Immune cell-derived serine protease as pathogenic drivers of vascular remodeling in pulmonary arterial hypertension

Abstract

In recent years, accumulating evidence has shown that pulmonary arterial hypertension (PAH) has a strong underlying inflammatory component. Vascular remodeling, a common pathology observed in all forms of pulmonary hypertension (PH), is accompanied by a pronounced accumulation of leukocytes around and within the vessels. Proteolytic products of immune cells, particularly neutrophil and mast cell serine proteases, have been shown to play a central pathogenic role in vascular remodeling and PAH development. Serine proteases are involved in many aspects of the inflammatory response, such as extracellular matrix degradation, regulation of bioavailability of cytokines, chemokines, and growth factors, and dysregulation of their activity can have devastating consequences. In this review, we will focus on immune dysregulation in PAH and shed light on the pro-inflammatory role of serine proteases in vascular pathology observed in the context of this disease.

Keywords

Pulmonary arterial hypertension / serine proteases / pulmonary arterial remodeling / inflammation / mast cells / neutrophils

References

[1] Simonneau G,Celermajer DS.Haemodynamic definitions and updated clinical classification of pulmonary hypertension.Eur Respir J2019;53:1801913 PMCID:PMC6351336

[2] Chang KY,Badesch DB.PHAR Investigators*Mortality in pulmonary arterial hypertension in the modern era: early insights from the Pulmonary Hypertension Association Registry.J Am Heart Assoc2022;11:e024969 PMCID:PMC9238604

[3] Schermuly RT,Wilkins MR.Mechanisms of disease: pulmonary arterial hypertension.Nat Rev Cardiol2011;8:443-55 PMCID:PMC7097518

[4] Hoffmann J,Marsh LM.Distinct differences in gene expression patterns in pulmonary arteries of patients with chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis with pulmonary hypertension.Am J Respir Crit Care Med2014;190:98-111

[5] Tuder RM.Pulmonary vascular remodeling in pulmonary hypertensio.Cell Tissue Res2017;367:643-9

[6] Hoffmann J,Pieper M.Compartment-specific expression of collagens and their processing enzymes in intrapulmonary arteries of IPAH patients.Am J Physiol Lung Cell Mol Physiol2015;308:L1002-13 PMCID:PMC4437007

[7] Aiello VD,Chaves MJ,Higuchi ML.Morphology of the internal elastic lamina in arteries from pulmonary hypertensive patients: a confocal laser microscopy study.Mod Pathol2003;16:411-6

[8] Sutendra G,Bonnet S.Pyruvate dehydrogenase inhibition by the inflammatory cytokine TNFα contributes to the pathogenesis of pulmonary arterial hypertension.J Mol Med (Berl)2011;89:771-83

[9] Stacher E,Hunt JM.Modern age pathology of pulmonary arterial hypertension.Am J Respir Crit Care Med2012;186:261-72 PMCID:PMC3886716

[10] Perros F,Montani D.Pulmonary lymphoid neogenesis in idiopathic pulmonary arterial hypertension.Am J Respir Crit Care Med2012;185:311-21

[11] Li C,Song R,Lei S.Immune cells and autoantibodies in pulmonary arterial hypertension.Acta Biochim Biophys Sin (Shanghai)2017;49:1047-57

[12] Becker MO,Kutsche M.Vascular receptor autoantibodies in pulmonary arterial hypertension associated with systemic sclerosis.Am J Respir Crit Care Med2014;190:808-17

[13] Soon E,Treacy CM.Elevated levels of inflammatory cytokines predict survival in idiopathic and familial pulmonary arterial hypertension.Circulation2010;122:920-7

[14] Kimura H,Tanabe N.Plasma monocyte chemoattractant protein-1 and pulmonary vascular resistance in chronic thromboembolic pulmonary hypertension.Am J Respir Crit Care Med2001;164:319-24

[15] Dorfmüller P,Durand-gasselin I.Chemokine RANTES in severe pulmonary arterial hypertension.Am J Respir Crit Care Med2002;165:5534-9

[16] Balabanian K,Dorfmüller P.CX(3)C chemokine fractalkine in pulmonary arterial hypertension.Am J Respir Crit Care Med2002;165:1419-25

[17] Chaisson NF.Systemic sclerosis-associated pulmonary arterial hypertension.Chest2013;144:1346-56 PMCID:PMC3787920

[18] Tselios K,Urowitz MB.Systemic lupus erythematosus and pulmonary arterial hypertension: links, risks, and management strategies.Open Access Rheumatol2017;9:1-9 PMCID:PMC5191623

[19] Duong H.Sarcoidosis-associated pulmonary hypertension: pathophysiology, diagnosis, and treatment.Clin Pulm Med2018;25:52-60 PMCID:PMC6168942

[20] Chaouat A,Weitzenblum E.Pulmonary hypertension in COPD.Eur Respir J2008;32:1371-85

[21] Tamosiuniene R,Dhillon G.Regulatory T cells limit vascular endothelial injury and prevent pulmonary hypertension.Circ Res2011;109:867-79 PMCID:PMC3204361

[22] Daley E,Guignabert C.Pulmonary arterial remodeling induced by a Th2 immune response.J Exp Med2008;205:361-72 PMCID:PMC2271018

[23] Crnkovic S,Fließer E.Single-cell transcriptomics reveals skewed cellular communication and phenotypic shift in pulmonary artery remodeling.JCI Insight2022;7 PMCID:PMC9714792

[24] Kurakula K,Tura-Ceide O,Quax PHA.Endothelial dysfunction in pulmonary hypertension: cause or consequence?.Biomedicines2021;9:57 PMCID:PMC7827874

[25] Le Hiress M,Ricard N.Proinflammatory signature of the dysfunctional endothelium in pulmonary hypertension. role of the macrophage migration inhibitory Factor/CD74 complex.Am J Respir Crit Care Med2015;192:983-97

[26] Marsh LM,Grünig G.The inflammatory cell landscape in the lungs of patients with idiopathic pulmonary arterial hypertension.Eur Respir J2018;51:1701214 PMCID:PMC6383570

[27] Heath D,Sukonthamarn P.Pulmonary mast cells in mitral stenosis.Cardiovasc Res1969;3:467-71

[28] Hoffmann J,Kukucka M.Mast cells promote lung vascular remodelling in pulmonary hypertension.Eur Respir J2011;37:1400-10

[29] Dahal BK,Kaulen C.Involvement of mast cells in monocrotaline-induced pulmonary hypertension in rats.Respir Res2011;12:60 PMCID:PMC3104382

[30] Montani D,Gambaryan N.C-kit-positive cells accumulate in remodeled vessels of idiopathic pulmonary arterial hypertension.Am J Respir Crit Care Med2011;184:116-23

[31] Kwapiszewska G,Dahal BK.PAR-2 inhibition reverses experimental pulmonary hypertension.Circ Res2012;110:1179-91

[32] Ormiston ML,Long LL.Impaired natural killer cell phenotype and function in idiopathic and heritable pulmonary arterial hypertension.Circulation2012;126:1099-109

[33] Rätsep MT,Jafri S.Spontaneous pulmonary hypertension in genetic mouse models of natural killer cell deficiency.Am J Physiol Lung Cell Mol Physiol2018;315:L977-90 PMCID:PMC6337009

[34] Qiu H,Ouyang F,Guo S.The role of regulatory T cells in pulmonary arterial hypertension.J Am Heart Assoc2019;8:e014201 PMCID:PMC6912965

[35] Jandl K,Mutgan AC.Impairment of the NKT-STAT1-CXCL9 axis contributes to vessel fibrosis in pulmonary hypertension caused by lung fibrosis.Am J Respir Crit Care Med2022;206:981-98

[36] Koudstaal T,Das T.DNGR1-Cre-mediated deletion of Tnfaip3/A20 in conventional dendritic cells induces pulmonary hypertension in mice.Am J Respir Cell Mol Biol2020;63:665-80

[37] Savai R,Kolbe J.Immune and inflammatory cell involvement in the pathology of idiopathic pulmonary arterial hypertension.Am J Respir Crit Care Med2012;186:897-908

[38] Ucero AC,Roediger B.Fra-2-expressing macrophages promote lung fibrosis in mice.J Clin Invest2019;129:3293-309 PMCID:PMC6668681

[39] Florentin J,Vasamsetti SB.Inflammatory macrophage expansion in pulmonary hypertension depends upon mobilization of blood-borne monocytes.J Immunol2018;200:3612-25 PMCID:PMC5940510

[40] Özpelit E,Özpelit ME.Prognostic value of neutrophil-to-lymphocyte ratio in pulmonary arterial hypertension.J Int Med Res2015;43:661-71

[41] Harbaum L,Simon M.Exploratory analysis of the neutrophil to lymphocyte ratio in patients with pulmonary arterial hypertension.BMC Pulm Med2017;17:72 PMCID:PMC5405506

[42] Brinkmann V,Goosmann C.Neutrophil extracellular traps kill bacteria.Science2004;303:1532-5

[43] Phillipson M.The neutrophil in vascular inflammation.Nat Med2011;17:1381-90 PMCID:PMC7095830

[44] Galiè N,Manes A.Pulmonary arterial hypertension: from the kingdom of the near-dead to multiple clinical trial meta-analyses.Eur Heart J2010;31:2080-6 PMCID:PMC2930983

[45] Korkmaz B,Jenne DE.Neutrophil elastase, proteinase 3, and cathepsin G as therapeutic targets in human diseases.Pharmacol Rev2010;62:726-59 PMCID:PMC2993259

[46] Pham CT.Neutrophil serine proteases fine-tune the inflammatory response.Int J Biochem Cell Biol2008;40:1317-33 PMCID:PMC2440796

[47] Cowland JB.The individual regulation of granule protein mRNA levels during neutrophil maturation explains the heterogeneity of neutrophil granules.J Leukoc Biol1999;66:989-95

[48] Adkison AM,Kelley DG.Dipeptidyl peptidase I activates neutrophil-derived serine proteases and regulates the development of acute experimental arthritis.J Clin Invest2002;109:363-71 PMCID:PMC150852

[49] Tkalcevic J,Phylactides M,Segal AW.Impaired immunity and enhanced resistance to endotoxin in the absence of neutrophil elastase and cathepsin G.Immunity2000;12:201-10

[50] Kim YM,Spiekerkoetter E.Neutrophil elastase is produced by pulmonary artery smooth muscle cells and is linked to neointimal lesions.Am J Pathol2011;179:1560-72 PMCID:PMC3157285

[51] Dollery CM,Sukhova GK,Shapiro SD.Neutrophil elastase in human atherosclerotic plaques: production by macrophages.Circulation2003;107:2829-36

[52] Rose F,Gakisch S.Increased neutrophil mediator release in patients with pulmonary hypertension--suppression by inhaled iloprost.Thromb Haemost2003;90:1141-9

[53] Sweatt AJ,Rhodes CJ.Severe pulmonary arterial hypertension is characterized by increased neutrophil elastase and relative elafin deficiency.Chest2021;160:1442-58 PMCID:PMC8546243

[54] Jandl K,Hoffmann J.Basement membrane remodeling controls endothelial function in idiopathic pulmonary arterial hypertension.Am J Respir Cell Mol Biol2020;63:104-17

[55] Thompson K.Exogenous leukocyte and endogenous elastases can mediate mitogenic activity in pulmonary artery smooth muscle cells by release of extracellular matrix-bound basic fibroblast growth factor.J Cell Physiol1996;166:495-505

[56] Senior RM,Mecham RP.Chemotactic activity of elastin-derived peptides.J Clin Invest1980;66:859-62 PMCID:PMC371663

[57] Zhu Y,Ji Q.Interplay between Extracellular Matrix and Neutrophils in Diseases.J Immunol Res2021;2021:8243378 PMCID:PMC8302397

[58] Geraghty P,Greene CM.Neutrophil elastase up-regulates cathepsin B and matrix metalloprotease-2 expression.J Immunol2007;178:5871-8

[59] Pham CT.Neutrophil serine proteases: specific regulators of inflammation.Nat Rev Immunol2006;6:541-50

[60] Standish AJ.Human neutrophils kill Streptococcus pneumoniae via serine proteases.J Immunol2009;183:2602-9

[61] Clancy DM,Moran HBT.Extracellular neutrophil proteases are efficient regulators of IL-1, IL-33, and IL-36 cytokine activity but poor effectors of microbial killing.Cell Rep2018;22:2937-50

[62] Fukuta T,Takemura G.Neutrophil elastase inhibition ameliorates endotoxin-induced myocardial injury accompanying degradation of cardiac capillary glycocalyx.Shock2020;54:386-93 PMCID:31764619

[63] Suzuki K,Takemura G.Neutrophil elastase damages the pulmonary endothelial glycocalyx in lipopolysaccharide-induced experimental endotoxemia.Am J Pathol2019;189:1526-35

[64] Schmidt EP,Janssen WJ.The pulmonary endothelial glycocalyx regulates neutrophil adhesion and lung injury during experimental sepsis.Nat Med2012;18:1217-23 PMCID:PMC3723751

[65] Grechowa I,Wallrath A,Dorweiler B.Human neutrophil elastase induces endothelial cell apoptosis by activating the PERK-CHOP branch of the unfolded protein response.FASEB J2017;31:3868-81

[66] Ushakumari CJ,Wang YH.Neutrophil elastase increases vascular permeability and leukocyte transmigration in cultured endothelial cells and obese mice.Cells2022;11:2288 PMCID:PMC9332277

[67] Burton VJ,Holmes AM,Walker C.Bone morphogenetic protein receptor II regulates pulmonary artery endothelial cell barrier function.Blood2011;117:333-41

[68] Nickel NP,Gu M.Elafin reverses pulmonary hypertension via Caveolin-1-dependent bone morphogenetic protein signaling.Am J Respir Crit Care Med2015;191:1273-86 PMCID:PMC4476518

[69] Zaidi SH,Ciura S,Rabinovitch M.Overexpression of the serine elastase inhibitor elafin protects transgenic mice from hypoxic pulmonary hypertension.Circulation2002;105:516-21

[70] Cowan KN,Humpl T,Ito S.Complete reversal of fatal pulmonary hypertension in rats by a serine elastase inhibitor.Nat Med2000;6:698-702

[71] Halbwachs-Mecarelli L,Lesavre P,Witko-Sarsat V.Bimodal distribution of proteinase 3 (PR3) surface expression reflects a constitutive heterogeneity in the polymorphonuclear neutrophil pool.FEBS Lett1995;374:29-33

[72] Coeshott C,Pilyavskaya A.Converting enzyme-independent release of tumor necrosis factor alpha and IL-1beta from a stimulated human monocytic cell line in the presence of activated neutrophils or purified proteinase 3.Proc Natl Acad Sci USA1999;96:6261-6 PMCID:PMC26869

[73] Hurst LA,Long L.TNFα drives pulmonary arterial hypertension by suppressing the BMP type-II receptor and altering NOTCH signalling.Nat Commun2017;8:14079 PMCID:PMC5241886

[74] Lane KB,Pauciulo MW.International PPH ConsortiumHeterozygous germline mutations in BMPR2, encoding a TGF-beta receptor, cause familial primary pulmonary hypertension.Nat Genet2000;26:81-4

[75] Wiedow O,Utecht B.Elafin is a potent inhibitor of proteinase 3.Biochem Biophys Res Commun1991;174:6-10

[76] Ying Q.Kinetics of the Inhibition of Proteinase 3 by Elafin.Am J Respir Cell Mol Biol2001;24:83-9

[77] Wittamer V,Guillabert A,Parmentier M.Neutrophil-mediated maturation of chemerin: a link between innate and adaptive immunity.J Immunol2005;175:487-93

[78] Macvanin MT,Radovanovic J,Paneni F.Role of chemerin in cardiovascular diseases.Biomedicines2022;10:2970 PMCID:PMC9687862

[79] Wittamer V,Vulcano M.Specific recruitment of antigen-presenting cells by chemerin, a novel processed ligand from human inflammatory fluids.J Exp Med2003;198:977-85 PMCID:PMC2194212

[80] Hanthazi A,Vegh G.Chemerin added to endothelin-1 promotes rat pulmonary artery smooth muscle cell proliferation and migration.Front Physiol2020;11:926 PMCID:PMC7406802

[81] Hanthazi A,Vegh G.Chemerin influences endothelin- and serotonin-induced pulmonary artery vasoconstriction in rats.Life Sci2019;231:116580

[82] Peng L,Li Y.Chemerin regulates the proliferation and migration of pulmonary arterial smooth muscle cells via the ERK1/2 signaling pathway.Front Pharmacol2022;13:767705 PMCID:PMC8971604

[83] Jankowich MD,Choudhary G.Association of elevated plasma endothelin-1 levels with pulmonary hypertension, mortality, and heart failure in african american individuals: The Jackson Heart Study.JAMA Cardiol2016;1:461-9

[84] Owen CA.Angiotensin II generation at the cell surface of activated neutrophils: novel cathepsin g-mediated catalytic activity that is resistant to inhibition.J Immunol1998;160:1436-43

[85] de Man FS,Handoko ML.Dysregulated renin-angiotensin-aldosterone system contributes to pulmonary arterial hypertension.Am J Respir Crit Care Med2012;186:780-9 PMCID:PMC5104838

[86] Bjornsson J.Primary pulmonary hypertension: a histopathologic study of 80 cases.Mayo Clin Proc1985;60:16-25

[87] Sambrano GR,Faruqi T,Craik C.Cathepsin G activates protease-activated receptor-4 in human platelets.J Biol Chem2000;275:6819-23

[88] Rigg RA,Chu TT.Protease-activated receptor 4 (PAR4) activity promotes platelet granule release and platelet-leukocyte interactions.Platelets2019;30:126-35

[89] Nufer O,Walz A.Amino-terminal processing of chemokine ENA-78 regulates biological activity.Biochemistry1999;38:636-42

[90] Richter R,Escher S.Quantum proteolytic activation of chemokine CCL15 by neutrophil granulocytes modulates mononuclear cell adhesiveness.J Immunol2005;175:1599-608

[91] Stoeckle C,Adamopoulou E.Cathepsin G is differentially expressed in primary human antigen-presenting cells.Cell Immunol2009;255:41-5

[92] Farha S,Asosingh K.Mast cell number, phenotype, and function in human pulmonary arterial hypertension.Pulm Circ2012;2:220-8 PMCID:PMC3401876

[93] Bartelds B,Mohaupt S.Mast cell inhibition improves pulmonary vascular remodeling in pulmonary hypertension.Chest2012;141:651-60

[94] Caughey GH.Mast cell proteases as pharmacological targets.Eur J Pharmacol2016;778:44-55 PMCID:PMC4636979

[95] Schwartz LB,Roller K,Schechter NM.Quantitation of histamine, tryptase, and chymase in dispersed human T and TC mast cells.J Immunol1987;138:2611-5

[96] Schwartz L,Austen K.Tryptase from human pulmonary mast cells. Purification and characterization.J Biol Chem1981;256:11939-43

[97] Lützelschwab C,Aveskogh M.Secretory granule proteases in rat mast cells. Cloning of 10 different serine proteases and a carboxypeptidase A from various rat mast cell populations.J Exp Med1997;185:13-29 PMCID:PMC2196094

[98] Pejler G,Waern I.Mast cell proteases: multifaceted regulators of inflammatory disease.Blood2010;115:4981-90

[99] Kosanovic D,Peters DM.Histological characterization of mast cell chymase in patients with pulmonary hypertension and chronic obstructive pulmonary disease.Pulm Circ2014;4:128-36 PMCID:PMC4070756

[100] Compton SJ,Holgate ST.Human mast cell tryptase stimulates the release of an IL-8-dependent neutrophil chemotactic activity from human umbilical vein endothelial cells (HUVEC).Clin Exp Immunol2000;121:31-6 PMCID:PMC1905680

[101] Compton SJ,Holgate ST.The role of mast cell tryptase in regulating endothelial cell proliferation, cytokine release, and adhesion molecule expression: tryptase induces expression of mRNA for IL-1β and IL-8 and stimulates the selective release of IL-8 from human umbilical vein endothelial cells.J Immunol1998;161:1939-46

[102] Iddamalgoda A,Ito K,Kojima H.Mast cell tryptase and photoaging: possible involvement in the degradation of extra cellular matrix and basement membrane proteins.Arch Dermatol Res2008;300 Suppl 1:S69-76

[103] Cairns JA.Mast cell tryptase stimulates the synthesis of type I collagen in human lung fibroblasts.J Clin Invest1997;99:1313-21 PMCID:PMC507947

[104] Abe M,Ishikawa O,Kido H.Mast cell tryptase stimulates both human dermal fibroblast proliferation and type I collagen production.Clin Exp Allergy1998;28:1509-17

[105] Bagher M,Rosmark O,Bjermer L.Mast cells and mast cell tryptase enhance migration of human lung fibroblasts through protease-activated receptor 2.Cell Commun Signal2018;16:59 PMCID:PMC6139170

[106] D'Orléans-Juste P,Rae GA,Carrier E.Endothelin-1 (1-31): from chymase-dependent synthesis to cardiovascular pathologies.Vascul Pharmacol2008;49:51-62

[107] Simard E,Takai S,Brochu I.Chymase-dependent conversion of big Endothelin-1 in the mouse in Vivo.J Pharmacol Exp Ther2009;328:540-8

[108] Koga T,Inoue Y.Human chymase expression in a mice induces mild hypertension with left ventricular hypertrophy.Hypertens Res2003;26:759-68

[109] Heutinck KM,Hack CE,Rowshani AT.Serine proteases of the human immune system in health and disease.Mol Immunol2010;47:1943-55

[110] Lazaar AL,Kucich U.Mast cell chymase modifies cell-matrix interactions and inhibits mitogen-induced proliferation of human airway smooth muscle cells.J Immunol2002;169:1014-20

[111] Frank BT,Caughey GH.Mast cell tissue inhibitor of metalloproteinase-1 is cleaved and inactivated extracellularly by alpha-chymase.J Immunol2001;166:2783-92

[112] Tchougounova E,Fajardo I,Abrink M.A key role for mast cell chymase in the activation of pro-matrix metalloprotease-9 and pro-matrix metalloprotease-2.J Biol Chem2005;280:9291-6

[113] Kosanovic D,Dahal BK.Chymase: a multifunctional player in pulmonary hypertension associated with lung fibrosis.Eur Respir J2015;46:1084-94

[114] Weng M,Bloch KD,Lee JJ.Eosinophils are necessary for pulmonary arterial remodeling in a mouse model of eosinophilic inflammation-induced pulmonary hypertension.Am J Physiol Lung Cell Mol Physiol2011;301:L927-36 PMCID:PMC3233831

[115] Shu T,Zhou Y.Eosinophils protect against pulmonary hypertension through 14-HDHA and 17-HDHA.Eur Respir J2023;61:2200582 PMCID:PMC9978164

[116] Ikutani M,Yanagibashi T.Elimination of eosinophils using anti-IL-5 receptor alpha antibodies effectively suppresses IL-33-mediated pulmonary arterial hypertrophy.Immunobiology2018;223:486-92

[117] Alzghoul BN,Moreno BF.Pulmonary hypertension in eosinophilic versus noneosinophilic COPD.ERJ Open Res2021;7:00772-2020 PMCID:PMC7938054

[118] Wang T,Zhang SF.Role of chymase in cigarette smoke-induced pulmonary artery remodeling and pulmonary hypertension in hamsters.Respir Res2010;11:36 PMCID:PMC2853423

[119] Lan NSH,Kulkarni SS.Pulmonary arterial hypertension: pathophysiology and treatment.Diseases2018;6:38 PMCID:PMC6023499

[120] Mangano DT,Dietzel C.Multicenter Study of Perioperative Ischemia Research GroupIschemia Research and Education FoundationThe risk associated with aprotinin in cardiac surgery.N Engl J Med2006;354:353-65

[121] Chalmers JD,Metersky ML.WILLOW InvestigatorsPhase 2 trial of the DPP-1 inhibitor brensocatib in bronchiectasis.N Engl J Med2020;383:2127-37

[122] Hart TC,Bowden DW.Mutations of the cathepsin C gene are responsible for Papillon-Lefèvre syndrome.J Med Genet1999;36:881-7 PMCID:PMC1734286