The complement system is important for cellular integrity and tissue homeostasis. Complement activation mediates the removal of microorganisms and the clearance of modified self cells, such as ...apoptotic cells. Complement regulators control the spontaneously activated complement cascade and any disturbances in this delicate balance can result in damage to tissues and in autoimmune disease. Therefore, insights into the mechanisms of complement regulation are crucial for understanding disease pathology and for enabling the development of diagnostic tools and therapies for complement-associated diseases.
Persistent inflammation is a hallmark of many human diseases, including anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) and atherosclerosis. Here, we describe a dominant trigger of ...inflammation: human serum factor H-related protein FHR1. In vitro, this protein selectively binds to necrotic cells via its N-terminus; in addition, it binds near necrotic glomerular sites of AAV patients and necrotic areas in atherosclerotic plaques. FHR1, but not factor H, FHR2 or FHR3 strongly induces inflammasome NLRP3 in blood-derived human monocytes, which subsequently secrete IL-1β, TNFα, IL-18 and IL-6. FHR1 triggers the phospholipase C-pathway via the G-protein coupled receptor EMR2 independent of complement. Moreover, FHR1 concentrations of AAV patients negatively correlate with glomerular filtration rates and associate with the levels of inflammation and progressive disease. These data highlight an unexpected role for FHR1 during sterile inflammation, may explain why FHR1-deficiency protects against certain diseases, and identifies potential targets for treatment of auto-inflammatory diseases.
Factor H‐related protein 1 (FHR‐1) is a member of the factor H protein family, which is involved in regulating innate immune complement reactions. Genetic modification of the encoding gene, CFHR1 on ...human chromosome 1, is involved in diseases such as age‐related macular degeneration, C3 glomerulopathy and atypical haemolytic uraemic syndrome, indicating an important role for FHR‐1 in human health. Recent research data demonstrate that FHR‐1 levels increase in IgA nephropathy and anti‐neutrophilic cytoplasmic autoantibodies (ANCA) vasculitis and that FHR‐1 induces strong inflammation in monocytes on necrotic‐type surfaces, suggesting a complement‐independent role. These new results increase our knowledge about the role of this complement protein in pathology and provide a new therapeutic target, particularly in the context of inflammatory diseases induced by necrosis. This review summarizes current knowledge about FHR‐1 and discusses its role in complement reactions and inflammation.
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This article is part of a themed issue on Canonical and non‐canonical functions of the complement system in health and disease. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.14/issuetoc
Complement is a major defense system of innate immunity and aimed to destroy microbes. One of the central complement regulators is factor H, which belongs to a protein family that includes CFHL1 and ...five factor H-related (CFHR) proteins. Recent evidence shows that factor H family proteins (factor H and CFHRs) are associated with diverse and severe human diseases and are also used by human pathogenic microbes for complement evasion. Therefore, dissecting the exact functions of the individual CFHR proteins will provide insights into the pathophysiology of such inflammatory and infectious diseases and will define the therapeutic potential of these proteins.
Plasminogen Is a Complement Inhibitor Barthel, Diana; Schindler, Susann; Zipfel, Peter F.
Journal of biological chemistry/The Journal of biological chemistry,
05/2012, Letnik:
287, Številka:
22
Journal Article
Recenzirano
Odprti dostop
Plasminogen is a 92-kDa single chain glycoprotein that circulates in plasma as a zymogen and when converted to proteolytically active plasmin dissolves preformed fibrin clots and extracellular matrix ...components. Here, we characterize the role of plasmin(ogen) in the complement cascade. Plasminogen binds the central complement protein C3, the C3 cleavage products C3b and C3d, and C5. Plasminogen binds to C3, C3b, C3d, and C5 via lysine residues, and the interaction is ionic strength-dependent. Plasminogen and Factor H bind C3b; however, the two proteins bind to different sites and do not compete for binding. Plasminogen affects complement action in multiple ways. Plasminogen enhanced Factor I-mediated C3b degradation in the presence of the cofactor Factor H. Plasminogen when activated to plasmin inhibited complement as demonstrated by hemolytic assays using either rabbit or sheep erythrocytes. Similarly, plasmin either in the fluid phase or attached to surfaces inhibited complement that was activated via the alternative and classical pathways and cleaved C3b to fragments of 68, 40, 30, and 17 kDa. The C3b fragments generated by plasmin differ in size from those generated by the complement protease Factor I, suggesting that plasmin-mediated C3b cleavage fragments lack effector function. Plasmin also cleaved C5 to products of 65, 50, 30, and 25 kDa. Thus, plasmin(ogen) regulates both complement and coagulation, the two central cascade systems of a vertebrate organism. This complement-inhibitory activity of plasmin provides a new explanation why pathogenic microbes utilize plasmin(ogen) for immune evasion and tissue penetration.
Plasminogen regulates the coagulation cascade.
Plasminogen binds to complement C3 and to C5. Activated plasmin inhibited complement as demonstrated by hemolytic assays.
Plasmin is a potent complement inhibitor that inactivates complement at the level of C3 and C5.
This complement-inhibitory activity of plasmin provides a new explanation why pathogenic microbes utilize plasmin(ogen) for immune evasion and tissue penetration.
Atherosclerotic cardiovascular disease (ACVD) is a lipid-driven inflammatory disease and one of the leading causes of death worldwide. Lipid deposits in the arterial wall lead to the formation of ...plaques that involve lipid oxidation, cellular necrosis, and complement activation, resulting in inflammation and thrombosis. The present study found that homozygous deletion of the CFHR1 gene, which encodes the plasma complement protein factor H-related protein 1 (FHR-1), was protective in two cohorts of patients with ACVD, suggesting that FHR-1 accelerates inflammation and exacerbates the disease. To test this hypothesis, FHR-1 was isolated from human plasma and was found to circulate on extracellular vesicles and to be deposited in atherosclerotic plaques. Surface-bound FHR-1 induced the expression of pro-inflammatory cytokines and tissue factor in both monocytes and neutrophils. Notably, plasma concentrations of FHR-1, but not of factor H, were significantly (p < 0.001) elevated in patients with ACVD, and correlated with the expression of the inflammation markers C-reactive protein, apolipoprotein serum amyloid protein A, and neopterin. FHR-1 expression also significantly correlated with plasma concentrations of low-density lipoprotein (LDL) (p < 0.0001) but not high-density lipoprotein (HDL). Taken together, these findings suggest that FHR-1 is associated with ACVD.
Atypical hemolytic uremic syndrome (aHUS) is a severe renal disease that is associated with defective complement regulation caused by multiple factors. We previously described the deficiency of ...factor H–related proteins CFHR1 and CFHR3 as predisposing factor for aHUS. Here we identify in an extended cohort of 147 aHUS patients that 16 juvenile individuals (ie, 11%) who either lacked the CFHR1/CFHR3 completely (n = 14) or showed extremely low CFHR1/CFHR3 plasma levels (n = 2) are positive for factor H (CFH) autoantibodies. The binding epitopes of all 16 analyzed autoantibodies were localized to the C-terminal recognition region of factor H, which represents a hot spot for aHUS mutations. Thus we define a novel subgroup of aHUS, termed DEAP HUS (deficiency of CFHR proteins and CFH autoantibody positive) that is characterized by a combination of genetic and acquired factors. Screening for both factors is obviously relevant for HUS patients as reduction of CFH autoantibody levels represents a therapeutic option.
Sequence and copy number variations in the human
gene cluster comprising the complement genes
,
,
,
,
, and
are linked to the human kidney diseases atypical hemolytic uremic syndrome (aHUS) and C3 ...glomerulopathy. Distinct genetic and chromosomal alterations, deletions, or duplications generate hybrid or mutant
genes, as well as hybrid
genes, and alter the FHR and Factor H plasma repertoire. A clear association between the genetic modifications and the pathologic outcome is emerging:
,
, and
gene alterations combined with intact
,
, and
genes are reported in atypical hemolytic uremic syndrome. But alterations in each of the five
genes in the context of an intact
gene are described in C3 glomerulopathy. These genetic modifications influence complement function and the interplay of the five FHR proteins with each other and with Factor H. Understanding how mutant or hybrid FHR proteins, Factor H::FHR hybrid proteins, and altered Factor H, FHR plasma profiles cause pathology is of high interest for diagnosis and therapy.
Complement is a central homeotic system of mammals and represents the first defense line of innate immunity. The human complement system is aimed to maintain homeostasis by recognizing and removing ...damaged or modified self material, as well as infectious foreign microbes. However, pathogenic microbes also control and escape the host complement and immune attack. The increasing resistance of microbial pathogens to either antibiotics or antifungal drugs is a major health problem and is of global interest. Therefore the topic how pathogenic microbes escape human complement and immune control is of high and of central interest. Identifying and defining the action of proteins involved in this intense immune interaction and understanding how these proteins interact is of relevance to design new control strategies. In this review we summarize the complement system of the human host and how this cascade drives effector functions. In addition, we summarize how diverse pathogenic microbes control, modulate and block the complement response of their host. The characterization of pathogen derived virulence factors and complement escape proteins reveals patterns of multiplicity, diversity and redundancy among pathogen encoded proteins. Sequence variability of immune and also complement escape proteins is largely driven by antigenic diversity and adaptive immunity. However common complement escape principles are, emerging in terms of conserved binding repertoire for host regulators and evasion among the large variety of infectious microbes. These conserved and common escape features are relevant and they provide challenging options for new therapeutic approaches.
Acinetobacter baumannii is an important nosocomial pathogen, causing a variety of opportunistic infections of the skin, soft tissues and wounds, urinary tract infections, secondary meningitis, ...pneumonia and bacteremia. Over 63% of A. baumannii infections occurring in the United States are caused by multidrug resistant isolates, and pan-resistant isolates have begun to emerge that are resistant to all clinically relevant antibiotics. The complement system represents the first line of defense against invading pathogens. However, many A. baumannii isolates, especially those causing severe bacteremia are resistant to complement-mediated killing, though the underlying mechanisms remain poorly understood. Here we show for the first time that A. baumannii binds host-derived plasminogen and we identify the translation elongation factor Tuf as a moonlighting plasminogen-binding protein that is exposed on the outer surface of A. baumannii. Binding of plasminogen to Tuf is at least partly dependent on lysine residues and ionic interactions. Plasminogen, once bound to Tuf can be converted to active plasmin and proteolytically degrade fibrinogen as well as the key complement component C3b. Thus, Tuf acts as a multifunctional protein that may contribute to virulence of A. baumannii by aiding in dissemination and evasion of the complement system.
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