molecular structure, SALSA contains a stretch of 13 scavenger receptor cysteine-rich (SRCR) domains separated by SRCR interspersed domains. These are followed by two C1r/C1s, urchin embryonic growth factor and bone morphogenetic protein-1 (CUB) domains surrounding the 14th SRCR domain. Finally, a zona pellucida (ZP) domain is found at the most C-terminal end of the protein.