macrophages are involved in several pathological conditions , including severe sepsis , autoimmune disorders , cancer and low - grade inflammatory disorders , such as metabolic syndrome , atherosclerosis and asthma . macrophages are essential in regulating the activation and resolution of immune responses , and can influence the progression of a disease ( 1 ) . cluster of differentiation ( cd)163 is a monocyte / macrophage - associated antigen that has been identified as a hemoglobin ( hb ) scavenger receptor with anti - inflammatory and immunoregulatory properties . this surface receptor undergoes ectodomain shedding , triggered by an inflammatory stimulus , generating the soluble(s ) form , scd163 , in plasma ( 2 ) . cd163 is a scavenger receptor for the endocytosis of hb and haptoglobin ( hp)-hb complexes ( 3 ) . it is almost exclusively expressed on monocytes and macrophages , and participates in the modulation of inflammatory responses ( 3,4 ) . scd163 is a novel marker associated with states of low - grade inflammation characteristic of conditions such as diabetes , obesity , liver disease and atherosclerosis ( 5 ) . the proteolytic cleavage of monocyte - bound cd163 by matrix metalloproteinases ( mmps ) , which is triggered by exposure to oxidative stress or an inflammatory stimulus , releases scd163 ( 68 ) . oxidative stress pathways , induced by prostaglandin f2 ( pgf2 ) and 8-iso - pgf2 , enhance the expression of tumor necrosis factor ( tnf)- and cd163 ( 8) . lipopolysaccharide ( lps ) can also increase the levels of scd163 and tnf- , via stimulation of a disintegrin and metalloproteinase metallopeptidase domain 17 ( adam17 ) , which is known to mediate the shedding of the extracellular domains of cd163 and tnf- ( 9 ) . the significant negative correlation , which was revealed between membrane cd163 expression and scd163 levels , suggests that plasma scd163 may be derived from circulating monocytes , in addition to being secreted by tissue macrophages ( 10 ) . scd163 is constitutively being shed from the cell surface into the circulation , and it is stable and easily detectable in serum . the present review focuses on examining the role of scd163 in various inflammatory disorders , including inflammatory disorders of the airways , and specifically in the pathogenesis of asthma . classically activated m1 macrophages are the first line of defense against bacterial infections and obtain energy through glycolysis . cell - surface markers of classically activated macrophages are not well defined ; however , cd40 is predominantly used ( 11,12 ) . conversely , alternatively activated m2 macrophages , which are cd163 and cd206 , are involved in tissue repair and wound healing , and use oxidative metabolism to fuel their long - term functions . granulocyte - macrophage colony - stimulating factor ( gm - csf ) and interferons ( ifns ) can enhance the macrophage lineage , and modulate macrophage differentiation and function . m1 macrophages can be produced in vitro by culture and subsequent differentiation of human peripheral blood monocytes . the cytokines m - csf , interleukin ( il)-4 and il-10 stimulate monocyte differentiation into m2 macrophages ( 13 ) . m1 macrophages secrete proinflammatory cytokines , such as il-12 and tnf- , and also have antigen - presenting capacity and promote th1 immune responses . conversely , m2 macrophages secrete anti - inflammatory mediators , such as il-10 , and have poor antigen - presenting capabilities and stimulate the generation of regulatory t cells ( 1315 ) . the activation of m2 macrophages is primarily triggered by t helper ( th ) 2 cytokines , such as il-4 , il-13 and il-10 , as well as anti - inflammatory mediators , such as glucocorticoids ( 16 ) . cd163 m2 macrophages reduce m1 populations through the release of anti - inflammatory cytokines , such as il-10 . macrophage mannose receptor ( mrc)-1 , il-13 , il-1 receptor antagonist ( il-1ra ) and cd163 serve important roles in m2 differentiation ( 17 ) . monocyte - derived macrophages , classically activated via ifn- priming and lps stimulation , demonstrate a decreased cd163 expression ; however , the alternative activation route , involving il-4/il-13 priming , does not affect the expression of cd163 and calprotectin on macrophages ( 18 ) . the presence of ifn- , indicative of th1 inflammation , or a prolonged exposure to il-4 , promotes apoptosis of macrophages and suppresses m2 differentiation , which leads to a reduction in the clearance of apoptotic neutrophils , increased accumulation of apoptotic cells and persistent inflammation ( 19 ) . conversely , in the presence of il-17 , indicative of a th17 response , macrophage apoptosis is prevented and m2 differentiation is stimulated , which ensures that apoptotic neutrophils are cleared efficiently and anti - inflammatory conditions are restored ( fig . m2 macrophages derived from peripheral blood mononuclear cells exhibit markedly increased mrna expression levels of thymus activation regulating chemokine ( ccl ) 11 , ccl17 , ccl24 and ccl26 , and the production of ccl17 and ccl24 is also potentiated ( 20 ) . cd163 is a 130-kda , type i transmembrane protein , which belongs to class b of the cysteine - rich scavenger receptor family , and was first identified in 1987 ( 21 ) . the expression of cd163 on circulating monocytes and most tissue macrophages is constitutive and/or induced by some stimuli ( 22 ) . cd163 has been reported to bind human pathogenic bacteria ( 10,23 ) and tnf--like weak inducer of apoptosis ( tweak ) ( 24 ) . using western blot analysis of cd163 variants , a panel of 10 monoclonal antibodies was mapped to scavenger receptor cysteine - rich ( srcr ) domains 1 , 3 , 4 , 6 , 7 and 9 ( 25 ) . four of the srcr domains of cd163 ( domains 2 , 3 , 7 and 9 ) have conserved consensus motifs for ca binding , whereas domain 5 has a potentially / semi - conserved ca binding site . the other four srcr domains have at least one non - conservative mutation of an essential residue in the consensus ca binding sequences ( 26 ) . this is an exposed domain and a critical factor regulating the ca - sensitive coupling of hp - hb complexes ( 25 ) . since cd163 is a scavenger receptor on the surface of macrophages , its extracellular region , consisting of nine srcr domains , can be stimulated by inflammation or other stimuli , resulting in the release of its soluble form , scd163 , in the plasma ( 22,25 ) . ligands of toll - like receptors ( tlr ) 2 , 4 and 5 can stimulate ectodomain shedding of cd163 , thereby releasing scd163 ( 3 ) . cd163 and pro - tnf- are transmembrane proteins subjected to hydrolytic cleavage by the inflammation - responsive proteases adam17 ( 23,27 ) and adam10 ( 23 ) from the monocyte surface . a sequence comparison of their juxtamembrane region identified similar palindromic sequences in human cd163 ( 1044arg - ser - ser - arg ) and pro - tnf- ( 78arg - ser - ser - ser - arg ) ( fig . 2 ) ( 27 ) . scd163 and immunoglobulin g interact with the free hb in plasma , leading to the endocytosis of the scd163-hb - igg complex via the fc receptor ( fcr ) into monocytes . the endocytosed scd163 is recycled to restore the homeostasis of cd163 on the monocyte membrane , whereas the internalized hb is catabolized ( 28 ) . paracrine transactivation of endothelial cells is mediated by the shed scd163 , which detoxifies and clears residual hb . circulating scd163 only weakly competes with membrane cd163 for the uptake of hp - hb complexes , and hp - hb saturation of scd163 in serum can only be achieved with a large surplus of hp - hb complex . these findings indicated that the hp - hb complex may be harder to dissociate from the membrane form of cd163 ( fig . cd163 is expressed only on cells of the monocytic - macrophage lineage , and its expression increases as monocytes mature into macrophages . cd163 expression is particularly high on macrophages in the liver ( kupffer cells ) , red pulp of the spleen , lungs and bone marrow ( 21 ) . scd163 is a marker of activated macrophages ( 30 ) . following an inflammatory stimulus or oxidative stress , scd163 is released from the cell surface by proteolytic cleavage of monocyte - bound cd163 through the action of mmps ( 68 ) and after lps stimulation ( 22,31 ) , whereas proinflammatory cytokines , such as tnf , reduce cd163 expression ( 3 ) . furthermore , tlr7 levels have been associated with concentrations of il-10 , il-1ra and cd163 ( 32 ) . the expression of cd163 is induced by corticosteroids ( 3,3335 ) , il-10 ( 3,22,3335 ) , il-6 ( 12,34,36 ) , il-12 ( 37 ) , the chemokine ( c - x - c motif ) ligand ( cxcl ) 10 ( 37 ) , and oxidative stress ( 8) . scd163 protects monocytes from hyperactivation during bacterial infections by dampening the secretion of the proinflammatory cytokines tnf- , il-1 , il-6 and il-8 ( 38 ) . the actions of scd163 and tnf- seem to be interconnected , and the scd163/tnf- ratio is higher in patients with uncomplicated malaria ( 39 ) . in vitro , stimulation of murine monocyte - macrophage cells resulted in increased tnf- release accompanied by elevated cd163 expression ( 17 ) . in patients with cirrhosis and hepatitis c infection elevated scd163 serum levels are currently the most specific marker for distinguishing bacterial infections , such as brucellosis , or those caused by staphylococcus aureus and haemophilus influenzae ( 41,42 ) , from non - bacterial infections , based on previously described results comparing lumbar puncture with composite reference standards ( 43 ) . scd163 expression is correlated with levels of il-6 ( 21,41 ) , il-10 and il-8 ( 44 ) , but not with lps - binding protein , procalcitonin ( pct ) or c - reactive protein ( crp ) levels ( 41 ) . plasma levels of crp , pct and scd163 are increased in patients with bacterial infections ( 45 ) . crp and pct are also valuable diagnostic tools and can be used as markers of bacterial infections . in patients with sepsis , scd163 levels were significantly lower than in patients with severe sepsis ; however , scd163 levels in both groups were considerably increased compared with in the control group ( 46,47 ) . furthermore , higher scd163 levels were reported in patients with sepsis who succumbed compared with in surviving patients ( 4648 ) . mrc and scd163 expression is markedly increased in septic patients compared with in non - septic patients and healthy controls ( 48 ) . increases in serum scd163 levels were delayed in animals that were infected with virulent strains of haemophilus parasuis ( 44 ) . scd163 serum levels are elevated in patients with acute and chronic liver diseases . in patients with cirrhosis , scd163 concentration is ~3 times higher compared with in healthy controls ( 49,50 ) . in addition , although scd163 is linearly associated with the pressure gradient in the portal vein , its concentration remained unaltered after a transjugular intrahepatic portosystemic shunt procedure ( 51 ) . high scd163 serum levels are considered an independent risk factor for variceal / gastrointestinal bleeding , portal hypertension and mortality in patients with cirrhosis ( 49,52,53 ) . high serum scd163 concentrations have been reported during acute liver damage , but are lower in acute hepatitis ; however , in both conditions , they are higher than those reported in patients with chronic hepatitis ( 12,26,30 ) . hepatitis b infection is characterized by higher serum scd163 levels when compared with hepatitis c , particularly when accompanied by liver fibrosis ( 40,54 ) , whereas higher serum scd163 concentrations have been associated with higher mortality ( 55,56 ) . scd163 is also associated with obesity , insulin resistance , and the development of type 2 diabetes ( 5759 ) . in patients with type 2 diabetes , scd163 appears strongly associated with known risk factors , such as physical inactivity , body mass index , elevated crp levels and triglyceride content ( 60 ) . high serum scd163 levels have been associated with complications in patients with type 2 and type 1 diabetes mellitus ( 59,61 ) ; conversely , levels of soluble tweak , a cytokine that regulates inflammation , angiogenesis and tissue remodeling , follow an opposite trend ( 61 ) . serum scd163 levels are significantly higher in obese patients compared with in lean patients , whereas efferocytosis by m2 macrophages appears to be impaired in obese patients ( 6163 ) . a low - fat diet reduced the levels of scd163 ( 64,65 ) ; however , a 12-week exercise program had no such effect ( 66 ) . scd163 has been associated with arterial inflammation , non - calcified plaque formation , perivascular fat accumulation and carotid atherosclerosis ( 67,68 ) . neutrophil elastase has been demonstrated to promote cd163 shedding , and cd163 expression on the surfaces of macrophages was decreased , resulting in impaired of hb clearance by macrophages . these effects may be correlated with acute coronary syndrome and stable angina pectoris , and may increase the risk of myocardial infarction ( 69 ) . it has been demonstrated that cd163 can bind and neutralize tweak ( 70 ) , whereas scd163 functions as a decoy receptor for tweak . furthermore , the cd163/tweak plasma ratio may have potential as a biomarker of atherosclerosis in asymptomatic individuals ( 71 ) . substantially elevated scd163/stweak ratios have been reported in patients with critical limb ischemia and peripheral artery disease ( 72,73 ) . serum scd163 levels were estimated in patients with systemic sclerosis ( ssc ) as an indicator of disease deterioration , pulmonary fibrosis and pulmonary hypertension ( 4,6,74,75 ) . scd163 levels and the scd163/stweak ratio were significantly increased in patients with ssc compared with in controls . elevated plasma scd163 and an increased scd163/stweak ratio were associated with a lower risk of digital ulcers in patients with ssc ( 70 ) . early rheumatoid arthritis ( ra ) patients have significantly increased scd163 plasma levels , which are reduced following treatment . therefore it may be hypothesized that scd163 is implicated in ra activity , although an association between scd163 and disease activity has yet to be demonstrated ( 37,76 ) . scd163 in addition , scd163 levels have been correlated with the systemic lupus erythematosus disease activity index ( 78 ) . patients with elevated serum scd163 levels exhibit significantly higher rates of anti - double - strand - dna antibodies ( 79 ) . macrophages serve key roles in tumor development and invasion in several types of human cancer , and scd163 is a marker of alternatively activated m2 macrophages . high scd163 concentrations have been detected in hepatocellular carcinoma ( 80 ) , ovarian cancer ( 81,82 ) , t cell lymphoma ( 83 ) and multiple myeloma ( 84 ) . furthermore , elevated scd163 concentrations are associated with a poor prognosis in patients with cancer ( 40,8183 ) . in conclusion , scd163 levels in infection , liver disease , autoimmune disorders , metabolic disease and cancer are elevated , whereas the clinical significance of this elevation varies among the various diseases ( table i ) . house dust mite ( hdm)-challenged cd163 mice have been reported to exhibit increased concentrations of airway eosinophils and develop mucous cell metaplasia ( 85 ) . in addition , cd163 mice may demonstrate transiently elevated tweak levels , which can stimulate muscle satellite cell proliferation and tissue regeneration in ischemic and non - ischemic limbs . these results suggested a role for scd163 in muscle regeneration following ischemic injury ( 86 ) . in cd163-deficient mice , the overall clearance of hb has been demonstrated to be slightly impaired and follow a one - phase decaying trend ( 87 ) . macrophages have a central role in the regulation and efficiency of the immune response , and participate in innate and adaptive immunity . macrophages exert important functions in autoimmune disorders , including ra , crohn 's disease , psoriasis , sarcoidosis and atherosclerosis . m2 macrophages are associated with responses to anti - inflammatory stimuli and tissue remodeling ( 88 ) . since they participate in tissue repair and in the restoration of lung microenvironment homeostasis , m2 macrophages may serve a major role in asthma ( 89 ) . macrophages represent the majority of immune cells present in lungs under physiological conditions and serve to dictate the innate defense mechanisms of the airways . pulmonary macrophage populations are heterogeneous and demonstrate notable plasticity , due to variations in their origin , tissue residency and environmental influences ( 90 ) . in mice with moderately severe asthma , the population of m1 macrophages is elevated and negatively correlated with the population of m2 ( cd163 ) macrophages . decreased numbers of m2-like macrophages are reported after hdm exposure , and they are negatively correlated with the number of m1 macrophages ( 88 ) . in addition , macrophages have been implicated in the pathogenesis of chronic obstructive pulmonary disease ( copd ) . ex - smokers with copd have a higher percentage of cd163 macrophages in bronchoalveolar lavage ( bal ) than current smokers . furthermore , the percentage of cd163 m2 macrophages is higher in bal than in sputum ( 91 ) . in ovalbumin ( ova)-sensitized mice , exposure to the airborne particulate matter pm2.5 caused a slight increase in the number of neutrophils and macrophages ( 92 ) . the balance between macrophage phenotypes fluctuates , depending on the severity of allergic airway inflammation ( 88 ) . this balance is regulated by cytokines , such as il-13 , which is a typical pro - m2-th2 cytokine that has been linked to allergic diseases and asthma . microrna ( mir)-155 may also be involved in regulation of the m1/m2 balance via modulating the effects of il-13 . mir-155 directly targets the il-13ra1 gene and reduces the protein levels of il-13ra1 , thus preventing the activation of the signal transducer and activator of transcription ( stat ) 6 ( 93 ) . serum amyloid p ( sap ) inhibits the generation of m2 markers , such as arginase and the chitinase ym-1 , through an fcr - dependent mechanism in cultured macrophages . this effect has been correlated with a decrease in stat6 phosphorylation in sap - treated m2 macrophages ( 94 ) . type 2 cytokines , i.e. il-4 and il-13 , can drive the differentiation of macrophages into m2 macrophages . monocytes co - cultured with regulatory t cells display typical features of alternatively activated macrophages , including upregulated expression of cd206 ( macrophage mannose receptor ) and cd163 , and increased production of ccl18 ( 96 ) . ova - sensitized and challenged mice exhibit a significant increase in white blood cells , eosinophilia , mucus accumulation and goblet cell hyperplasia , which were correlated with increased expression of genes associated with alternatively activated m2 macrophages , such as arginase 1 , ym-1 , ym-2 , resistin like- , and eosinophil - associated , ribonuclease a family member 11 . the expression of other genes associated with asthma , including fcriib , mmp-14 , ccl-8 , ccl-17 ( 20,97 ) , adam-8 , lymphotoxin  receptor 1 ( ltr1 ) , aquaporin-9 and il-7r , is also upregulated in bronchoalveolar macrophages isolated from ova - sensitized / challenged mice compared with in macrophages from healthy controls ( 97 ) . cd163 may function as a pulmonary defense element , as suggested by its local expression in the lungs , and its secretion during lung infection and as part of inflammatory respiratory responses ( 98 ) . cell surface expression of cd163 on alveolar macrophages is reduced in human subjects with asthma , which suggests that cd163 may participate in the regulation of airway inflammatory responses in the lung ( 85 ) . in addition , scd163 is inversely associated with predicted forced expiratory volume in 1 sec in patients with asthma ( 9 ) and copd , particularly in those with severe disease ( 94 ) . during dermatophagoides pteronyssinus ( dp)-induced bronchoconstriction , alterations in monocyte cd163 expression and scd163 this impairment is associated with altered monocyte programming , impaired response to glucocorticoids and systemic oxidative stress ( 62 ) . obese asthmatic children exhibit increased scd163 expression , in addition to sex - specific macrophage activation , which may impair asthma control and lung function ( 9 ) . furthermore , scd163 concentration in sputum is significantly higher in patients with allergic asthma compared with in controls . treatment with inhaled corticosteroids results in a significant increase in scd163 concentrations in sputum ( 33 ) . macrophages isolated from sputum samples from patients with asthma demonstrate significantly higher ccl17 and lower cd163 mrna expression levels compared with macrophages from healthy subjects ( 100 ) . cd163 alveolar macrophages were decreased in patients with asthma ( 85 ) , whereas sputum scd163 levels were increased ( 33 ) . this inverse relationship between surface and soluble cd163 has already been described ( 44 ) . therefore , we speculate that airway inflammation and some inflammatory mediators induce alveolar macrophages to release cd163 from the cell surface in patients with asthma , and scd163 participates in the airway inflammatory response , and the phagocytosis of cd163 m2 macrophages is impaired in asthma . cd163 , which is a transmembrane scavenger receptor found on the surface of macrophages , is released in the circulation in its soluble form , scd163 , via cleavage by mmps following oxidative stress or inflammatory stimuli . scd163 is involved in the pathogenesis of autoimmune diseases , atherosclerosis , diabetes and cancer . bronchial asthma is characterized by nonspecific inflammation of the airways , and the alternatively activated cd163 m2 macrophages have a key role in this pathological condition . through phagocytosis and the subsequent release of biologically active substances , macrophages effectively eliminate apoptotic neutrophils , a process critical in suppressing acute inflammation and restoring homeostasis . neutrophil elastase has been revealed to enhance cd163 shedding , and scd163 is a marker of macrophage activation . neutrophil elastase serves as a neutrophil activation marker , which suggests that macrophage activation is associated with the activation of neutrophils . th2 cytokines , such as il-4 , il-13 and il-10 , can influence m2 macrophage activation . il-10 and il-6 promote scd163 shedding from m2 macrophages , whereas release of th17 and il-17 can inhibit the apoptosis of cd163 m2 macrophages . scd163 , a marker of m2 macrophages , is associated with the eosinophil count through several cytokines . furthermore , scd163 is associated with body mass index in patients with asthma , and the concentration of scd163 in plasma or induced sputum is inversely correlated to predicted forced expiratory volume in 1 sec . therefore , investigating the role of scd163 may contribute to elucidating the underlying molecular mechanisms of asthma , and may represent a promising target for the development of effective therapeutic agents for the treatment of asthma .
macrophages exert important functions in the balance and efficiency of immune responses , and participate in innate and adaptive immunity . 
 the proinflammatory actions of macrophages are implicated in autoimmune diseases . unlike classically activated m1 macrophages , the alternatively activated cluster of differentiation ( cd)163 + and cd206 + m2 macrophages are involved in tissue repair and wound healing , and use oxidative metabolism to support their long - term functions . 
 cd163 is a member of the scavenger receptor superfamily , categorized into class b , and its soluble(s ) form , scd163 , is a marker of activated m2 macrophages . 
 cd163 is selectively expressed in cells of the monocyte and macrophage lineages ; however , its biological role has yet to be elucidated . 
 the expression of scd163 is markedly induced by anti - inflammatory mediators , such as glucocorticoids and interleukin-10 , whereas it is inhibited by proinflammatory mediators , such as interferon-. these findings suggest that cd163 may serve as a potential target for the therapeutic modulation of inflammatory responses . 
 the concentration of scd163 in blood is associated with acute and chronic inflammatory processes in autoimmune disorders of connective tissue , fat metabolism and cardiovascular diseases , and it can be used for the assessment of cancer prognosis . a role for scd163 in the pathogenesis of asthma has also been proposed . the present review serves to present the available knowledge concerning the implication of scd163 in the pathophysiological mechanisms of asthma , and evaluate its potential as a biomarker and possible therapeutic target for asthma .