-
Molecular Immunology Oct 2018Properdin, the widely known positive regulator of the alternative pathway (AP), has undergone significant investigation over the last decade to define its function in... (Review)
Review
Properdin, the widely known positive regulator of the alternative pathway (AP), has undergone significant investigation over the last decade to define its function in inflammation and disease, including its role in arthritis, asthma, and kidney and cardiovascular diseases. Properdin is a glycoprotein found in plasma that is mainly produced by leukocytes and can positively regulate AP activity by stabilizing C3 and C5 convertases and initiating the AP. Promotion of complement activity by properdin results in changes in the cellular microenvironment that contribute to innate and adaptive immune responses, including pro-inflammatory cytokine production, immune cell infiltration, antigen presenting cell maturation, and tissue damage. The use of properdin-deficient mouse models and neutralizing antibodies has contributed to the understanding of the mechanisms by which properdin contributes to promoting or preventing disease pathology. This review mainly focusses on the multifaceted roles of properdin in inflammation and diseases, and how understanding these roles is contributing to the development of new disease therapies.
Topics: Animals; Complement Activation; Complement Pathway, Alternative; Humans; Inflammation; Mice; Properdin
PubMed: 29954621
DOI: 10.1016/j.molimm.2018.05.018 -
Immunological Reviews Nov 2016The complement alternative pathway is a powerful arm of the innate immune system that enhances diverse inflammatory responses in the human host. Key to the effects of... (Review)
Review
The complement alternative pathway is a powerful arm of the innate immune system that enhances diverse inflammatory responses in the human host. Key to the effects of the alternative pathway is properdin, a serum glycoprotein that can both initiate and positively regulate alternative pathway activity. Properdin is produced by many different leukocyte subsets and circulates as cyclic oligomers of monomeric subunits. While the formation of non-physiological aggregates in purified properdin preparations and the presence of potential properdin inhibitors in serum have complicated studies of its function, properdin has, regardless, emerged as a key player in various inflammatory disease models. Here, we review basic properdin biology, emphasizing the major hurdles that have complicated the interpretation of results from properdin-centered studies. In addition, we elaborate on an emerging role for properdin in thromboinflammation and discuss the potential utility of properdin inhibitors as long-term therapeutic options to treat diseases marked by increased formation of platelet/granulocyte aggregates. Finally, we describe the interplay between properdin and the alternative pathway negative regulator, Factor H, and how aiming to understand these interactions can provide scientists with the most effective ways to manipulate alternative pathway activation in complex systems.
Topics: Animals; Complement Factor H; Complement Pathway, Alternative; Humans; Immunomodulation; Inflammation; Molecular Targeted Therapy; Platelet Aggregation; Properdin; Thrombosis
PubMed: 27782331
DOI: 10.1111/imr.12466 -
Advances in Immunology 2022The complement system consists of three pathways (alternative, classical, and lectin) that play a fundamental role in immunity and homeostasis. The multifunctional role... (Review)
Review
The complement system consists of three pathways (alternative, classical, and lectin) that play a fundamental role in immunity and homeostasis. The multifunctional role of the complement system includes direct lysis of pathogens, tagging pathogens for phagocytosis, promotion of inflammatory responses to control infection, regulation of adaptive cellular immune responses, and removal of apoptotic/dead cells and immune complexes from circulation. A tight regulation of the complement system is essential to avoid unwanted complement-mediated damage to the host. This regulation is ensured by a set of proteins called complement regulatory proteins. Deficiencies or malfunction of these regulatory proteins may lead to pro-thrombotic hematological diseases, renal and ocular diseases, and autoimmune diseases, among others. This review focuses on the importance of two complement regulatory proteins of the alternative pathway, Factor H and properdin, and their role in human diseases with an emphasis on: (a) characterizing the main mechanism of action of Factor H and properdin in regulating the complement system and protecting the host from complement-mediated attack, (b) describing the dysregulation of the alternative pathway as a result of deficiencies, or mutations, in Factor H and properdin, (c) outlining the clinical findings, management and treatment of diseases associated with mutations and deficiencies in Factor H, and (d) defining the unwanted and inadequate functioning of properdin in disease, through a discussion of various experimental research findings utilizing in vitro, mouse and human models.
Topics: Animals; Autoimmune Diseases; Complement Factor H; Humans; Mice; Phagocytosis; Properdin
PubMed: 35469595
DOI: 10.1016/bs.ai.2021.12.001 -
Molecular Immunology Dec 2013The plasma protein properdin is the only known positive regulator of complement activation. Although regarded as an initiator of the alternative pathway of complement... (Review)
Review
The plasma protein properdin is the only known positive regulator of complement activation. Although regarded as an initiator of the alternative pathway of complement activation at the time of its discovery more than a half century ago, the role and mechanism of action of properdin in the complement cascade has undergone significant conceptual evolution since then. Despite the long history of research on properdin, however, new insight and unexpected findings on the role of properdin in complement activation, pathogen infection and host tissue injury are still being revealed by ongoing investigations. In this article, we provide a brief review on recent studies that shed new light on properdin biology, focusing on the following three topics: (1) its role as a pattern recognition molecule to direct and trigger complement activation, (2) its context-dependent requirement in complement activation on foreign and host cell surfaces, and (3) its involvement in alternative pathway complement-mediated immune disorders and considerations of properdin as a potential therapeutic target in human diseases.
Topics: Animals; Autoimmune Diseases; Autoimmunity; Complement Activation; Complement Pathway, Alternative; Complement System Proteins; Humans; Properdin
PubMed: 23816404
DOI: 10.1016/j.molimm.2013.06.002 -
ELife Jan 2021Properdin stabilizes convertases formed upon activation of the complement cascade within the immune system. The biological activity of properdin depends on the...
Properdin stabilizes convertases formed upon activation of the complement cascade within the immune system. The biological activity of properdin depends on the oligomerization state, but whether properdin oligomers are rigid and how their structure links to function remains unknown. We show by combining electron microscopy and solution scattering, that properdin oligomers adopt extended rigid and well-defined conformations which are well approximated by single models of apparent n-fold rotational symmetry with dimensions of 230-360 Å. Properdin monomers are pretzel-shaped molecules with limited flexibility. In solution, properdin dimers are curved molecules, whereas trimers and tetramers are close to being planar molecules. Structural analysis indicates that simultaneous binding through all binding sites to surface-linked convertases is unlikely for properdin trimer and tetramers. We show that multivalency alone is insufficient for full activity in a cell lysis assay. Hence, the observed rigid extended oligomer structure is an integral component of properdin function.
Topics: Binding Sites; HEK293 Cells; Humans; Molecular Conformation; Properdin
PubMed: 33480354
DOI: 10.7554/eLife.63356 -
Annual Review of Immunology 2010Complement is an innate immune system that is a first line of defense against pathogens and facilitates elimination of apoptotic and injured cells. During complement... (Review)
Review
Complement is an innate immune system that is a first line of defense against pathogens and facilitates elimination of apoptotic and injured cells. During complement activation, the complement convertases are assembled on target surfaces and initiate their proteolytic activities, a process that marks targets for phagocytosis and/or lysis. The complement alternative activation pathway has been implicated in a number of autoimmune conditions including arthritis and age-related macular degeneration. Properdin, a plasma component that is also released by activated neutrophils, is critical in the stabilization of alternative pathway convertases. Recently, it has been shown that properdin is also a pattern-recognition molecule that binds to certain microbial surfaces, apoptotic cells, and necrotic cells. Once bound to a surface, properdin can direct convertase formation and target uptake. New studies are now focusing on a role for properdin in inflammatory and autoimmune diseases. This review examines the new properdin findings and their implications.
Topics: Animals; Autoimmune Diseases; Complement Activation; Complement System Proteins; Humans; Inflammation; Neutrophils; Properdin
PubMed: 19947883
DOI: 10.1146/annurev-immunol-030409-101250 -
Molecular Immunology Oct 2008Properdin was first described over 50 years ago by Louis Pillemer and his collaborators as a vital component of an antibody-independent complement activation pathway. In... (Review)
Review
Properdin was first described over 50 years ago by Louis Pillemer and his collaborators as a vital component of an antibody-independent complement activation pathway. In the 1970s properdin was shown to be a stabilizing component of the alternative pathway convertases, the central enzymes of the complement cascade. Recently we have reported that properdin can also bind to target cells and microbes, provide a platform for convertase assembly and function, and promote target phagocytosis. Evidence is emerging that suggests that properdin interacts with a network of target ligands, phagocyte receptors, and serum regulators. Here we review the new findings and their possible implications.
Topics: Animals; Complement Pathway, Alternative; Complement System Proteins; Humans; Models, Immunological; Properdin
PubMed: 18692243
DOI: 10.1016/j.molimm.2008.06.034 -
Journal of Neuroinflammation Nov 2023Emerging evidence has shown that myeloid cells that infiltrate into the peri-infarct region may influence the progression of ischemic stroke by interacting with...
BACKGROUND
Emerging evidence has shown that myeloid cells that infiltrate into the peri-infarct region may influence the progression of ischemic stroke by interacting with microglia. Properdin, which is typically secreted by immune cells such as neutrophils, monocytes, and T cells, has been found to possess damage-associated molecular patterns (DAMPs) properties and can perform functions unrelated to the complement pathway. However, the role of properdin in modulating microglia-mediated post-stroke neuroinflammation remains unclear.
METHODS
Global and conditional (myeloid-specific) properdin-knockout mice were subjected to transient middle cerebral artery occlusion (tMCAO). Histopathological and behavioral tests were performed to assess ischemic brain injury in mice. Single-cell RNA sequencing and immunofluorescence staining were applied to explore the source and the expression level of properdin. The transcriptomic profile of properdin-activated primary microglia was depicted by transcriptome sequencing. Lentivirus was used for macrophage-inducible C-type lectin (Mincle) silencing in microglia. Conditioned medium from primary microglia was administered to primary cortex neurons to determine the neurotoxicity of microglia. A series of cellular and molecular biological techniques were used to evaluate the proinflammatory response, neuronal death, protein-protein interactions, and related signaling pathways, etc. RESULTS: The level of properdin was significantly increased, and brain-infiltrating neutrophils and macrophages were the main sources of properdin in the ischemic brain. Global and conditional myeloid knockout of properdin attenuated microglial overactivation and inflammatory responses at the acute stage of tMCAO in mice. Accordingly, treatment with recombinant properdin enhanced the production of proinflammatory cytokines and augmented microglia-potentiated neuronal death in primary culture. Mechanistically, recombinant properdin served as a novel ligand that activated Mincle receptors on microglia and downstream pathways to drive primary microglia-induced inflammatory responses. Intriguingly, properdin can directly bind to the microglial Mincle receptor to exert the above effects, while Mincle knockdown limits properdin-mediated microglial inflammation.
CONCLUSION
Properdin is a new medium by which infiltrating peripheral myeloid cells communicate with microglia, further activate microglia, and exacerbate brain injury in the ischemic brain, suggesting that targeted disruption of the interaction between properdin and Mincle on microglia or inhibition of their downstream signaling may improve the prognosis of ischemic stroke.
Topics: Mice; Animals; Microglia; Ischemic Stroke; Properdin; Neuroinflammatory Diseases; Macrophages; Infarction, Middle Cerebral Artery; Brain Injuries; Brain Ischemia; Mice, Inbred C57BL
PubMed: 37951917
DOI: 10.1186/s12974-023-02946-z -
Annals of Internal Medicine Sep 1957
Topics: Properdin
PubMed: 13459136
DOI: 10.7326/0003-4819-47-3-599 -
Immunobiology Jul 2022The complement system does not only play an important role in the defence against microorganism and pathogens, but also contributes to the regulation of innate and...
The complement system does not only play an important role in the defence against microorganism and pathogens, but also contributes to the regulation of innate and adaptive immunity. Especially activation fragments C3a and C5a and complement activation at the interface of antigen presenting cell (APC) and T cell, were shown to have a role in T cell activation and proliferation. Whereas most complement factors are produced by the liver, properdin, a positive regulator of the C3 convertase, is mainly produced by myeloid cells. Here we show that properdin can be detected in myeloid cell infiltrate during human renal allograft rejection. In vitro, properdin is produced and secreted by human immature dendritic cells (iDCs), which is further increased by CD40-L-matured DCs (mDCs). Transfection with a specific properdin siRNA reduced properdin secretion by iDCs and mDCs, without affecting the expression of co-stimulatory markers CD80 and CD86. Co-culture of properdin siRNA-transfected iDCs and mDCs with human allogeneic T cells resulted in reduced T cell proliferation, especially under lower DC-T cell ratio's (1:30 and 1:90 ratio). In addition, T cell cytokines were altered, including a reduced TNF-α and IL-17 secretion by T cells co-cultured with properdin siRNA-transfected iDCs. Taken together, these results indicate a local role for properdin during the interaction of DCs and allogeneic T cells, contributing to the shaping of T cell proliferation and activation.
Topics: Cells, Cultured; Dendritic Cells; Humans; Kidney Transplantation; Properdin; RNA, Small Interfering; T-Lymphocytes
PubMed: 35843030
DOI: 10.1016/j.imbio.2022.152246