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

Abstract

Tissue Factor (TF) is a transmembrane glycoprotein that plays an essential role in hemostasis by activating coagulation. TF is also expressed by monocytes/macrophages as part of the innate immune response to infections. In the current study, we determined the role of TF expressed by myeloid cells during Mycobacterium tuberculosis (M. tb) infection by using mice lacking the TF gene in myeloid cells (TFΔ) and human monocyte derived macrophages (MDMs). We found that during M. tb infection, a deficiency of TF in myeloid cells was associated with reduced inducible nitric oxide synthase (iNOS) expression, enhanced arginase 1 (Arg1) expression, enhanced IL-10 production and reduced apoptosis in infected macrophages, which augmented M. tb growth. Our results demonstrate that a deficiency of TF in myeloid cells promotes M2 like phenotype in M .tb infected macrophages. A deficiency in TF expression by myeloid cells was also associated with reduced fibrin deposition and increased matrix metalloproteases (MMP)-2 and MMP-9 mediated inflammation in M. tb infected lungs. Our studies demonstrate that TF expressed by myeloid cells has newly recognized abilities to polarize macrophages and to regulate M. tb growth.

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“…Total RNA was extracted from lung leukocytes or lung tissue as described previously [39]. Total RNA was reverse transcribed using the Clone AMV First-Strand cDNA synthesis kit (Life Technologies).…”

A TLR9 agonist promotes IL-22-dependent pancreatic islet allograft survival in type 1 diabetic mice

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Inflammation and the coagulation system in tuberculosis: Tissue Factor leads the dance

“…In conclusion, Venkatasubramanian et al. provide evidence that TF expressed by myeloid cells contributes to protective immunity against M. tuberculosis infection. This may have implications for both vaccine and chemotherapy programs.…”

“…Histology data in TF‐deficient mice have shown increased inflammation with elevated numbers of small granulomas containing elevated numbers of IL‐10‐positive foamy M2 macrophages . Whether or not these IL‐10‐positive foamy macrophages contain M. tuberculosis bacilli and express pro‐inflammatory cytokines has not been investigated in the study of Venkatasubramania et al.…”

“…Whether or not these IL‐10‐positive foamy macrophages contain M. tuberculosis bacilli and express pro‐inflammatory cytokines has not been investigated in the study of Venkatasubramania et al. . Thus, the development of an exaggerated host inflammatory response in the presence of increased levels of IL‐10, clearly indicates that TF deficiency promotes an inappropriate (M2 type) innate response, supporting the concept that one of the major roles of the granuloma is to localize and contain not only the bacteria but also the inflammatory response to the bacteria itself.…”