Inflammation encompasses diverse tissue reactions classically triggered by microbial recognition and by tissue damage.
Dysmetabolic conditions, ranging from diabetes to obesity, elicit overt or subclinical inflammatory reactions.
- The general role of inflammatory reactions is in the amplification of innate resistance and tissue repair, leading to a return to homeostasis.
Manifestations of inflammation include fever, alterations in leukocyte counts, cardiovascular reactions, endocrine responses, and reorientation of metabolism in association with increased production of molecules referred to as acute-phase proteins.
The prototypic acute-phase protein, C-reactive protein, was originally described as a molecule that was present in the circulation of patients with infections and that was capable of recognizing the C-type polysaccharides of Streptococcus pneumoniae.
Increased levels of acute-phase proteins in blood and other body fluids is part of a complex response to local inflammation or to systemic inflammation, such as sepsis, that has been referred to as the acute-phase response.
An acute-phase response is characterized by decreased production of albumin by hepatocytes, reorientation of iron metabolism, and hormonal changes.
Such changes are also observed in the context of chronic inflammatory conditions and subclinical inflammation.
Acute-phase proteins serve as fundamental diagnostic tools that have applications in patients with a range of conditions, including infection, cardiovascular illness, cancer, neurodegeneration, and dysmetabolism.
Acute-phase proteins such as C-reactive protein, fibrinogen and its degradation product d-dimer, and ferritin serve as tools in the day-to-day management of illnesses and as prognostic indicators.
A fundamental function of the acute-phase response is to amplify antimicrobial resistance and tissue repair, with many of the acute-phase proteins serving as key components of humoral innate immunity.
Innate immunity is a first line of resistance against microbial pathogens and is involved in the activation of adaptive immune responses, as well as in tissue repair.
Innate immunity is made up of a cellular arm and a humoral arm.
The molecular strategies used by the cellular arm to sense microbial moieties and tissue damage involve cell-associated pattern-recognition molecules located in different cellular compartments.
These cellular compartments include: plasma membrane, endosomes, and cytoplasm and belong to different molecular families, including toll-like receptors (TLRs), nucleotide-binding oligomerization domain (NOD)–like and retinoic acid–inducible gene I (RIG-I)–like receptors, inflammasomes, stimulator of interferon genes (STING), C-type lectins, and scavenger receptors.
The activation of these receptors leads to the expression of cytokines, including interferons and chemokines, adhesion molecules, and antimicrobial effectors or to the scavenging of microbes through phagocytosis.
The humoral arm of the innate immune system is made up of different classes of molecules, which functionally act as ancestors of antibodies by initiating complement activation, opsonizing microbes and damaged cells, agglutinating or neutralizing microbes, and regulating inflammation.
Some of these molecules are key components of the acute-phase response that are rapidly induced in liver cells or other cell types by primary inflammatory cytokines.
The sensing of microbial moieties, tissue damage, or dysmetabolism by
cellular recognition molecules sets in motion a cytokine cascade that induces amplification and regulation of innate immunity and production of acute-phase proteins.
Primary inflammatory cytokines, typically interleukin-1, interleukin-6, and tumor necrosis factor (TNF), induce production of secondary mediators in tissues-chemokines, colony-stimulating factors, endothelial adhesion molecules, prostaglandins, and nitric oxide.
These mediators then amplify leukocyte recruitment, effector functions, and local innate immunity.
Amplification of local innate immunity activates adaptive antigen-specific immune responses.
Interleukin-6 stimulates chemokine production and favors the transition from acute to chronic inflammation, is a potent inducer of the production of acute-phase proteins in the liver through reprogramming and reorientation of metabolic functions by decreasing albumin production and increased production of acute-phase proteins.
Inflammatory cytokines also act on the central nervous system through their activation of the hypothalamus–pituitary–adrenal axis, resulting in production of adrenocorticotropic hormone and glucocorticoid hormones.
Glucocorticoid hormones, among their many functions, act as negative regulators of inflammation by suppressing, for instance, interleukin-1 and inducing the interleukin-1 decoy receptor interleukin-1R2.
Antiinflammatory cytokines (interleukin-10, transforming growth factor β, and interleukin-1Ra) are part of pathways of negative regulation.
The antiinflammatory cytokine interleukin-1Ra, acts as an interleukin-1R antagonist, has classically been considered a liver-derived acute-phase protein and is a product of macrophages and other cell types in tissues.
Interleukin-1 and interleukin-6 are the key regulators of acute-phase protein synthesis in the liver.
They activate a network of transcription factors (signal transducer and methylate CpG motifs in the binding sites of these transcription factors.
The liver is considered the source of the elevated blood levels of acute-phase proteins.
Approximately 200 acute-phase proteins are produced — mainly by hepatocytes, but other cell types also contribute to the acute-phase reaction.
These cell types include organ-infiltrating monocytes and tissue-resident macrophages such as Kupffer cells, hepatic stellate cells, and endothelial cells.
All of these cells are sources of proinflammatory cytokines that activate acute-phase protein synthesis by hepatocytes
In addition to hepatocytes, cells in peripheral tissues can produce some acute-phase proteins: macrophages and endothelial cells can produce complement components, serum amyloid A (SAA), iron transporters, α1-antitrypsin, and interleukin-1Ra.
The pentraxin 3 (PTX3), is released mainly in peripheral tissues by diverse cell types, most notably phagocytes and endothelial cells, on induction by microbial moieties or inflammatory cytokines.
At a local tissue level, local production of PTX3 complements the function of circulating acute-phase proteins produced by hepatocytes.
Adipose tissue is an important source of the overall systemic concentration of acute-phase proteins in response to proinflammatory stimuli by interleukin-1 and interleukin-6.
Adipocytes express complement factors (C3, D, and B), αl-acid glycoprotein, and lipocalin-2, as well as plasminogen activator inhibitor 1 (PAI-1) and serum amyloid A3 (SAA3).
With myopathy, skeletal muscle wasting, and atrophy associated with critical illness locally produced interleukin-6 and TNF contribute to the induction of acute-phase proteins in muscle cells.
Pentraxins are a family of proteins characterized by a cyclic multimeric structure and by the presence of a conserved 200-amino-acid pentraxin domain.
C-reactive protein (also called PTX1pp) and serum amyloid P component (SAP, or PTX2) are pentameric short pentraxins.
PTX3 is an octameric molecule, and each protomer has a pentraxin-like domain associated with a long N-terminal domain unrelated to those of other known proteins.
C-reactive protein is a prototypic liver-derived acute-phase protein.
C-reactive protein plasma levels increase by as much as 1000 times in response to an acute-phase stimulus, in particular to interleukin-6.
SAP is constitutively present in plasma.
PTX3 is rapidly induced in response to interleukin-1 and TNF or microbial components in various cell types
These cell types are myelomonocytic cells (monocytes, macrophages, dendritic cells), vascular and lymphatic endothelial cells, and stromal cells.
Neutrophils synthesize PTX3 during myelopoiesis, store it in lactoferrin-positive granules, and rapidly release it after microbial recognition.
Thus, PTX3 differs from short pentraxins in terms of structure, cell source, and regulation.
C-reactive protein, SAP, and PTX3 bind various bacteria, fungi, and viruses, promoting innate immune responses to these pathogens.
Pentraxins also bind to phospholipids and small nuclear ribonucleoproteins in apoptotic cells, promoting the disposal of these cells in a noninflammatory mode.
C-reactive protein, SAP, and PTX3 interact with different complement molecules broadening recognition potential.
In addition to promoting complement-dependent opsonization, short pentraxins and PTX3 promote phagocytosis of microbes and apoptotic cells, and interact with complement regulators promoting regulation of complement-dependent inflammation.
C-reactive protein levels in blood are associated with the risk of coronary heart disease.
An association is suggested a pathogenetic role for C-reactive protein in atherosclerosis.
SAP binds and stabilizes all forms of amyloid fibrils, contributing to amyloidosis.
Serum amyloid protein binds extracellular matrix components, such as laminin, type IV collagen, fibronectin, and proteoglycans, thereby regulating extracellular matrix deposition and inhibiting fibrosis.
In idiopathic pulmonary fibrosis, human SAP improves lung function by inhibiting alternative activation of macrophages and fibrocyte differentiation.
PTX3 plasma concentrations increase rapidly during a number of infections and are associated with disease severity and the risk of death.
PTX3 levels reflect the severity of inflammatory vascular diseases ranging from atherosclerosis to vasculitis.
PTX3 levels increase earlier than C-reactive protein levels in inflammatory processes.
PTX3 is stored in neutrophil granules.
PTX3 serves as an immediate early gene in tissues, with its transcription induced by TLR agonists and inflammatory cytokines.
C-reactive protein production in the liver occurs downstream of the cytokine cascade, which results in a later appearance.
PTX3 and SAP genetic polymorphisms have been associated with susceptibility to fungal and bacterial infections and to lung granuloma formation in sarcoidosis through regulation of complement.
Pentraxin trio of C-reactive protein–SAP–PTX3 plays a role in the amplification of innate resistance to selected pathogens and in the regulation of tissue remodeling.
Members of the serum amyloid A family are major acute-phase proteins.
Four genes encode different members of the family; SAA1 and SAA2 are typical liver-derived acute-phase proteins and are collectively termed A-SAA.
Extrahepatic synthesis of A-SAA in joints accounts for high SAA levels in the synovial fluid, in addition to high systemic plasma levels.
In the small intestine’s epithelial cells SAA induced by interleukin-22 and promotes T helper 17 cell differentiation and effector function, and barrier integrity.
A-SAA also reportedly induces antiinflammatory skewing of macrophages and opsonizes gram-negative pathogenic bacteria.
A-SAA has been used as a marker in several inflammatory conditions, such as rheumatoid arthritis, cardiovascular diseases, cancer, and infections, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.
Long-term or recurrent high plasma SAA concentrations can lead to amyloid A (AA) amyloidosis, a condition caused by the accumulation of AA fibrils in several organs, including the kidneys, spleen, and liver, impairing their function.
AA fibrils form as a consequence of SAA-derived C-terminal truncated AA protein folding into extremely hydrophobic β sheets that aggregate in oligomers, which generate insoluble, proteolysis-resistant fibrils.
The complement system is a central player in humoral innate immunity.
The complement system consists of approximately 50 soluble molecules, mostly produced by the liver and normally found in the circulation, and cell-associated receptors, which are expressed by several cell types.
The liver is the major site for the synthesis of most complement molecules.
Among them, both activating molecules (C3, C4, C9, and factor B) and negative regulators (C1 inhibitor and C4BP) are up-regulated during an acute-phase reaction, which underlines the relevance of activating balanced complement-mediated responses.
Besides hepatocytes, other cell types, including monocytes, macrophages, endothelial cells, fibroblasts, and adipocytes, can be local sources of complement proteins such as C1q, C3, and C529.
Several acute-phase proteins are involved in the metabolism of iron, whicha nutrient required for a number of host-cell functions as well as for the growth of microbial pathogens.
The general functions of acute-phase proteins in iron metabolism which include binding to the nutrient, preventing utilization of circulating free iron by pathogens, and retention of iron inside cells.
The complex regulation of iron metabolism results in metabolic resistance to selected pathogens.
The acute-phase proteins involved in iron control include the circulating peptide hormone hepcidin, ferritin, haptoglobin, and hemopexin.
They are up-regulated in the acute-phase reaction, whereas transferrin a negative acute-phase protein is down-regulated during the acute phase.
Hepcidin binds the transmembrane protein ferroportin, regulating the release of iron from cells to plasma.
Ferritin normally directly reflects iron levels in blood.
Anemia associated with chronic inflammatory diseases is characterized by higher levels of ferritin than normal because of its induction by the acute-phase reaction.
High plasma concentration of ferritin is observed in patients with pathologic inflammatory conditions, including septic shock, and Covid-19, in which ferritin is used as a marker of severity and prognosis.
Haptoglobin and hemopexin are acute-phase proteins that act as soluble scavengers of free hemoglobin and heme, respectively.
Free heme is highly toxic as it is a source of redox-active iron.
Free heme has the ability to enter into lipid membranes and promotes lipid peroxidation.
Up-regulation of haptoglobin and hemopexin in acute-phase reactions favors protection against heme-mediated oxidative stress, iron loss in inflammatory conditions associated with hemolysis, and infections by preventing the utilization of iron by pathogens.
Fibrinogen and its downstream degradation products (d-dimer and other fibrin degradation products) are used as diagnostic markers in inflammatory conditions, including Covid-19.
The fibrin mesh formed downstream of the coagulation cascade serves as a provisional matrix essential for tissue repair.
The removal by means of fibrinolysis is a prerequisite for subsequent steps in matrix maturation.
PTX3 protein, engages in a interaction with fibrinogen and plasminogen, promoting the timely degradation of the provisional fibrin mesh and subsequent tissue repair.
Inhibitors of proteolytic enzymes (e.g., α1-antitrypsin, α2-macroglobulin, and α1-acid glycoprotein) are produced during the acute-phase reaction, and these inhibitors may limit tissue damage.
α1-antitrypsin has host protective functions in autoimmunity and infection.
Extracellular matrix proteins, including fibrinogen and fibronectin bind microbes and facilitate their clearance by phagocytes.
Innate immune recognition of SARS-CoV-2 innate immune recognition is a fundamental first line of resistance, triggers adaptive immunity, and drives the immunopathologic effects of infection.
PTX3, unlike C-reactive protein and SAP, binds the viral nucleoprotein.
C-reactive protein, procalcitonin, and ferritin high plasma concentrations at hospital admission have been associated with severe disease and poor survival in Covid-19.
The concentration of d-dimer downstream of fibrinogen has been positively correlated with areas of hypoperfusion in patients with acute respiratory distress syndrome, a finding consistent with thromboembolic disease, and has been associated with higher mortality.
Dysregulated iron homeostasis, which is common in hospitalized patients with Covid-19, as reflected by the presence of anemia and an increased ferritin:transferrin ratio, has been found to predict ICU admission and receipt of mechanical ventilation.
PTX3 is a strong prognostic marker and independent predictor of death within 28 days in hospitalized patients.
PTX3 was found to be expressed by myeloid cells in peripheral blood and lungs and by lung endothelial cells in patients with Covid-19.
The strong independent prognostic significance of PTX3, which is better than that of C-reactive protein, interleukin-6, ferritin, or d-dimer, may reflect an integration of myeloid and microvascular endothelial cell activation.
PTX3, lactate dehydrogenase as an indicator of cell and tissue damage is found to correlate with the severity of lesions on computed tomography and subsequent disease progression in patients with paucisymptomatic Covid-19.
Acute-phase proteins have emerged as more than innocent bystanders of acute and chronic inflammation, and these molecules recognize microbial moieties and damaged cells or tissues.
These antibodies promote disposal of microbes and dead cells by activating and regulating the complement cascade and by mediating opsonic activity.
Increased production of matrix molecules of fibrinogen and fibronectin and protease inhibitors during the acute-phase response are a general mechanism to promote tissue repair.
This acute-phase response is an essential component of humoral innate immunity, promoting antimicrobial resistance and tissue repair.