Burden of infection on Insulin Resistance, Metabolic Syndrome, Thyroid, Stress, and Inflammation

Chlamydiapneumoniae is an obligate intracellular human pathogen causing diseases such as pneumonia, bronchitis, and pharyngitis. Because of its intracellular replication, cell-mediated immune responses are needed to mediate successful defenses of the host. Because dendritic cells play a central role in linking innate immunity and Ag-specific cell-mediated immune responses we asked whether dendritic cells are activated upon contact with C. pneumoniae and whether known Toll like receptors (TLR) are involved in this process. Here we show that C. pneumoniae was taken up by bone marrow-derived murine dendritic cells. Ingested C. pneumoniae appeared to be unable to develop mature inclusion inside dendritic cells. Furthermore, upon contact with C. pneumoniae dendritic cells were potently stimulated because NF-κB was activated and translocated to the nucleus, cytokines like IL-12p40 and TNF-α were secreted, and expression of MHC class II molecules, CD40, CD80, and CD86 was up-regulated. Importantly, secretion of cytokines as well as translocation of NF-κB were dependent on the presence of TLR2 and independent from TLR4 with the exception of IL-12p40 secretion, which was attenuated in the absence of either a functional TLR2 or 4. In conclusion, we show here that recognition of the Gram-negative bacterium C. pneumoniae depends largely on TLR2 and only to a minor extent on TLR4.

Atherosclerosis is a chronic inflammatory disease modulated by both genetic and environmental factors.1–3 Disease onset is thought to be triggered by hypertension, high plasma concentrations of low-density lipoprotein (LDL) cholesterol, diabetes mellitus, or even infection.1 Endothelial injury by these factors is central to atherogenesis. Lesion susceptibility is greatest in those vascular regions with altered hemodynamics, such as the outer edges of arterial branches or curvatures. In these low-shear sites, endothelial proliferation, apoptosis, and permeability are all increased. In addition, the expression of adhesion molecules and chemokines increases, which facilitates the recruitment of monocytes, lymphocytes, and platelets from the circulation into the artery wall, resulting in the formation of an advanced, complicated lesion.2,3 With progressive subendothelial accumulation of cholesterol-engorged macrophages ("foam cells") and the accompanying formation of a fibrous cap encapsulating a necrotic core, atheromatous lesions can rupture, resulting in a thrombus that can cause myocardial infarction or stroke.1–3 Although what initiates and maintains this inflammatory state is unclear, it is intriguing that both myocardial infarction and stroke are increased during acute infections3 and numerous pathogens have been detected in human lesions. However, how pathogens contribute to atherosclerosis remains unclear.

The detection of microbial infection and the initiation of the innate immune response are mediated via germline-encoded, pattern-recognition receptors, including the Toll-like receptors (TLRs), which recognize highly conserved pathogen-associated molecular patterns.4–7 The ligation of many TLRs, including TLR2 (summarized in the Figure) and TLR4, results in the recruitment of the adaptor protein myeloid differentiation factor 88 (MyD88) followed by the subsequent activation of nuclear factor–{kappa}B (NF-{kappa}B) and the mitogen-activated protein kinases (MAPKs). This results in the production of a cascade of cytokines, chemokines, and other pro-inflammatory molecules that contribute to the inflammatory response and bacterial clearance.4–7

In addition to their crucial role in innate immunity, TLRs have recently been associated with atherosclerosis. Indeed, Edfeldt et al8 have found elevated levels of TLR1, TLR2, and TLR4 in human atherosclerotic lesions. Furthermore, a polymorphism in the human TLR4 gene that impairs its ability to signal has also been associated with reduced development of carotid atherogenesis.

Chlamydia pneumoniae Stimulates IFN-γ Synthesis through MyD88-Dependent, TLR2- and TLR4-Independent Induction of IL-18 Release1
Mihai G. Netea2,*,‡, Bart Jan Kullberg*,‡, Liesbeth E. H. Jacobs*,‡, Trees J. G. Verver-Jansen*,‡, Johanna van der Ven-Jongekrijg*,‡, Jochem M. D. Galama†,‡, Anton F. H. Stalenhoef*, Charles A. Dinarello§ and Jos W. M. Van der Meer*
Departments of * Medicine and † Medical Microbiology, University Medical Center Nijmegen, and ‡ Nijmegen University Center for Infectious Diseases, Nijmegen, The Netherlands; and § Department of Medicine, University of Colorado Health Sciences Center, Denver, CO

Abstract

Recent studies suggest that inflammation plays a central role in the pathogenesis of atherosclerosis, and IFN-γ is a prominent proinflammatory mediator in this context. However, it is unclear what stimuli are responsible for initial stimulation of IFN-γ synthesis in the vessel wall. In the present study, we demonstrate that Chlamydia pneumoniae is an important stimulus for IFN-γ synthesis, and this production depends on release of endogenous IL-18, IL-12, and IL-1, but not of TNF. The production of the proinflammatory cytokines TNF and IL-1{beta} from PBMC by sonicated C. pneumoniae was mediated through TLR2-dependent pathways. In contrast, C. pneumoniae stimulated the production of IL-18 through MyD88-dependent, TLR2-, TLR4-, and CD14-independent pathways, mediated by posttranscriptional mechanisms not involving de novo protein synthesis. In conclusion, C. pneumoniae is a potent stimulus of IFN-γ production, in addition to the proinflammatory cytokines TNF and IL-1{beta}, which may contribute to its proatherogenic effects. Most interestingly, C. pneumoniae is also a potent inducer of IL-18 production through pathways independent of TLR2 and TLR4.