Toll-Like Receptors, Endocrine Stress Response, and Arteriosclerosis
http://www.100md.com
动脉硬化血栓血管生物学 2005年第9期
Department of Medicine, Medical Faculty Carl Gustav Carus, University of Technology Dresden, Germany
Henning Morawietz
Division of Vascular Endothelium and Microcirculation, Department of Medicine Carl Gustav Carus, University of Technology Dresden, Germany
To the Editor:
There is increasing evidence that Toll-like receptor (TLR)-dependent signaling and cell activation is critically involved in the pathogenesis of arteriosclerosis.
The article by M. Kazemi et al impressively demonstrates that Toll-like receptor agonists induce lipid accumulation and proteins involved in atherosclerotic plaque development such as adipocyte fatty acid-binding protein (aP2) in macrophages.1 Therefore there is a molecular link between TLR and foam cell formation.
While bacterial toxins activate macrophages through Toll-like receptor -2 and -4, noninfectious stimuli such as minimally oxidized LDL also use the same signaling pathways and will trigger a TLR-4–dependent proinflammatory response in macrophages.2
TLR may, however, not only be a "central gateway to the vessel wall"3 and mediate the local process of arteriosclerotic plaque formation but may also relate to systemic pathomechanism of arterial disease. The endocrine stress response, including the release of glucocorticoids and the activation of the renin–angiotensin aldosterone system, is clearly implicated in the process of endothelial dysfunction and arteriosclerosis both through the increase in blood pressure and direct effects on the endothelial cell wall.
We have recently demonstrated an important role for TLR-2 and TLR-4 in the adrenal stress response.4,5 TLRs are expressed in adrenal cells, and TLR agonists stimulate the release of steroids from human adrenal cells.6 TLR-2–deficient mice have an impaired steroid release during endotoxemia.5
Consistent with the increased lipid accumulation and adipocyte fatty acid binding protein (aP2) expression induced by Toll-like receptor agonists described by M. Kazemi et al,1 similarly mineralocorticoids and glucocorticoids are known to enhance cholesteryl ester formation and aP2 expression.7,8 Therefore, the activation of Toll-like receptors in the pathogenesis of atherosclerosis might include an endocrine stress response as well.
Thus TLR activation through both bacterial endo- or exotoxins and other noninfectious ligands will modulate arteriosclerotic plaque development not only through local immune/inflammatory actions but also through a humoral-endocrine and systemic response.
References
Kazemi MR, McDonald CM, Shigenaga JK, Grunfeld C, Feingold KR. Adipocyte fatty acid-binding protein expression and lipid accumulation are increased during activation of murine macrophages by toll-like receptor agonists. Arterioscler Thromb Vasc Biol. 2005; 25: 1220–1224.[Abstract/Free Full Text]
Miller YI, Viriyakosol S, Worrall DS, Boullier A, Butler S, Witztum JL. Toll-like receptor 4-dependent and -independent cytokine secretion induced by minimally oxidized low-density lipoprotein in macrophages. Arterioscler Thromb Vasc Biol. 2005; 25: 1213–1219.[Abstract/Free Full Text]
Hansson GK, Edfeldt K. Toll to be paid at the gateway to the vessel wall. Arterioscler Thromb Vasc Biol. 2005; 25: 1085–1087.[Free Full Text]
Bornstein SR, Schumann RR, Rettori V, McCann SM, Zacharowski K. Toll-like receptor 2 and Toll-like receptor 4 expression in human adrenals. Horm Metab Res. 2004; 36: 470–473.[CrossRef][Medline] [Order article via Infotrieve]
Bornstein SR, Zacharowski P, Schumann RR, Barthel A, Tran N, Papewalis C, Rettori V, McCann SM, Schulze-Osthoff K, Scherbaum WA, Tarnow J, Zacharowski K. Impaired adrenal stress response in Toll-like receptor 2-deficient mice. Proc Natl Acad Sci U S A. 2004; 101: 16695–16700.[Abstract/Free Full Text]
Vakharia K, Hinson JP. Lipopolysaccharide (LPS) directly stimulates cortisol secretion by human adrenal cells by a cyclooxygenase-dependent mechanism. Endocrinology. 2005; 146: 1398–1402.[Abstract/Free Full Text]
Cheng W, Lau OD, Abumrad NA. Two antiatherogenic effects of progesterone on human macrophages; inhibition of cholesteryl ester synthesis and block of its enhancement by glucocorticoids. J Clin Endocrinol Metab. 1999; 84: 265–271.[Abstract/Free Full Text]
Penfornis P, Viengchareun S, Le Menuet D, Cluzeaud F, Zennaro MC, Lombes M. The mineralocorticoid receptor mediates aldosterone-induced differentiation of T37i cells into brown adipocytes. Am J Physiol Endocrinol Metab. 2000; 279: E386–E394.[Abstract/Free Full Text]
Response
Mahmood R. Kazemi; Carl Grunfeld; Kenneth R. Feingold
Department of Medicine, Metabolism Section, University of California, San Francisco, Department of Veterans Affairs Medical Center, San Francisco, Calif
Drs Bornstein and Morawietz report an interesting extension of our findings regarding TLR activation and expression of lipid metabolism genes in macrophages in which they describe a systemic response that promotes atherosclerosis.1 Direct activation of TLRs in the adrenal glands mediate induction of adrenocortical hormone release, which in turn may modulate foam cell formation in a manner similar to TLR ligands of microbial origin. Other systemic changes that occur during the acute phase response to infection or illness that would also promote atherosclerosis include alterations in the circulating level and composition of lipoproteins that enhance the uptake of these particles by macrophages and accelerate foam cell formation. These alterations include an increase in serum triglyceride and small dense LDL, a decrease in HDL cholesterol, and an increase in lipoprotein oxidation as well as ceramide and sphingomyelin enrichment of LDL.2 The work of Bornstein and Morawietz and others demonstrate that multiple changes in the acute phase response could contribute to the pathogenesis of atherosclerosis.
References
Kazemi MR, McDonald CM, Shigenaga JK, Grunfeld C, Feingold KR. Adipocyte fatty acid-binding protein expression and lipid accumulation are increased during activation of murine macrophages by toll-like receptor agonists. Arterioscler Thromb Vasc Biol. 2005; 25: 1220–1224.
Khovidhunkit W, Kim MS, Memon RA, Shigenaga JK, Moser AH, Feingold KR, Grunfeld C. Effects of infection and inflammation on lipid and lipoprotein metabolism: mechanisms and consequences to the host. J Lipid Res. 2004; 45: 1169–1196.(Stefan R. Bornstein)
Henning Morawietz
Division of Vascular Endothelium and Microcirculation, Department of Medicine Carl Gustav Carus, University of Technology Dresden, Germany
To the Editor:
There is increasing evidence that Toll-like receptor (TLR)-dependent signaling and cell activation is critically involved in the pathogenesis of arteriosclerosis.
The article by M. Kazemi et al impressively demonstrates that Toll-like receptor agonists induce lipid accumulation and proteins involved in atherosclerotic plaque development such as adipocyte fatty acid-binding protein (aP2) in macrophages.1 Therefore there is a molecular link between TLR and foam cell formation.
While bacterial toxins activate macrophages through Toll-like receptor -2 and -4, noninfectious stimuli such as minimally oxidized LDL also use the same signaling pathways and will trigger a TLR-4–dependent proinflammatory response in macrophages.2
TLR may, however, not only be a "central gateway to the vessel wall"3 and mediate the local process of arteriosclerotic plaque formation but may also relate to systemic pathomechanism of arterial disease. The endocrine stress response, including the release of glucocorticoids and the activation of the renin–angiotensin aldosterone system, is clearly implicated in the process of endothelial dysfunction and arteriosclerosis both through the increase in blood pressure and direct effects on the endothelial cell wall.
We have recently demonstrated an important role for TLR-2 and TLR-4 in the adrenal stress response.4,5 TLRs are expressed in adrenal cells, and TLR agonists stimulate the release of steroids from human adrenal cells.6 TLR-2–deficient mice have an impaired steroid release during endotoxemia.5
Consistent with the increased lipid accumulation and adipocyte fatty acid binding protein (aP2) expression induced by Toll-like receptor agonists described by M. Kazemi et al,1 similarly mineralocorticoids and glucocorticoids are known to enhance cholesteryl ester formation and aP2 expression.7,8 Therefore, the activation of Toll-like receptors in the pathogenesis of atherosclerosis might include an endocrine stress response as well.
Thus TLR activation through both bacterial endo- or exotoxins and other noninfectious ligands will modulate arteriosclerotic plaque development not only through local immune/inflammatory actions but also through a humoral-endocrine and systemic response.
References
Kazemi MR, McDonald CM, Shigenaga JK, Grunfeld C, Feingold KR. Adipocyte fatty acid-binding protein expression and lipid accumulation are increased during activation of murine macrophages by toll-like receptor agonists. Arterioscler Thromb Vasc Biol. 2005; 25: 1220–1224.[Abstract/Free Full Text]
Miller YI, Viriyakosol S, Worrall DS, Boullier A, Butler S, Witztum JL. Toll-like receptor 4-dependent and -independent cytokine secretion induced by minimally oxidized low-density lipoprotein in macrophages. Arterioscler Thromb Vasc Biol. 2005; 25: 1213–1219.[Abstract/Free Full Text]
Hansson GK, Edfeldt K. Toll to be paid at the gateway to the vessel wall. Arterioscler Thromb Vasc Biol. 2005; 25: 1085–1087.[Free Full Text]
Bornstein SR, Schumann RR, Rettori V, McCann SM, Zacharowski K. Toll-like receptor 2 and Toll-like receptor 4 expression in human adrenals. Horm Metab Res. 2004; 36: 470–473.[CrossRef][Medline] [Order article via Infotrieve]
Bornstein SR, Zacharowski P, Schumann RR, Barthel A, Tran N, Papewalis C, Rettori V, McCann SM, Schulze-Osthoff K, Scherbaum WA, Tarnow J, Zacharowski K. Impaired adrenal stress response in Toll-like receptor 2-deficient mice. Proc Natl Acad Sci U S A. 2004; 101: 16695–16700.[Abstract/Free Full Text]
Vakharia K, Hinson JP. Lipopolysaccharide (LPS) directly stimulates cortisol secretion by human adrenal cells by a cyclooxygenase-dependent mechanism. Endocrinology. 2005; 146: 1398–1402.[Abstract/Free Full Text]
Cheng W, Lau OD, Abumrad NA. Two antiatherogenic effects of progesterone on human macrophages; inhibition of cholesteryl ester synthesis and block of its enhancement by glucocorticoids. J Clin Endocrinol Metab. 1999; 84: 265–271.[Abstract/Free Full Text]
Penfornis P, Viengchareun S, Le Menuet D, Cluzeaud F, Zennaro MC, Lombes M. The mineralocorticoid receptor mediates aldosterone-induced differentiation of T37i cells into brown adipocytes. Am J Physiol Endocrinol Metab. 2000; 279: E386–E394.[Abstract/Free Full Text]
Response
Mahmood R. Kazemi; Carl Grunfeld; Kenneth R. Feingold
Department of Medicine, Metabolism Section, University of California, San Francisco, Department of Veterans Affairs Medical Center, San Francisco, Calif
Drs Bornstein and Morawietz report an interesting extension of our findings regarding TLR activation and expression of lipid metabolism genes in macrophages in which they describe a systemic response that promotes atherosclerosis.1 Direct activation of TLRs in the adrenal glands mediate induction of adrenocortical hormone release, which in turn may modulate foam cell formation in a manner similar to TLR ligands of microbial origin. Other systemic changes that occur during the acute phase response to infection or illness that would also promote atherosclerosis include alterations in the circulating level and composition of lipoproteins that enhance the uptake of these particles by macrophages and accelerate foam cell formation. These alterations include an increase in serum triglyceride and small dense LDL, a decrease in HDL cholesterol, and an increase in lipoprotein oxidation as well as ceramide and sphingomyelin enrichment of LDL.2 The work of Bornstein and Morawietz and others demonstrate that multiple changes in the acute phase response could contribute to the pathogenesis of atherosclerosis.
References
Kazemi MR, McDonald CM, Shigenaga JK, Grunfeld C, Feingold KR. Adipocyte fatty acid-binding protein expression and lipid accumulation are increased during activation of murine macrophages by toll-like receptor agonists. Arterioscler Thromb Vasc Biol. 2005; 25: 1220–1224.
Khovidhunkit W, Kim MS, Memon RA, Shigenaga JK, Moser AH, Feingold KR, Grunfeld C. Effects of infection and inflammation on lipid and lipoprotein metabolism: mechanisms and consequences to the host. J Lipid Res. 2004; 45: 1169–1196.(Stefan R. Bornstein)