Local tissue complement synthesis-fine tuning a blunt instrument

Tags: complement, local environment, complement activation, proximal tubular, complement components, complement production, synthesis, Bone marrow cells, hepatocytes, complement regulatory proteins, complement synthesis, cellular activation, systemic inflammatory response, Thomas Guy House, The complement system, chronic damage, tissue damage, tissue injury, phagocytic cells, C3, complement proteins, immune complexes
Content: Archivum Immunologiae et Therapiae Experimentalis, 2001, Ў49, Suppl. 1, S41­S46 ў ЈPL ISSN 0004-069X Review
Local Tissue Complement Synthesis ­ Fine Tuning a Blunt Instrument ¤J. E. Marsh et al.: Local Tissue Complement Synthesis ҐJAMES E. MARSH, W¦UDING ZHOU and ST§ EVEN H. SACKS* Department of Nephrology and Transplantation, Floor 5, Thomas Guy House, Guy's Hospital, King's College, London, SE1 9RT, UK Abstract. Complement is important to host defense and the regulation of inflammation. The liver is oЁverwhelmingly the major source of circulating complement. However, many other organs are capable of synthesizing some ©or all of the complement components in a regulated tissue-specific manner. There is increasing evidence that this locally generated complement is biologically active and exerts powerful effects within the local environment. We review the role of local complement synthesis within different organs and speculate on its implication for immune and metabolic functions. Key words: complement; kidney; brain; bone marrow; adipocyte; glomerulonephritis.
The complement system is pivotal in the regulation
©of inflammation and the host defense against microor-
ganisms. In addition, it also helps target specific adap-
tive Immune Responses towards pathogens. It consists
©of at least 30 structural proteins, inhibitors and enzymes
which interact in a cascade manner to generate a num-
is the main source of systemic complement, it has
become increasingly recognised that many other tissues
can synthesize different complement components28. It
is likely that most cell types are capable of producing
some or all of the complement proteins. Does this
ability represent an artefact, or does local complement
synthesis serve specific functions in different organs?
We review the evidence for the regulated local produc-
tion of complement in different tissues, and speculate
©on its biological significance.
The Liver as a Source of Local !and Systemic Complement Elegant studies of C3 allotype conversion in liver transplant recipients in the 1960s illustrated that the liver is the overwhelming source of plasma comple"ment1. Within the liver, hepatocytes are the primary cell type responsible for the synthesis of these complement #proteins29. As C3 behaves as an acute-phase protein21, the concept arose that the liver responds to an inflam"matory stimulus with increased production of complement, and that this source of complement helps to regu$late the systemic inflammatory response. It is now apparent that smaller amounts of complement proteins are also synthesized by a range of other cell types in %different organs. This locally produced complement "may, additionally allow differential regulation of inflammation and cellular activation within these tissues. &Interestingly, even within the liver, local comple-
* Correspondence to: Prof. Steven H. Sacks, Ph.D. FRCP, Department of Nephrology and Transplantation, Floor 5, Thomas Guy 'House, Guy's Hospital, King's College, London, SE1 9RT, UK, tel.: +44 20 7955 4305, fax: +44 20 7955 4303, e-mail: ([email protected]
AJ. E. Marsh et al.: Local Tissue Complement Synthesis
"ment production has a paracrine effect. Hepatocytes have receptors for C5a, and locally activated complement stimulates the acute-phase response via stimulation of hepatocytes. Ligation of the C5a receptor results in increased hepatic synthesis of 1-antitrypsin, 1-antichymotrypsin, and other complement components, and %decreased production of albumin and transferrin)4, 25. Thus, locally generated complement within the liver can augment systemic inflammatory responses in the 0early stages of host defense against microorganisms by #providing a rapid positive feedback signal to hepatocytes. 1Although hepatocytes produce the vast majority of #plasma C3, the liver is not the primary source of all the individual complement components. Hepatocytes pro%duce relatively little C7 compared with the bone marrow231. It is not clear why the liver should synthesize all ©of the terminal pathway components yet produce only small amounts of C7. In addition, the liver does not #produce any of the classical pathway C1q, nor the alternative pathway components properdin and factor 3D. Factor D is primarily synthesized by adipocytes and #probably plays an important role in the regulation of fat metabolism. Significant amounts of C3 are also produced in ©other tissues. It is hard to define exactly how much circulating C3 is derived from extrahepatic sources in health. However, quantitative analysis of C3 allotype conversion following liver transplantation demonstrated that extrahepatic C3 production accounted for 4up to 5.7% of the total circulating C3230. This extrahe#patic complement synthesis was maintained for at least ©one year. The bone marrow is potentially a major source of extrahepatic circulating C3, as it contributed 4up to 2.6% of total serum C3 immediately following bone marrow transplantation. However, even at the #peak of production, the bone marrow is clearly not responsible for all the circulating C3 derived from extra-hepatic sources. Furthermore, as the levels of bone marrow-derived complement become undetectable following successful engraftment, it is likely that other 0extra-hepatic organs contribute significantly to the circulating pool of complement. Although this spillover into the circulation remains a relatively minor contribution to the systemic pool of complement, it is likely that the concentration of locally produced complement within different tissues is much higher. Furthermore, it is interesting that following transplantation, bone marrow-derived complement is highest in the period of engraftment, a period characterized by graft-versus-host %disease and infection. This suggests that local complement synthesis is regulated by inflammatory stimuli.
5Many different cell types have subsequently been %demonstrated to synthesize some or all of the complement components. The list includes hepatocytes, lym#phocytes, monocytes, platelets, neutrophils, macro#phages, fibroblasts, endothelial cells, epithelial cells, adipocytes, glial cells, renal and synovial tissue. The #potential effects of this local production are only just beginning to be understood. We shall review the evi%dence that many different tissues are capable of producing complement in a tightly regulated manner, and that this local complement production plays a significant role in health and disease. 6Extrahepatic Complement Synthesis The brain 1As many of the complement components are large #proteins (typically 150­200 kDa), the blood-brain barrier effectively bars the passage of plasma complement in the absence of inflammation. L7EVI-S8TRAUSS and M9ALLAT22 first demonstrated that astrocytes are capable of synthesizing complement components. It has subsequently been shown that astrocytes can produce all of the classical, alternative and terminal complement com#ponents17, 18, and that these cells are the major source ©of complement within the brain. In addition, they also 0express many complement receptors and regulatory #proteins16, 34. The expression of regulators of comple"ment activation renders these cells relatively resistant to lysis by the complement they produce. In contrast, ©oligodendrocytes and neurons can directly activate % complement, and are very sensitive to complement-mediated lysis. Microglia also produce classical pathway complement components. The complement produced by these cells and astrocytes may have a role in defense against micro-organisms either by direct killing or Ёvia opsonisation. In addition, it will also activate and attract other astrocytes and microglia in the local environment. The constitutive production of complement in vitro by astrocytes is low in comparison with hepatocytes. However, synthesis can be up-regulated 50 fold by [email protected] It seems likely that, although the contribution to total plasma complement is very low, significant local concentrations of biologically active complement can be achieved. Furthermore, astrocytes themselves secrete a range of inflammatory cytokines. Thus, a mechanism exists to regulate local complement pro%duction within the central nervous system (CNS) to sites of active inflammation. The abundant expression
AJ. E. Marsh et al.: Local Tissue Complement Synthesis
©of complement regulatory proteins by astrocytes ensures that complement activation is restricted to the local environment. This provides an elegant system for augmenting local inflammation without the need for stimulating systemic complement production. Local complement production can be viewed as an initial %defence mechanism, allowing rapid, localized inflammation confined to the precise site of invasion by pathogens. It is only when a pathogen escapes this control "mechanism that a systemic inflammatory response is necessary. Astrocytes are resistant to the lytic effects of complement and, as they express receptors for C3a and BC5a18, 27, it is likely that non-lethal complement attack is itself an important trigger for cellular activation in an autocrine manner. BComplement activation has been demonstrated in many pathological conditions of the brain, including multiple sclerosis43, Alzheimer's disease13, stroke and traumatic brain injury)42. Although some of these con%ditions are inflammatory, others are degenerative, im#plying that local complement synthesis occurs within the brain and has a role in the pathogenesis of some B CNS diseases. This illustrates the dual nature of com#plement: protecting against invading pathogens yet being potentially harmful. BComplement undoubtedly has a role in the pathogenesis of many CNS disorders, but it has been difficult to dissect out the relative importance of locally and systemically generated complement. Recently, the biological significance of local complement synthesis in the brain has been illustrated by an elegant study by DAVOUST et al10. Transgenic mice with astrocyte-specific expression of the soluble complement inhibitor sCrry were generated. Crry effectively blocks activation of both the classical and alternative pathways. These mice have no detectable sCrry in their serum, but Chigh secretion from astrocytes. This effectively limits local complement activation within the CNS, but not systemically. In a murine model of multiple sclerosis (allergic encephalomyelitis), these mice develop significantly delayed clinical signs of disease and reduced #pathological signs of inflammation, demyelination and complement deposition. It will be interesting to see if these observations can be extended to other inflammatory or degenerative central nervous system diseases. Bone marrow cells DVarious bone marrow-derived cells can produce complement, including neutrophils2, lymphocytes, "macrophages and monocytes47. Monocytes and tissue % macrophages produce most of this bone marrow-derived
complement. As bone marrow-derived cells infiltrate most tissues during inflammation, these cells can effectively take complement synthesis and activation to the site of injury, amplifying local inflammation without #producing systemic effects. It is not clear how much the bone marrow contributes to circulating complement leЁvels. Immediately following bone marrow transplantation, the amount of donor-derived complement in the circulation can be as high as 2.6%, but this rapidly %declines230. FISCHER et al.15 have demonstrated that this local source of complement synthesis can have important Efunctional consequences. Complement plays an important role in stimulating antibody responses at threshold %doses of antigen11. C3­/­ mice have impaired antibody responses to T dependent antigens. When reconstituted with bone marrow from C3-sufficient littermates, these mice appear to have a normal antibody response, suggesting that complement produced by bone marrow-derived cells within lymphatic sites is sufficient to compensate for a near absence of circulating comple"ment. Interestingly, following inoculation with antigen, macrophages within the splenic white pulp areas dem©onstrated dramatic up-regulation of C3 synthesis. This BC3 synthesis was dependent on immunization, as C3 mRNA could not be detected in nonimmunized mice. FThus, not only is locally synthesized complement functionally active, but there is also tight regulation of its #production. It is likely that local cytokine production within the germinal centres stimulates macrophage complement synthesis. It is conceivable that many other immunomodulatory and cell-activation effects of com#plement are mediated primarily through local rather than systemic complement production. G Adipocytes The curious link between mesangiocapillary glomerulonephritis and partial lipodystrophy (PLD) provided the stimulus for observing local complement synthesis
by adipocytes. These cells are the primary source of factor D .235 In addition, they have the ability to produce all of the complement components of the alternative H #pathway5. In PLD, subcutaneous fat is permanently lost Efrom the face and upper body. These patients often have dysregulated activation of the alternative pathway associated with the presence of nephritic factor (an IgG autoantibody that stabilizes the alternative pathway C3 convertase). Uncontrolled activation of locally pro%duced C3 results in adipocyte killing24. FThe alternative pathway is spontaneously activated ©on and around adipocytes generating C3a. C3a has po-
AJ. E. Marsh et al.: Local Tissue Complement Synthesis
tent activity as an acylation-stimulating protein, promoting esterification of fatty acids into triglyceride. BC3a increases the membrane transport of glucose into adipocytes and increases the activity of diacylglycerol acyltransferase, markedly increasing the rate of triglyceride synthesisI7. Factor D expression is increased in Efasting or catabolic statesP6 and decreased in various models of obesity233. It seems likely that complement has an unexpected but important role in fat metabolism. FThe adipocyte may regulate its capacity to activate the alternative pathway according to the need for triglyceride storage or release. further study of other tissues may reveal unforeseen actions of local complement synthesis other than the well-described systemic Efunctions. The kidney 5Many cells within the kidney are capable of producing complement, including glomerular mesangial236, epithelial237 and endothelial cells41. However, the predominant source of complement synthesis within the kidney are tubular epithelial cells23. Complement synthesis within the kidney can be up-regulated by inflammatory cytokines such as IL-119, TNF-20, 41, IL-223 and [email protected])49, whilst TGF- reduces expression of C3 and C420. A1 striking observation is that IL-1 and endotoxin administered in vivo to mice increased gene expression of complement within the kidney, but not within the liver14. In addition, various inflammatory conditions stimulate differential complement synthesis within different regions of the kidney46. Thus, the kidney, like "many other organs, has its own specific sites of com#plement synthesis, and evidence exists of site-specific regulation, allowing the kidney to adapt its immune response to different stimuli. QFurthermore, this locally derived C3 can make a substantial contribution to circulating complement45. &It is likely that local tissue concentrations of complement are higher than within other extrahepatic sites. This raises the question of whether local generation of BC3 augments any specific function of the kidney. Two #particular pathological processes merit consideration. ROne is the susceptibility to immune-complex injury observed in complement-deficient states. The second is chronic tissue injury consequent to many renal diseases, but especially following transplantation. The kidney, with its high blood flow and filtration Efunction, is often the major organ affected in systemic complement deficiency. Immune-complex nephritis is common in patients with complement deficiency23. It is #possible, therefore, that local synthesis of complement
Chas a modifying effect on either the stability of immune
complexes reaching the kidney or on their clearance by
#phagocytic cells, such as mesangial cells. Indeed, the
0expression of local complement is increased in ex-
#perimental and clinical forms of immune-mediated ne-
#phritis. Although many animal models of glomerulone-
#phritis are complement dependent8, 38, 39, it is likely that
complement has a different effect in florid acute tissue
injury and either more insidious injury or the more
chronic phase of subsequent tubulointerstitial damage.
Far from increasing inflammatory injury, local secre-
tion of C3 could produce a damping effect, enhancing
the clearance of locally formed or deposited immune
complexes. Support for this comes from the finding that
C3 B
"mune complexes across the glomerular basement mem-
brane when exposed to locally formed complexes be-
tween planted bovine gamma globulin and
autoantibodies)40. Experiments are currently underway
to try to differentiate the local and systemic effects of
complement in models of glomerulonephritis.
&In renal transplantation, by far the greatest site of
complement gene expression is the renal tubule. During
rejection episodes, the contribution of the kidney to
circulating C3 increases up to 16%, compared with
4.5% in the uninjured kidney45. Stimulated tubular epi-
thelial cells secrete complement mainly in a basolateral
%direction)44. Fibroblasts12 (which predominate in the in-
terstitial tissue) as well as proximal tubular epithelial
cellsS9 are vulnerable to complement attack. It is
#possible that hypersecretion of C3 could enhance the
inflammatory or destructive effects of complement.
5Moreover, since complement gene expression seems to
be a function of time, in experiMental models of renal
injury, increasing in parallel with the development of
%disease232, 48, continued overproduction of complement
could contribute to chronic damage. We have recently
transplanted mouse kidneys between complement-defi-
cient and -sufficient animals to assess the contribution
©of local synthesis of C3 to chronic damage. Preliminary
results are extremely encouraging and indicate an im-
#portant effect on graft fibrosis and tubular damage
(PTRATT personal communication).
Conclusions Plasma complement is important to host defense and immune-complex handling, but many extrahepatic tissues are capable of producing some or all of the com#plement components. Although the total contribution of local synthesis to circulating complement levels is rela-
AJ. E. Marsh et al.: Local Tissue Complement Synthesis
tively minor, there is increasing evidence that local tissue synthesis exerts powerful effects, finely tuned to the demands of the local environment. Some sites of the body are excluded from systemic complement, necessitating local complement production for host %defence. At other sites, local production may provide rapid, but geographically limited inflammation and cellular activation at sites of tissue damage. Furthermore, it may regulate cellular metabolism and activation in a tissue-specific manner. Thus, complement activation is not just a blunt first line of defense against pathogens. As yet, although extrahepatic complement synthesis has been demonstrated in many different pathological models, its true significance is poorly understood. &It is likely that more subtle effects of complement activation will be recognized in different tissues. Further characterization of the biology of complement within different ©organs may provide a spur for the development of thera#peutic tissue-targeted complement inhibition. UReferences 1. ALV PER C. A., JWOHNSON A. M., BIX RTCH A. G. and MWOORE F. D. (1969): Human C3: evidence for the liver as the primary site of synthesis. Science, Y163, 286­288. 2. BWOTTO M., LISSANDRINI D., SWORIO C. and WALPORT M. J. (1992): Biosynthesis and secretion of complement component (C3) by activated human polymorphonuclear leukocytes. J. Immunol., 149, 1348­1355. ў 3. BROOIMANS R. A., STEGMANN A. P., `VAN DWORP W. T., `van der ARK A. A., `VAN DER WWOUDE F. J., `VAN ESa L. A. and DAHA M. R. (1991): Interleukin 2 mediates stimulation of complement C3 biosynthesis in human proximal tubular epithelial b cells. J. Clin. Invest., 88, 379­384. 4. BcUCHNER R. R., HcUGLI T. E., EMBER J. A. and MWORGAN E. L. (1995): Expression of functional receptors for human C5a anaphylatoxin (CD88) on the human hepatocellular carcinoma cell line HepG2. Stimulation of acute-phase protein-specific mRNA and Protein Synthesis by human C5a anaphylatoxin. J. Immunol., 155, 308­315. 5. CHOY L. N., RWOSEN B. S. and SPIEGELMAN B. M. (1992): Adipsin and an endogenous pathway of complement from adipose cells. J. Biol. Chem., 267, 12736­12741. 6. CIANFLONE K., KALANT D., MARLISS E. B., GWOUGEON R. and SdNIDERMAN A. D. (1995): Response of plasma ASP to a prolonged fast. Int. J. Obes. Relat. Metab. Disord., 19, 604­609. 7. CIANFLONE K., RWONCARI D. A., MASLOWSKA M., BALDO A., FWORDEN J. and SdNIDERMAN A. D. (1994): Adipsin/acylation stimulating protein system in human adipocytes: regulation of triacylglycerol synthesis. Biochemistry, 33,ў 9489­9495. 8. CWOUSER W. G. and ABRASS C. K. (1988): Pathogenesis of membranous nephropathy. Ann. Rev. Med., 39ў, 517­530. 9. DeAVID S., BIX ANCONE L., CeASERTA C., BcUSSOLATI B., CeAMBI V. and CAMUSSI G. (1997): Alternative pathway complement activation induces proinflammatory activity in human proximal tubular epithelial cells. Nephrol. Dial. Transplant., 12ў, 51­56.
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