Experimental Biology and Medicine 229:1105-1110 (2004)
© 2004 Society for Experimental Biology and Medicine
SYMPOSIA
Fibrin(ogen)-
Mß2 Interactions Regulate Leukocyte Function and Innate Immunity In Vivo
Matthew J. Flick,
Xinli Du and
Jay L. Degen1
Children’s Hospital Research Foundation and the University of Cincinnati College of Medicine, Cincinnati, Ohio 45229
1To whom requests for reprints should be addressed at Children’s Hospital Research Foundation, Developmental Biology ML7007, CHRF Rm. 2042, 3333 Burnet Ave., Cincinnati, OH 45229–3039. E-mail: degenjl{at}cchmc.org
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Abstract
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In addition to its well-characterized role in hemostasis, fibrin(ogen) has been proposed to be a central regulator of the inflammatory response. Multiple in vitro studies have demonstrated that this hemostatic factor can alter leukocyte function, including cell adhesion, migration, cytokine and chemokine expression, degranulation, and other specialized processes. One important link between fibrin(ogen) and leukocyte biology appears to be the integrin receptor 
Mß2/Mac-1, which binds to immobilized fibrin(ogen) and regulates leukocyte activities. Although it is well established that fibrin(ogen) is a ligand for Mß2, the precise molecular determinants that govern this interaction are only now becoming clear. A novel line of mice expressing a mutant form of fibrinogen (Fib
390–396A) has revealed that chain residues 390–396 are important for the high-affinity engagement of fibrinogen by Mß2 and leukocyte unction in vivo. Fibrinogen 390–396A failed to support Mß2-mediated adhesion of primary neutrophils, monocytes, and macrophages, and mice expressing this fibrinogen variant were found to exhibit a major defect in the host inflammatory response following acute challenges. Most notably, Fib390–396A mice display a profound impediment in Staphylococcus aureus elimination by leukocytes following intraperitoneal inoculation. These findings have positively established the physiological importance of fibrin(ogen) as a ligand for Mß2 and illustrate that the fibrin(ogen) chain residues 390–396 constitute a critical feature of the Mß2 binding motif. Finally, the Fib390–396A mice represent a valuable system for better defining the contribution of fibrin(ogen) to the inflammatory response in the absence of any confounding alteration in clotting function.
Key Words: coagulation • integrin • inflammation • innate immunity
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Crosstalk Between the Hemostatic and Inflammatory Systems
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The hemostatic and inflammatory systems are activated by the same spectrum of challenges (e.g., mechanical, thermal, chemical, or toxic tissue injury and microbial infection), but these systems have historically been viewed as functioning independently. However, it is becoming increasingly clear that hemostatic and inflammatory pathways are highly integrated with considerable regulatory cross talk (Figure 1
) (1–6). The capacity of inflammatory factors to regulate the coagulation and fibrinolytic systems is well recognized (1–3, 5, 7, 8). Acute inflammatory events are known to shift the hemostatic balance toward a prothrombotic state in which there is an increase in circulating levels of several key procoagulants. One established mechanism whereby inflammatory mediators can promote coagulation is by elevating levels of the cell surface initiator of the clotting cascade, tissue factor (9). The systemic activation of the coagulation and fibrinolytic systems following acute inflammatory events, such as sepsis, can lead to potentially devastating consumptive coagulopathy and disseminated intravascular coagulation (10). A reciprocal pathway whereby hemostatic factors affect inflammatory processes has been less obvious but is becoming increasingly appreciated (2, 3, 7, 11–13). The conversion of prothrombin to the active serine protease thrombin, a central event in coagulation, appears to be a critical event in the regulation of inflammatory processes. Thrombin and G-protein–coupled protease-activated receptors (PARs) coupled to thrombin have been shown to control the expression of a large number of cytokines and chemokines (e.g., interleukin-1 [IL-1], IL-6, IL-8, migration inhibitory factor, granulocyte-macrophage colony-stimulating factor, and monocyte chemotactic protein–1) in different cell types, including endothelial cells, smooth muscle cells, lung epithelial cells, and mononuclear cells (14–17). Furthermore, the activation of platelets by thrombin and other agonists is known to result in the release of a cocktail of chemokines and cytokines stored in platelet granules (e.g., platelet factor–4, IL-8, macrophage inflammatory protein–1, RANTES, MCP-3, CCL17, CCXL1, and CXCL5) and expression of platelet surface adhesion molecules (e.g., P-selectin and CD40 ligand) that control leukocyte trafficking and activity (18–21). The inhibitors that regulate thrombin generation or activity (tissue factor pathway inhibitor, antithrombin III, and activated protein C [APC]), have been shown to exhibit anti-inflammatory properties and enhance survival in models of bacterial sepsis (22–24). Activated protein C appears to modulate the inflammatory response by limiting thrombin-coupled events and by directly altering inflammatory regulatory pathways. Activated protein C binding to monocytic cells has been shown to alter NF-
B–mediated gene expression and induce the production of antiapoptotic gene products (2–5). Activated protein C binding to the endothelial cell protein C receptor also regulates the expression of proinflammatory cytokines and adhesion molecules critical for rolling and firm adhesion of leukocytes along activated endothelium (25).
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Figure 1. Regulatory crosstalk between hemostatic system components and the inflammatory system. Like the initiator of coagulation (tissue factor [TF]) and the natural anticoagulants (activated protein C [APC], antithrombin III [ATIII], and tissue factor pathway inhibitor–1 [TFPI-1]), recent evidence suggests that fibrinogen directly modulates the innate immune system.
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Fibrinogen and the Leukocyte Integrin Receptor Mß2/Mac-1
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Among all known thrombin substrates, fibrinogen stands out as a central factor in hemostasis and a contributor to the inflammatory response. Fibrinogen is a classic "acute-phase reactant," with serious inflammatory challenges resulting in increased hepatic expression, the induction of extrahepatic expression, and increased circulating protein (26–29). Fibrin(ogen) deposition is a universal feature within injured tissues and inflammatory foci. Notably, fibrin appears to locally regulate inflammatory responses. In vitro studies (30–34) have shown that fibrin(ogen) can profoundly alter leukocyte function, leading to changes in cell migration, phagocytosis, NF-B–mediated transcription, production of chemokines and cytokines, degranulation, and other processes. Many of the effects of fibrin(ogen) on leukocyte activity appear to be mediated by a specific receptor on leukocytes, the integrin receptor Mß2 (35–37).
Four members of the ß2 subfamily of integrins have been identified: Mß2 (Mac-1, CD11b/CD18, and CR3), Lß2 (leukocyte function–associated antigen and CD11a/ CD18), Xß2 (p150,95 and CD11c/CD18), and Dß2 (CD11d/CD18) (38, 39). The importance of this integrin family in leukocyte function is underscored by the fact that a genetic deficiency in ß2 results in a severe immunological disorder, leukocyte adhesion deficiency type 1, characterized by profound defects in leukocyte function and chronic infections (40). Based in part on the prominent expression of Mß2 on the surface of neutrophils, monocytes, macrophages, and mast cells, this integrin is generally thought to play a pivotal role in inflammatory cell function. This view has been supported by detailed studies (41, 42) of mice with a specific genetic deficit in the M subunit. Although Mß2 is likely to contribute to leukocyte trafficking, it appears to be particularly instrumental in leukocyte activation and the regulation of cell survival and apoptosis. A confounding factor in defining the general importance of this integrin in leukocyte biology has been the extraordinary number of potential ligands that have been identified. To date, more than 30 different putative ligands have been reported, including the endothelial intracellular adhesion molecule–1 (ICAM-1), the complement derivative C3bi, glycoprotein Ib (GPIb), plasminogen activator, urokinase-type plasminogen activator receptor (uPAR), plasminogen, and fibrinogen, among others (39, 43–47). Defining which of the many proposed Mß2 ligands, if any, are biologically relevant in vivo has been a significant lingering problem that is just beginning to be resolved.
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The Fibrin(ogen) Motif Recognized by Mß2
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Fibrin(ogen) was established as a high-affinity ligand for Mß2 more than a decade ago. In 1988, two different research groups identified Mß2 as the cell surface receptor on monocytes and polymorphonuclear cells that supported leukocyte interaction with fibrinogen (48, 49). In 1993, it was established that the "I-domain" within the M subunit, a 200–amino acid "insert" within the ß-propeller structure, was central to integrin engagement of fibrinogen (47). Additional studies (46, 50, 51) of integrin site–directed mutants have further substantiated that the M I-domain constitutes the fibrinogen-binding motif, and this assignment has remained experimentally unchallenged. What has been far more difficult to define is the region of fibrinogen recognized by Mß2. Synthetic peptide inhibitor studies initially pointed to a region within the fibrinogen chain globular domain in the neighborhood of Gly190–Val202 (termed the "P1" site) as a region critical for the Mß2 interaction (52). However, more detailed work revealed that mutations introduced into the P1 site did not diminish the ability of the recombinant fibrinogen globular domain to support Mß2-dependent cell adhesion (53). A second search for the fibrinogen motif recognized by Mß2 revealed another possible binding site (termed the "P2" site) in the neighborhood of 377–395 of the fibrinogen chain (53). Like the P1 peptide, the P2 peptide inhibited Mß2-mediated cell adhesion to immobilized fibrinogen and directly supported saturable binding to the M I-domain (53). Additional analyses identified the residues 383–395 (referred to as "P2-C") as the core recognition motif (53). The potential importance of this region in Mß2 binding was supported by studies (53, 54) showing that monoclonal antibodies directed against residues 392–406 inhibited binding of Mß2-expressing cells to immobilized P2-C and recombinant globular domains.
Analysis of the three-dimensional structure of the fibrinogen globular domain placed the P1 and P2 regions in close proximity (53, 54). This suggested the attractive hypothesis that both P1 and P2 could participate in binding to fibrinogen. Under this theory, the P2-C sequence could represent the major binding interface for Mß2, with residues within the P1 sequence providing supplementary contact points. This hypothesis would account for (i) the robust binding activity of the P2-C peptide, (ii) the inhibitory and adhesive properties of the isolated P1 peptide, and (iii) the finding that mutations in P1 in the context of a recombinant -module are insufficient to ablate binding. However, this hypothesis was challenged by a study (55) describing the generation and characterization of several novel recombinant globular domain derivatives carrying mutations within the P1 and P2 regions. Whereas mutations in the P2 motif resulted in significantly diminished adhesion to the M I-domain, multiple alanine substitution mutations in the P1 region had no effect on engagement of the M I-domain (55). This same study concluded that the P2 domain residues 390–395 constituted a minimal integrin recognition motif. Nevertheless, the precise fibrinogen motif recognized by Mß2 has remained extraordinarily controversial. Recombinant globular domain derivatives where portions of the P2 site had been deleted were reported to retain at least partial binding activity with isolated M I-domain (55). Furthermore, a recombinant human fibrinogen chain truncation mutant lacking a portion of the P2 site was reported to retain Mß2 binding potential (55). Multiple confounding factors are likely to account for the apparent inconsistencies within reported findings. Potential confounding factors include the use of differing assay systems, the uncertain structural integrity of deletion mutants, the use of fibrinogen fragments rather than the whole fibrinogen molecule, the use of isolated M I-domain rather than the whole integrin molecule, and a failure to focus exclusively on high-affinity interactions. The possibility of multiple distinct Mß2 binding motifs on fibrinogen may also provide a partial explanation for seemingly conflicting reports. There is some support for this latter concept, including reports suggesting that the globular domain of the fibrinogen Bß chain or the globular domain found within the uncommon (2% of total) splice variant of the A chain (i.e., AE) may support Mß2 interactions (50, 56). However, it is difficult to imagine what evolutionary pressure could preserve functionally redundant and independent Mß2 binding motifs within a single fibrinogen molecule.
Regardless of what features of fibrinogen constitute the Mß2 binding motifs, it seems clear that the structural conformation of fibrin(ogen) is critical to high-affinity Mß2 binding. This is highlighted by the fact that soluble fibrinogen is a very poor ligand for Mß2, whereas immobilized fibrinogen or fibrin is readily bound by the integrin. The cryptic Mß2 binding sites on soluble fibrinogen also can be made accessible for integrin binding by certain types of proteolytic cleavage, including proteolytic events that expose the P2-C region sufficiently to permit the binding of epitope-mapped antibody (54, 55). One important inference from the conformation-dependent interaction between fibrin(ogen) and Mß2 is that soluble fibrinogen is unlikely to be "instructive" in leukocyte activation. Rather, immobilized fibrin deposited locally at sites of injury is likely to be the most informative form of this molecule, presumably supporting local leukocyte activation events and the expression of specialized functions.
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Fibrinogen Engagement of Mß2 Through Residues 390–396 Regulates Leukocyte Function In Vivo
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To better understand the contribution, if any, of residues N390RLSIGE396 of the fibrinogen chain to the engagement of the leukocyte integrin Mß2 in the context of intact fibrinogen, these residues were recently mutated within the endogenous fibrinogen chain gene in mice (35). These specific amino acids were selected for mutation based on the fact that these residues (i) were conserved between species (note that the sequence is N390RLTIGE396 in the human molecule), (ii) were largely solvent exposed in the crystal structure of fibrinogen derivatives, (iii) were spatially far removed from the chain "hole" known to support fibrin polymerization, and (iv) were a consistent element within P2 peptides shown to block Mß2 binding to fibrinogen (53, 55, 57). As an experimental approach, the generation of this fibrinogen variant offered two experimental advantages. First, the contribution of the 390–396 region to Mß2 binding could be defined in the context of intact fibrinogen synthesized in native hepatocytes. Second, the functional importance of the fibrinogen-Mß2 interaction in vivo could be evaluated without imposing any alteration in Mß2 that might preclude Mß2 interactions with other potential ligands or crosstalk with other receptors. Residues 390–396 were converted to a series of alanines to retain normal spacing between protein domains and the overall structural integrity of the assembled molecule. Mice homozygous for the mutation (termed "fibrinogen 390–396A") were found to be viable to adulthood, never experienced spontaneous bleeding events, carried normal levels of circulating fibrinogen, maintained normal clotting function, retained normal fibrinogen engagement by other integrin receptors (e.g., IIbß3), retained normal platelet aggregation, and exhibited normal thrombus formation in vivo. However, unlike wild-type fibrinogen, immobilized fibrinogen 390–396A failed to support Mß2-mediated adhesion of different cell types, including primary neutrophils and macrophages. Most important, the disruption in Mß2 engagement of fibrin(ogen) via residues 390–396 was found to have dramatic consequences on the inflammatory response in vivo. Fib390–396A mice exhibited a remarkable impediment in the elimination of the microbial pathogen Staphylococcus aureus using an acute peritonitis model. Four major conclusions were drawn from these studies. First, fibrin(ogen) is an important regulator of inflammatory cell function and innate immunity. Second, fibrin(ogen) constitutes a physiologically relevant ligand for the leukocyte integrin Mß2. Third, the biological consequence of a loss in the Mß2-fibrin(ogen) interaction is not (fully) compensated by the continued availability of all other potential ligands (e.g., ICAM-1 GPIb, uPAR, etc.). Finally, the biological importance of fibrinogen in regulating the inflammatory response can be appreciated outside of any alteration in clotting function or platelet thrombus formation.
The analyses of fibrinogen 390–396A unequivocally show that in the context of intact fibrinogen a preeminent feature of the Mß2 binding motif is located in the carboxy-terminal portion of the chain, consistent with earlier analyses focusing on the P2-C peptide. It should be emphasized that the interface between Mß2 and fibrinogen is likely to extend well beyond N390–E396 and that this region may not constitute the sole binding determinant. However, based on the available data, the contribution of other regions to integrin binding may only modulate the high-affinity interaction or merely support lower-affinity interactions. This view is consistent with recent comparative analyses of wild-type and 390–396A–fibrinogen interaction with Mß2 using surface plasmon resonance (Biacore analysis). Studies using wild-type mouse fibrinogen suggest the presence of a high-affinity integrin binding site and multiple low-affinity binding sites. In contrast, studies of fibrinogen 390–396A indicate that the high-affinity site is lost, whereas low-affinity interactions remain (J.L.D., unpublished data).
Comparative analyses of S. aureus clearance from the peritoneal cavity of control and Fib390–396A mice have provided additional support for a prevailing hypothesis that Mß2 primarily controls leukocyte function upon arrival at sites of inflammatory challenge (35). Detailed studies of S. aureus infection in fibrinogen-deficient and Fib390–396A mice have shown that fibrinogen per se, and fibrinogen-Mß2 interaction in particular, is required for the full implementation of leukocyte antimicrobial activity (X.D. and J.L.D., unpublished data). A simple extension of these observations is that, in the context of soluble inflammatory mediators, leukocyte engagement of immobilized fibrin(o-gen) within inflamed or damaged tissues may be an important cue in leukocyte "target recognition," ultimately regulating the expression of specialized functions. Consistent with this view, neutrophil engagement of fibrin(ogen) via Mß2 results in dramatic cellular changes in vitro, including calcium mobilization, activation of NF-B, increased phosphorylation events, degranulation, upregulation of cell surface adhesion molecules, increased migration, and decreased apoptosis (30–34). The concept that leukocyte interaction with immobilized fibrin(ogen) is an important event in target recognition has two attractive features. First, fibrin could provide a unique, nondiffusible, or spatially defined signal, modulating inflammatory cell function. Second, fibrin would be found within the extracellular matrix at virtually any site of tissue damage, regardless of the underlying insult, but would be distinctly absent within normal tissues. Therefore, fibrin could flag the precise site of any challenge and provide another means to locally regulate leukocyte function. Of course, this theory does not preclude the seminal contribution of soluble inflammatory mediators (e.g., cytokines and chemokines) or a significant contribution of other Mß2 ligands. Nevertheless, it is now clear that, even when the engagement of all other ligands remains intact, the loss of Mß2 interaction with fibrin(ogen) compromises leukocyte function, including the ability to efficiently clear an infectious agent in vivo.
Although fibrin(ogen) appears to be important in innate immunity, it is not strictly required for mounting an inflammatory response. Bacterial foci clearly attract inflammatory cell infiltrates in Fib390–396A mice ands well as in animals entirely lacking fibrinogen, and both types of mutants appear to support partial bacterial containment. The residual capacity to eliminate bacteria in the absence of fibrin(ogen) could be in part a consequence of Mß2-mediated leukocyte activation events via other known ligands. However, alternative leukocyte integrins undoubtedly contribute to antimicrobial function based on the finding that Mß2-deficient animals do not exhibit a general defect in leukocyte trafficking and do not develop spontaneous infections unless the deficit extends to all ß2 integrins (41, 42, 58, 59).
The fibrinogen-Mß2 axis can now be viewed as a potentially useful target in the development of new therapeutic strategies for the treatment or prevention of inflammatory diseases, such as sepsis and inflammatory lung, bowel, and joint disease. Like APC, fibrinogen may be a critical hemostatic component that stands at the interface between the hemostatic and inflammatory systems. In fact, the potential usefulness of fibrinogen as a target in inflammatory disease has already been underscored in studies showing that the pharmacological or genetic depletion of fibrinogen in mice can diminish the progression of arthritis (J.L.D., unpublished data; and Ref. 60). Of course, an important implication of the findings with fibrinogen 390–396A mice is that effective anti-inflammatory strategies focusing on fibrin(ogen)-leukocyte interactions could potentially be devised that would not necessarily compromise hemostatic function. Therefore, in principle, inflammatory responses could be controlled at the level of hemostatic factors without increasing the risk of bleeding or thrombotic events.
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Abstract
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