BRIEF REVIEW www.jasn.org

Role of Mast Cells in Progressive Renal Diseases

Stephen R. Holdsworth and Shaun A. Summers

Centre for Inflammatory Diseases, Department of Medicine, Monash Medical Center, Melbourne, Australia

ABSTRACT Advances in understanding biology reveal their diverse functional capac- nerves in connective tissues, allowing ity well beyond already established roles in host defense against parasites and their participation in homeostatic func- allergic disease. Mast cells can initiate, amplify, and direct innate and adaptive tions as well as being strategic sentinels at immune responses. They also modulate and regulate immunity. Mast primary immune barriers where their cells potentially induce tissue repair and direct fibrosis; however, they also play density is increased. Their anatomic dis- other roles in tissue remodeling and repair. Various activation and differentiating tribution and structural relationships al- signals result in a diverse range of functional phenotypes called “mast cell heter- low mast cells to modulate innate im- ogeneity.” Mast cells are significant participants in chronic progressive kidney mune and adaptive effector responses; disease, and their presence is associated with function loss and fibrosis. This however, this role requires mast cell acti- suggests a potential role in the fibrotic process, which may involve mast cell vation to stimulate cell degranulation to- activation of local renin-angiotensin systems. Experimental animal studies suggest, gether with synthetic molecule release. however, they do not directly cause renal fibrosis but rather spark inflammation. The best known, classical pathway of Evidence for both pro- and anti-inflammatory roles in nephritis is emerging. mast cell activation is through IgE-Fc␧ cross-linking.5 The role mast cells serve J Am Soc Nephrol 19: 2254–2261, 2008. doi: 10.1681/ASN.2008010015 in expulsion of parasites from their host is well known.2 More recent studies rec- ognized additional, alternative, activat- The mast cell, originally named “fattened inflammation and autoimmunity. Their ing pathways including complement and or well-fed cell” (Mastzellen) by Ehr- participation in a diverse range of human signaling through microbial pattern rec- lich,1 is a sentinel for host defense.2 After kidney diseases is also now clear, and their ognition receptors, toll-like receptors recent discoveries demonstrated an ex- phenotypic characterization; mechanism (TLR). This work has expanded our un- panded role for mast cells in both sys- of recruitment and proliferation; and pos- derstanding of a role for mast cells in host temic and local host immune responses, sible roles in inflammation, fibrosis, re- defense in other diseases. Galli3 suggested the name “master” cell modeling, and repair are now open to ex- In animal models of bacterial infec- would be more appropriate. Mast cells ploration. This review focuses on the tion, including bacterial peritonitis, mast are present in low numbers in all vascular biology of mast cells, mast cells in fibrosis, cells are required for optimal innate im- organs, including the kidney. In chronic the renin-angiotensin system (RAS) in mune responses conferring survival ben- progressive kidney diseases, mast cell mast cell fibrosis, and the role of mast cells efit.6,7 Complement also activates mast proliferation in tubulointerstitial injury in autoimmune kidney diseases. cells, and complement-dependant mi- is prominent regardless of the initiating crobial killing is at least partially depen- disease and correlates with progressive dent on mast cell function for full expres- loss of function and poor outcome. MAST CELL BIOLOGY sion.8 The pattern recognition receptors, Outside the kidney, mast cell biology TLR, serve as an important link between is a rapidly advancing field. Mast cells Mast cells derive from hematopoietic have diverse functional capacities well progenitor cells. They migrate through Published online ahead of print. Publication date beyond those associated with allergy and vascularized tissue to complete their available at www.jasn.org. IgE. Rodents genetically deficient in mast maturation.4 Mast cells are tissue-spe- Correspondence: Prof. Stephen R. Holdsworth, cells have been extensively studied to de- cific multifunctional cells, with diverse Monash Medical Centre, Monash University, Level 5/Block E, 246 Clayton Road, Clayton, Victoria, 3168, termine whether these cells play a role in phenotypes in different anatomic sites in Australia. Phone: 61-3-9594-5525; Fax: 61-3-9594-6437; models of human disease, and, as it turns various species, collectively referred to as E-mail: [email protected] 2,4 out, mast cells have functional roles in “mast cell heterogeneity.” They locate Copyright ᮊ 2008 by the American Society of vivo in chronic diseases associated with close to blood vessels, epithelia, and Nephrology

2254 ISSN : 1046-6673/1912-2254 J Am Soc Nephrol 19: 2254–2261, 2008 www.jasn.org BRIEF REVIEW innate and adaptive immunity. Both MAST CELLS IN RENAL Early events in this process involve leu- mouse9,10 and human mast cells11 express INFLAMMATION AND FIBROSIS kocyte (including mast cell) recruitment TLR. In animal models, the important syn- and epithelial-mesenchymal transition ergistic interaction between TLR in mast Although mast cells are found infre- forming fibroblasts. Profibrotic stimuli cells demonstrates upregulated cytokine quently in normal kidney tissue, their include key growth factors, TGF-␤45 and production12 and increased survival from numbers increase significantly in the set- fibroblast growth factor, as well as inflam- bacterial infection.13 In addition to com- ting of renal disease. Mast cells are prom- matory cytokines and chemokines facili- plement and TLR activation, stress hor- inent in tubulointerstitial nephritis asso- tating leukocyte recruitment and activa- mones, in particular corticotrophin-re- ciated with progressive fibrosis and renal tion. Tubular epithelial cells play an leasing hormone, enhances mast cell failure. These include almost all of the important role in these processes, and the activation and degranulation, facilitating primary and secondary forms of glomer- release of proteolytic , including further mediator release.14 ulonephritis,19–30 diabetic nephropa- matrix metalloproteases (MMP), mediates As well as these novel pathways, sev- thy,31,32 and allograft rejection,33–38 as fibrogenic injury. The balance of overall eral other molecules can initiate mast cell well as amyloid,39 renovascular isch- activators and inhibitors is altered in a activation. These include growth factors emia,40 reflux nephropathy,41 polycystic manner favoring net matrix deposition such as stem cell factor, co-stimulatory kidney disease,42 and drug-induced ne- and scarification. molecules CD28 (and ligands CD80/86), phropathy.19 Mast cell presence is corre- Mast cells have the potential to sup- the integrins, and CCR1.15 The close lated semiquantitatively with fibrosis, port this process actively. They elaborate proximity of mast cells to neurons facili- progressive decline in glomerular filtra- cytokines,46 chemokines,47 and leukotri- tates neuropeptide activation of mast tion, and poor outcome.20–22,24,25,27,29 enes48 recruiting and activating leuko- cells.16 Mast cells are also important in The intensity and extent of tubulointer- cytes. They also indirectly support leuko- chronic inflammation with the capacity stitial damage is one of the strongest de- cyte recruitment by affecting vascular to produce a range of bioactive amines, terminants of progressive functional de- endothelial expression of selectins and proteoglycans, growth hormones, che- cline.43,44 adhesion molecules.49,50 Mast cell de- mokines, and cytokines, which mediate a Interstitial inflammation and fibrosis granulation leads to the release of hista- diverse range of mast cell function (Fig- involve a common sequence of events re- mine, heparin, and cytokines, in particu- ure 1). This breadth of activity has been quiring the interaction of tubular and in- lar IL-451 and TNF-␣,52 which can reviewed extensively.2,17,18 terstitial cells with infiltrating leukocytes. influence fibroblast function. Further- more, the release of TGF-␤,53 MMP-9,54 and a variety of proteases, principally MEDIATOR RELEASE AND PHYSIOLOGICAL tryptase and , contributes to REACTIONS OF MAST CELL DEGRANULATION progressive fibrogenesis.55,56 In addition to direct injury, some proteases are capa- Mast cell ble of activating latent MMP and other proteases. They also serve as chemoat- Growth factors Cytokines and tractants and mitogens for fibroblasts. • Stem cell factor chemokines • Granulocyte macrophage • Interferon γ Growth factors are mediators of mast • Colony stimulating factor • Tumour necrosis factor cell–associated histologic and functional • Gonadotrophin • Macrophage inhibitory factor kidney injury,57 although their mecha- releasing hormone • Transforming growth factor • Fibroblast growth factor • Interleukin 1, 3-6, 9, 10, 13, 16 nism of action is complex. • Vascular endothelial • CCL 2-5 growth factor Proteases Leukotrienes • CXCL ligand 8-11 • Nerve growth factor • Tryptase • LeukotrieneC4 Action • Chymase • LeukotrieneB4 • Pro and anti-inflammatory RAS IN MAST CELL–INDUCED • Carboxypeptidase • Platelet activating factor responses FIBROSIS • Histamine • Prostaglandin D2 • Immune regulation • Proteoglycan (heparin) • Prostaglandin E2 Action Action Current understanding of the systemic • Tissue remodeling • Bronchoconstriction RAS suggests it is rate limited by renin • Cellular recruitment • Vascular permeability • Vascular permeability • Eosinophil recuitment release from juxtaglomerular cells in re- • Acute allergic disease • Neutrophil recruitment sponse to renal baroreceptors or sodium chloride delivery to the macula densa.58 Figure 1. Mediator release and physiologic responses to mast cell degranulation. Mast cell degranulation results in the release of preformed mediators and the release of others There is growing interest in the local role that are responsible for their diverse physiologic effects. These mediators include growth of the RAS in specific tissues. factors, proteases, leukotrienes, cytokines, and chemokines. Release of these mediators The kidney provides all of the neces- facilitates the actions of mast cells ranging from enhanced vascular permeability and sary molecular components for a func- leukocyte recruitment to fibrosis and immunomodulation. tional RAS, and there is increasing evi-

J Am Soc Nephrol 19: 2254–2261, 2008 Mast Cells in Renal Disease 2255 BRIEF REVIEW www.jasn.org dence of the participation of the It has been known for some time that chemoattractants and ACE-indepen- intrarenal RAS in the pathophysiology of there are alternative pathways for con- dent generation of AngII by mast chronic renal injury.59 RAS activity pre- verting AngI to AngII that do not require cells.81 These studies collectively pro- dictably plays a profibrotic role in ACE. This has provided support for the vide evidence for mast cell–induced re- chronic renal disease. Angiotensin II argument that therapeutic combinations nal fibrosis by newly discovered path- (AngII) stimulates TGF-␤ production60 of angiotensin receptor blockers (ARB) ways leading to mast cell activation of and suppresses matrix degradation,61 fa- and ACE inhibitors are theoretically su- local RAS. voring increased extracellular matrix perior to ACE inhibitors alone in block- deposition.62 Mounting evidence sup- ing local RAS. One alternative AngII- ports the role of the local RAS through generating pathway is through the EXPERIMENTAL STUDIES AngII in regulating cell proliferation, ap- chymase. This is a major path- EXPLORING THE ROLE OF MAST optosis, and fibrosis.63,64 way for AngII generation in renal artery CELLS IN RENAL FIBROSIS There is immunohistochemical evi- clipping–induced hypertension.77 Fur- dence of increased expression of the local thermore, chymase inhibitors prevented Mast cells have been associated with fi- RAS in human proliferative glomerulo- AngII and TGF-␤ generation in a model brosis in other organs besides the kidney, nephritis65,66 and experimental evidence of cardiac failure.78 Mast cells are the ma- including skin,82 experimental models of to support a functional role in injury jor tissue source of chymase.79 lung fibrosis,83 and scleroderma.84 The 80 through AT1 receptors in anti–glomeru- Huang et al. demonstrated marked availability of mast cell–deficient and lar basement membrane (anti-GBM) upregulation of chymase in human dia- mast cell–“knock-in” (bone marrow re- disease.67 In anti–Thy-1 antibody–in- betic nephropathy where ACE was also constituted) mice confirm a role for mast duced glomerulonephritis, infusion of upregulated. Whereas no difference in cells in some forms of tissue fibrosis in AngII receptor blocker attenuates injury ACE expression was seen in normal ver- vivo. The models include homocysteine- and reduces matrix expansion and scle- sus hypertensive patients, chymase ex- induced cardiac remodeling85 and pan- rosis.68 In diabetic nephropathy, there pression was significantly higher in pa- creatic fibrosis,86 where the unexpected also is evidence of renal RAS activation, tients with hypertension, suggesting that outcomes suggest mast cells protect as gene activation of angiotensin con- chymase may be an important therapeu- against the development of fibrosis. In verting enzyme (ACE) is enhanced de- tic target in addition to ACE.80 The im- several other models, including bleomy- spite normal to low renin expression.69 portance of chymase is also confirmed by cin-induced pulmonary fibrosis,87,88 car- Blockade of the RAS reduces the rate of studies in polycystic kidney disease, bon tetrachloride–induced liver fibro- progression of renal dysfunction in both where mast cells are associated with tu- sis,89 and murine scleroderma,90 mast type 1 and type 2 diabetes.70,71 Further- bulointerstitial damage. Strong AngII- cell–deficient mice showed no reduction more, AngII induces TGF-␤ in diabetic generating capacity, as a result of chy- in fibrosis. nephropathy.72 ACE inhibition in hu- mase, was found in 13 of 14 patients with Models of renal injury producing fi- man type 2 diabetic nephropathy re- polycystic disease, and mast cells were brosis in mast cell–deficient mice have duces renal TGF-␤ gene expression.73 found to be the source of chymase.42 not been as extensively studied, but pre- The possible relevance of the close as- In streptozotocin-induced diabetes, liminary data do not show a functional sociation among interstitial fibrosis, fibrosis in mesenteric vessel is associated role for mast cells in this fibrogenesis. In mast cell accumulation, and the role of with mast cell infiltration. Mast cells puromycin aminonucleoside–induced the local renal RAS is highlighted by re- stain for chymase, TGF-␤, and tryptase. nephrosis, mast cell–deficient mice had cent studies showing that mast cells in- Administration of a mast cell stabilizer enhanced fibrosis. These KitW-sh/KitW-sh duce RAS activation. Mast cells also syn- reduces fibrosis and the number of chy- null mice surprisingly had increased lev- thesize renin.74 Renin released during mase-positive mast cells, without affect- els of mRNA encoding TGF-␤, suggest- mast cell degranulation also generates ing TGF-␤ expression, consistent with a ing an unexpected role for mast cells in AngI.75 Cardiac mast cell–derived renin role for fibrosis-induced by chymase- modulating TGF-␤ expression in this is pathologically important in models of generated AngII.31 A further link be- model. In vitro experiments showed that ischemia-induced cardiac arrhythmias.75 tween AngII and mast cells comes from a heparin inhibited the expression of Renin overflow and arrhythmias in car- rodent study of fibrosis after five-sixths mRNA encoding TGF-␤ in cultured rat diac ischemia/reperfusion injury both nephrectomy. TGF-␤ staining, chymase- fibroblasts.91 Preliminary studies in a were significantly reduced in mast cell– positive mast cells infiltrate areas of fi- murine model of ureteral obstruction deficient mice and in normal mice given brosis in association with increased ex- also suggested that mast cells protect mast cell stabilizers. In the heart, as in the pression of stem cell factor and IL-8, against fibrosis.92 Thus, data from exper- kidney, mast cell infiltration is seen in known mast cell attractants. This fibro- imental mast cell–deficient mice do not most forms of chronic injury, including sis was prevented by treatment with support the attractive hypothesis that coronary atherosclerosis and cardiomy- ACE inhibitors, suggesting a feedback mast cells play a profibrotic role in opathies.76 link between AngII-induced mast cell chronic renal disease. In fact, the data

2256 Journal of the American Society of Nephrology J Am Soc Nephrol 19: 2254–2261, 2008 www.jasn.org BRIEF REVIEW suggest that the net outcome of mast cell cruit effector T cells indirectly by their interaction supporting the development of involvement is either mitigation of fibro- cytokine activation of local vascular en- T cell responses is the likely explanation for sis or facilitation of repair. dothelia enhancing the expression of in- the injurious role of mast cells in these tercellular adhesion molecule 1 and vas- models. In some of these T cell models, cular cellular adhesion molecule, mast cell IgE-Fc␧ linking may also be nec- ROLE OF MAST CELLS IN leukocyte adherence, and transmigra- essary to prime mast cells for subsequent INFLAMMATORY AND tion.105 T cell/mast cell activation is also T cell activation and injury.120,121 Mast cell AUTOIMMUNE KIDNEY DISEASE bidirectional. T cell cytokines activate priming by IgE is necessary to facilitate T mast cells106 and enhance their prolifera- effector cell responses causing contact hy- The central role of mast cells in asthma, tion through IL-3.107 persensitivity.120 Interestingly, such prim- allergy, hypersensitivity, and anaphylac- Mast cells also have the potential to ing occurs with antigen-independent IgE. tic reactions has been extensively studied act as immunoregulators of adaptive im- A number of studies have also ana- and recently reviewed.93–95 As outlined munity because of their potential to pro- lyzed the facilitative injury of mast cells already, mast cells now feature much duce TGF-␤, IL-4 and -10, and hista- in anti-GBM nephritis. Timoshanko et broader roles in immunity and inflam- mine. There have been only limited al.122 demonstrated a role for mast cells mation. The predominant sense sur- examples of this in vivo induction of con- in inducing functional renal injury by the rounding mast cells in these settings is tact hypersensitivity by ultraviolet irradi- mechanism of infiltrating mast cells that they facilitate, among other facilitators, ation leading to mast cell histamine re- recruit DTH effector leukocytes. These the development of immune responses lease in vivo.108 Recent work on local effects were comparable to studies and inflammation at multiple levels, and transplant tolerance (mediated by local showing a role for mast cells in dermal this inflammation can be fibrogenic. graft T regulatory cells) showed a new DTH.112 Two other studies demon- There are data, albeit more limited, that role for mast cells as immune modula- strated a potential protective role for suggest that mast cells can also act as tors. Transplanted skin allografts into mast cells in this model. This was not at- modulators of inflammation. class II mismatched (KitW-sh/KitW-sh) tributable to local effects, because mast In addition to their role in host de- mast cell–deficient recipients were re- cells were not visible in renal sections. fense through activation of the innate jected but this did not happen in mast With the association of mast cells and T , mast cells confer resis- cell–reconstituted recipients. Other evi- regulatory cells already established,109 tance to endogenous and exogenous tox- dence suggests that T regulatory cells re- one study suggested that systemic mast ins and by interactions with cruit mast cells by their production of IL- cells infiltrate local lymphoid organs and adaptive immunity through IgE-Fc␧ re- 9.109 IL-9 is a cytokine that enhances activate regulatory T cells to confer pro- ceptors.96 Exaggerated IgE/mast cell re- mast cell growth and functionality.110 tection.123 Kanamaru et al.124 attributed sponses are widely known to cause ana- Mast cell–deficient mice have been the beneficial outcome of mast cell– phylactic and allergic disease.97 These used in a number of animal models of competent mice to improved repair latter responses have limited relevance to human autoimmune disease. They in- function in the kidney. In a model of au- kidney injury except for some drug-in- clude experimental allergic encephalo- toimmune immune complex disease, the duced nephropathies. myelitis,111 delayed-type hypersensitivity absence of mast cells facilitated an altered Mast cells also have close adjacencies (DTH),112 the Arthus response,113 Bul- pattern of disease but did not alter the to T cells in secondary lymphoid organs lous pemphigoid,114 experimental vascu- severity of injury.125 A recent study using and in the periphery.98 They present an- litis,115 atherosclerosis,116 antigen-in- anti-GBM nephritis in rats showed that tigens to naive T cells in an MHC-re- duced arthritis,117 anti-GPI antibody– histamine and histamine agonists can stricted manner.99,100 Mast cells stimu- induced arthritis in KBxN mice,118 and significantly attenuate renal inflamma- late the migration of antigen-presenting dermal contact hypersensitivity.119 These tion. In this Th1-driven, DTH-mediated cells to nodes through the release of IL-1, studies provide increasing evidence for a model, histamine reduced the expression -3, and -6 and TNF.101 They also influ- functional role of mast cells in disease. of the Th1-inducing cytokine IL-12.126 ence T cell differentiation: IL-4 and his- The mechanisms of facilitation by 102 tamine direct Th2 responses as well as mast cells in these models are variable ϩ modulate the differentiation of Th17 and speculative in some. In models in- CONCLUSIONS CD4 cells.103 It is in the generation of ef- duced by antibody (pemphigoid, K/BxN fector responses, however, where mast arthritis), complement anaphylatoxins There is a role for mast cells in immune cells may have the greatest impact. Mast and FcR cross-linking are likely mast cell homeostasis beyond simple allergy. Mast cells in the periphery enhance effector T activators. The resulting mast cell activa- cells participate in many inflammatory cell recruitment directly by the produc- tion enhances pathologic immunity. kidney diseases, particularly those asso- tion of chemoattractants. LTB4 from Most of the other models are dependant on ciated with fibrosis. Mast cells have very mast cells recruits CD8 cells,104 and IL-16 T cell–directed immune responses. As dis- diverse roles ranging from proinflamma- recruits CD4 cells.46 Mast cells also re- cussed, the bidirectional T cell–mast cell tory to immunomodulatory. Currently,

J Am Soc Nephrol 19: 2254–2261, 2008 Mast Cells in Renal Disease 2257 BRIEF REVIEW www.jasn.org the mechanisms determining the spe- responses of mast cell Toll-like receptors 2 26. Ravinal RC, Costa RS, Coimbra TM, Dantas cific, functional phenotype of involve- and 4 in allergy and innate immunity. J Clin M, dos Reis MA: Mast cells, TGF-beta1 and Invest 109: 1351–1359, 2002 myofibroblasts expression in lupus nephri- ment are not fully understood. Mast cells 11. Okumura S, Kashiwakura J, Tomita H, Ma- tis outcome. Lupus 14: 814–821, 2005 also have the potential to induce injury tsumoto K, Nakajima T, Saito H, Okayama 27. 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