Factor XII-Driven Inflammatory Reactions with Implications for Anaphylaxis

Abstract

Anaphylaxis is a life-threatening allergic reaction. It is triggered by the release of pro-inflammatory cytokines and mediators from mast cells and basophils in response to immunologic or non-immunologic mechanisms. Mediators that are released upon mast cell activation include the highly sulfated polysaccharide and inorganic polymer heparin and polyphosphate (polyP), respectively. Heparin and polyP supply a negative surface for factor XII (FXII) activation, a serine protease that drives contact system-mediated coagulation and inflammation. Activation of the FXII substrate plasma kallikrein leads to further activation of zymogen FXII and triggers the pro-inflammatory kallikrein-kinin system that results in the release of the mediator bradykinin (BK). The severity of anaphylaxis is correlated with the intensity of contact system activation, the magnitude of mast cell activation, and BK formation. The main inhibitor of the complement system, C1 esterase inhibitor, potently interferes with FXII activity, indicating a meaningful cross-link between complement and kallikrein-kinin systems. Deficiency in a functional C1 esterase inhibitor leads to a severe swelling disorder called hereditary angioedema (HAE). The significance of FXII in these disorders highlights the importance of studying how these processes are integrated and can be therapeutically targeted. In this review, we focus on how FXII integrates with inflammation and the complement system to cause anaphylaxis and HAE as well as highlight current diagnosis and treatments of BK-related diseases.

Keywords: anaphylaxis; bradykinin; contact system; factor XII; heparin; kallikrein–kinin system; mast cells; polyP.

Figure 1

Factor XII (FXII)-driven contact system in activation of anaphylaxis. Zymogen scFXII becomes activated to FXIIa either by endogenous activators [misfolded proteins, RNA/DNA, neutrophil extracellular traps (NETs), polyP, oversulfated chondroitin sulfate-contaminated heparin (OSCS-heparin) and heparin] or by artificial surfaces. Anaphylaxis can activate mast cells with the release of their mediators (polyP and heparin), which also leads to FXIIa. FXIIa proceeds to activate prekallikrein, which reciprocally cleaves both FXIIa into β-FXIIa and high-molecular-weight kininogen (HK) to bradykinin (BK). BK binds receptor B2 (B2R) and triggers inflammation, edema, and symptoms of anaphylaxis. BK can be further proceeding to des-Arg-BK and mediates B1 receptor (B1R) activation resulting in hypotension and bronchoconstriction. The contact system can be inhibited by the C1INH that inhibits both FXIIa and plasma kallikrein.

Figure 2

Cross talk between the kallikrein–kinin system and the complement system. The complement system can be activated by three different pathways: (1) C1q initiates the activation of the classical pathway, (2) the mannose-binding lectin (MBL) or ficolins trigger the lectin pathway for glycosylation on the surface of pathogens. Activation of either the classical pathway or MBL generates C3 convertase. (3) If C3 is spontaneously hydrolyzed, the alternative pathway is activated and generates activated C3b. C3 and C5 release C3a and C5a, which can trigger inflammation. The activation of the complement system via the kallikrein–kinin system is indicated, mainly FXIIa and plasma kallikrein are involved in activation of C3 and C5. FXIIa can trigger the C1r/C1s complex. C1INH inhibits the complement system in all three different pathways and furthermore via the inhibition of the kallikrein–kinin system.