Roles of Factor XII in Innate Immunity

Abstract

Factor XII (FXII) is the zymogen of serine protease, factor XIIa (FXIIa). FXIIa enzymatic activities have been extensively studied and FXIIa inhibition is emerging as a promising target to treat or prevent thrombosis without creating a hemostatic defect. FXII and plasma prekallikrein reciprocally activate each other and result in liberation of bradykinin. Due to its unique structure among coagulation factors, FXII exerts mitogenic activity in endothelial and smooth muscle cells, indicating that zymogen FXII has activities independent of its protease function. A growing body of evidence has revealed that both FXII and FXIIa upregulate neutrophil functions, contribute to macrophage polarization and induce T-cell differentiation. In vivo, these signaling activities contribute to host defense against pathogens, mediate the development of neuroinflammation, influence wound repair and may facilitate cancer maintenance and progression. Here, we review the roles of FXII in innate immunity as they relate to non-sterile and sterile immune responses.

Keywords: cancer progression; contact activation; factor XII; innate immunity; neutrophil extracellular traps; sepsis; uPAR; wound healing.

Figure 1

Role of FXII in non-sterile inflammation. In infectious conditions, Factor XII (FXII) activation occurs through various mechanisms including pathogen surfaces, bacterial products, polyP, neutrophils, and NETs. Activated FXII (FXIIa) leads to BK generation and activates components of the complement system. Both FXII and FXIIa increase the expression of pro-inflammatory cytokines and influence leukocyte functions. In certain settings, the sum of these activities contributes to prevention of dissemination. Alternatively, the presence of FXII and subsequent FXIIa and BK generation, lead to adverse outcomes and increased mortality independently of Factor XI activation. PolyP, polyphosphate; BK, Bradykinin; NETs, Neutrophil Extracellular Traps.

Figure 2

Regulatory functions of FXII and FXIIa in sterile inflammation. Zymogen FXII functions as an autocrine messenger through uPAR to promote Akt2S⁴⁷⁴ phosphorylation. Propagation of FXII-mediated neutrophil activities includes adhesion, chemotaxis that leads to neutrophil trafficking at sites of inflammation and NET formation. Subsequent contact activation on the surface of preformed NETs leads to FXIIa generation and fibrin formation. In monocytes and macrophages, FXII and FXIIa upregulate the expression of pro-inflammatory mediators and promote cell polarization toward an M2 phenotype. In dendritic cells, FXII signals through uPAR to induce the differentiation of naive T-cells to TH17 cells. These immune cell responses contribute to impaired wound healing, propagation of venous thrombosis, tumor maintenance, and invasion as well as tissue damage during CNS autoimmunity. NETs, neutrophil extracellular traps; Mono, Monocytes; Macro, Macrophages; DC, Dendritic cells; TH17, T-helper cells.