Hydrodynamic Regulation of Monocyte Inflammatory Response to an Intracellular Pathogen

Abstract

Systemic bacterial infections elicit inflammatory response that promotes acute or chronic complications such as sepsis, arthritis or atherosclerosis. Of interest, cells in circulation experience hydrodynamic shear forces, which have been shown to be a potent regulator of cellular function in the vasculature and play an important role in maintaining tissue homeostasis. In this study, we have examined the effect of shear forces due to blood flow in modulating the inflammatory response of cells to infection. Using an in vitro model, we analyzed the effects of physiological levels of shear stress on the inflammatory response of monocytes infected with chlamydia, an intracellular pathogen which causes bronchitis and is implicated in the development of atherosclerosis. We found that chlamydial infection alters the morphology of monocytes and trigger the release of pro-inflammatory cytokines TNF-α, IL-8, IL-1β and IL-6. We also found that the exposure of chlamydia-infected monocytes to short durations of arterial shear stress significantly enhances the secretion of cytokines in a time-dependent manner and the expression of surface adhesion molecule ICAM-1. As a functional consequence, infection and shear stress increased monocyte adhesion to endothelial cells under flow and in the activation and aggregation of platelets. Overall, our study demonstrates that shear stress enhances the inflammatory response of monocytes to infection, suggesting that mechanical forces may contribute to disease pathophysiology. These results provide a novel perspective on our understanding of systemic infection and inflammation.

Shear Stress Enhances Chemokine Secretion from Chlamydia pneumoniae-infected Monocytes

“…Since chemokine upregulation was concomitant with shear exposure, it is likely that this shear-induced enhancement is mediated at the translational level or released from existing stores. Together with our previous study, 16 this work underscores the importance of the interaction between biochemical and biomechanical stimuli in determining the inflammatory response.…”

“…26,43 The cytokines from infected monocytes can activate the endothelium to recruit leukocytes from the blood. 16 The chemokine gradient triggers leukocyte migration into the plaque site, which is a critical step in inflammation. The increase in chemokine gradient due to infection and shear exposure correlates well with the increase in monocyte migration across the barrier.…”

“…We have recently shown that shear stress exacerbates the release of cytokine IL-1 β in monocytes infected with the mouse respiratory pathogen, C. muridarum , and also increases endothelial adhesion. 16 …”

Biophysical and Biochemical Outcomes of Chlamydia pneumoniae Infection Promotes Pro-atherogenic Matrix Microenvironment

“…We also observed that infected macrophages form clusters, which are densely packed cells in certain areas of the 3D collagen matrix, thus supporting the cause of higher actin polymerization, spreading, and movement of infected cells ( Figure 5C ). This clustering may also be a result of aggregation due to the upregulation/activation of adhesion receptors, including integrin, and ICAM-1 in infected cells ( Evani et al, 2011 , 2013 ). Although macrophages infected with chlamydial antigen did not show clustering at the end of 1 week; at the end of 2 weeks, they also exhibited areas with significantly high cell density (data not shown).…”

A case of interstitial pneumonia, myocarditis and severe sepsis caused byChlamydia pneumoniae

“…Although uncommon, severe sepsis caused by C. pneumoniae has previously been reported 1 . C. pneumoniae infection can alter monocyte morphology and trigger release of proinflammatory cytokines 2. Its role in the pathogenesis of atherosclerosis has been well studied; however, antibiotic treatment trials for secondary prevention of late stage coronary disease were negative 3…”