Complement factor H modulates the activation of human neutrophil granulocytes and the generation of neutrophil extracellular traps

Abstract

Factor H (FH) is a major inhibitor of the alternative pathway of complement activation in plasma and on certain host surfaces. In addition to being a complement regulator, FH can bind to various cells via specific receptors, including binding to neutrophil granulocytes through complement receptor type 3 (CR3; CD11b/CD18), and modulate their function. The cellular roles of FH are, however, poorly understood. Because neutrophils are important innate immune cells in inflammatory processes and the host defense against pathogens, we aimed at studying the effects of FH on various neutrophil functions, including the generation of extracellular traps. FH co-localized with CD11b on the surface of neutrophils isolated from peripheral blood of healthy individuals, and cell-bound FH retained its cofactor activity and enhanced C3b degradation. Soluble FH supported neutrophil migration and immobilized FH induced cell spreading. In addition, immobilized but not soluble FH enhanced IL-8 release from neutrophils. FH alone did not trigger the cells to produce neutrophil extracellular traps (NETs), but NET formation induced by PMA and by fibronectin plus fungal β-glucan were inhibited by immobilized, but not by soluble, FH. Moreover, in parallel with NET formation, immobilized FH also inhibited the production of reactive oxygen species induced by PMA and by fibronectin plus β-glucan. Altogether, these data indicate that FH has multiple regulatory roles on neutrophil functions. While it can support the recruitment of neutrophils, FH may also exert anti-inflammatory effects and influence local inflammatory and antimicrobial reactions, and reduce tissue damage by modulating NET formation.

Complement factor H family proteins in their non-canonical role as modulators of cellular functions

“…Factor H binding to neutrophils was demonstrated by Avery and Gordon in 1993, which binding was found to be specific and could be enhanced by neutrophil activation [95]. This receptor-mediated binding was confirmed by other groups and the β2 integrin CR3 was identified as the major factor H receptor [55,59,63]. While factor H can bind to CR4, as well, it is difficult to dissect CR3-and CR4-specific factor H effects on neutrophils because these cells express little amount of CR4.…”

“…(3) Third, factor H can bind to various cells through receptors. Receptor-bound factor H could still act as cofactor for factor I and aid in cellular protection against complement attack [55]. In addition, receptor-bound factor H can mediate or regulate cellular adhesion and activation, i.e.…”

Complement factor H in host defense and immune evasion

“…For example, Avery et al first identified complement receptor 3 (CR3, also known as CD11b/CD18 or integrin αMβ2) as a FH receptor on human neutrophils [99], where CR3 engagement by FH and FHL-1 modulates cell activation and function [100]; interestingly, recent data show that while FH can support neutrophil recruitment, it may also play an anti-inflammatory role, reducing tissue damage by influencing the formation of neutrophil extracellular traps [101]. Available data indicate that FH likely also binds CR4, possibly triggering a similar cellular response, e.g.…”

Factor H Family Proteins in Complement Evasion of Microorganisms

“…In this non-canonical role, FH was described to act as a bridging molecule between complement receptor 3 (CR3; CD11b/CD18) and pathogens, and helping either pathogen entry into host cells or the antimicrobial response of the host cells (51, 58–62). Such scenarios were described for FH bound to S. pneumoniae, N. gonorrhoeae , and Candida albicans (58–61).…”