Role of Tissue Factor in Mycobacterium tuberculosis-Induced Inflammation and Disease Pathogenesis

Abstract

Tuberculosis (TB) is a chronic lung infectious disease characterized by severe inflammation and lung granulomatous lesion formation. Clinical manifestations of TB include hypercoagulable states and thrombotic complications. We previously showed that Mycobacterium tuberculosis (M.tb) infection induces tissue factor (TF) expression in macrophages in vitro. TF plays a key role in coagulation and inflammation. In the present study, we investigated the role of TF in M.tb-induced inflammatory responses, mycobacterial growth in the lung and dissemination to other organs. Wild-type C57BL/6 and transgenic mice expressing human TF, either very low levels (low TF) or near to the level of wild-type (HTF), in place of murine TF were infected with M.tb via aerosol exposure. Levels of TF expression, proinflammatory cytokines and thrombin-antithrombin complexes were measured post M.tb infection and mycobacterial burden in the tissue homogenates were evaluated. Our results showed that M.tb infection did not increase the overall TF expression in lungs. However, macrophages in the granulomatous lung lesions in all M.tb-infected mice, including low TF mice, showed increased levels of TF expression. Conspicuous fibrin deposition in the granuloma was detected in wild-type and HTF mice but not in low TF mice. M.tb infection significantly increased expression levels of cytokines IFN-γ, TNF-α, IL-6 and IL-1ß in lung tissues. However, no significant differences were found in proinflammatory cytokines among the three experimental groups. Mycobacterial burden in lungs and dissemination into spleen and liver were essentially similar in all three genotypes. Our data indicate, in contrast to that observed in acute bacterial infections, that TF-mediated coagulation and/or signaling does not appear to contribute to the host-defense in experimental tuberculosis.

A Beneficial Effect of Low-Dose Aspirin in a Murine Model of Active Tuberculosis

“…The role of TF in TB is controversial. Thus, while some authors have stated that although this factor is increased, TF-mediated coagulation does not contribute to the host’s defense ( 41 ), others have suggested a protective role for TF during M. tuberculosis infection by demonstrating, in a mouse model of TB, that TF deficiency is associated with increased M. tuberculosis replication in lungs ( 42 ). LXA4 was found to be able to promote a proinflammatory and prothrombotic profile in vitro by inducing TF expression ( 43 ).…”

The coagulation system in host defense

“…A lack of myeloid cell TF resulted in less fibrin deposition and a M2 macrophage phenotype within the lung . However, when using a global TF deficient mouse (LowTF mice) this difference was not detectable which could be due a low but still sufficient TF expression in macrophages . Further, Rauch's group found that the FXa inhibitor fondaparinux increased a M2 macrophage phenotype in the mouse heart during viral myocarditis .…”

Tissue factor expression by myeloid cells contributes to protective immune response against Mycobacterium tuberculosis infection

“…However, TF in lung tissues was 100‐fold lower in the low TF mice compared to the HTF mice, whereas M. tb infected bone marrow‐derived macrophages from the low TF mice expressed ∼30% TF activity of that observed in M. tb infected bone marrow‐derived macrophages from HTF mice. These results suggest TF expression was insufficiently reduced in macrophages to impact M. tb infection . In the current study, we deleted the TF gene in myeloid cells of mice and infected them with M. tb .…”

“…Previous studies have shown that human monocyte derived macrophages (MDMs) express TF in response to M. tb exposure [10]. A recent study using low TF expressing mice in M. tb suggested that TF exerts a limited role in TB pathogenesis [11]. We posited that specific deletion of TF in myeloid cells could enhance pulmonary M. tb infection and sought to test this inference in the present study.…”