PTX3, a Humoral Pattern Recognition Molecule, in Innate Immunity, Tissue Repair, and Cancer

Abstract

Innate immunity includes a cellular and a humoral arm. PTX3 is a fluid-phase pattern recognition molecule conserved in evolution which acts as a key component of humoral innate immunity in infections of fungal, bacterial, and viral origin. PTX3 binds conserved microbial structures and self-components under conditions of inflammation and activates effector functions (complement, phagocytosis). Moreover, it has a complex regulatory role in inflammation, such as ischemia/reperfusion injury and cancer-related inflammation, as well as in extracellular matrix organization and remodeling, with profound implications in physiology and pathology. Finally, PTX3 acts as an extrinsic oncosuppressor gene by taming tumor-promoting inflammation in murine and selected human tumors. Thus evidence suggests that PTX3 is a key homeostatic component at the crossroad of innate immunity, inflammation, tissue repair, and cancer. Dissecting the complexity of PTX3 pathophysiology and human genetics paves the way to diagnostic and therapeutic exploitation.

Figure 1. Source and main functions of the long pentraxin PTX3.

Proinflammatory stimuli, TLR engagement and microbial recognition can induce PTX3 production by a wide variety of cell types, including cells of the myeloid lineage, vascular and lymphatic endothelial cells, smooth muscle cells, fibroblasts, epithelial cells, adipocytes, mesangial cells, astrocytes and cells of microglia. PTX3 gene is organized in three exons, the first coding the leader peptide, the second coding for the N-terminal domain and the third coding for the C-terminal, pentraxin like domain. The protein participates in matrix remodeling, plays a non-redundant role in the resistance to selected pathogens, has a regulatory role in inflammation and in fertility. The multifunctional properties of PTX3 are connected with the capacity to interact with different ligands.

Figure 2. Synergistic interaction of PTX3 with other fluid phase PRM.

The interaction of PTX3 with other fluid phase PRM, namely C1q, MBL and ficolins, results in a broader repertoire of effective microbial recognition leading to increased Complement activation and effector functions.

Figure 3. An acidic pH sets the PTX3 molecule in a tissue repair mode.

While at neutral pH PTX3 mainly participates to host defense and regulation of inflammation, at acidic pH PTX3 can interact with fibrin and plasminogen, promoting pericellular fibrinolysis by tissue remodelling cells and contributing to an appropriate tissue repair.

Figure 4. The Yin-Yang of PTX3 in Innate Immunity.

Depending on the pathogen, functional effects and levels of production, PTX3 plays a Yin-Yang. In infectious diseases PTX3 can exert protective roles (in green) or may contribute to pathogenesis (in pink).

Figure 5. Role of PTX3 in cancer.

PTX3 regulates complement activation and tumor promoting inflammation, as well as FGF-dependent neo-angiogenesis and tumor growth. Indeed, genetic or epigenetic silencing of PTX3 results in increased tumor growth.