Relative Levels of M-CSF and GM-CSF Influence the Specific Generation of Macrophage Populations during Infection withMycobacterium tuberculosis

Abstract

Members of the CSF cytokine family play important roles in macrophage recruitment and activation. However, the role of M-CSF in pulmonary infection with Mycobacterium tuberculosis is not clear. In this study, we show the lungs of mice infected with M. tuberculosis displayed a progressive decrease in M-CSF in contrast to increasing levels of GM-CSF. Restoring pulmonary M-CSF levels during infection resulted in a significant decrease in the presence of foamy macrophages and increased expression of CCR7 and MHC class II, specifically on alveolar macrophages. In response to M-CSF, alveolar macrophages also increased their T cell-stimulating capacity and expression of DEC-205. These studies show that the levels of expression of M-CSF and GM-CSF participate in the progression of macrophages into foamy cells and that these cytokines are important factors in the differentiation and regulation of expression of dendritic cell-associated markers on alveolar macrophages. In addition, these studies demonstrate that M-CSF may have a role in the adaptive immune response to infection with M. tuberculosis.

Intrapulmonary Delivery of XCL1-Targeting Small Interfering RNA in Mice Chronically Infected withMycobacterium tuberculosis

“…Therefore, workers on many other respiratory diseases will clearly be able to use the approaches described here to elucidate the role of different molecules in pathogenesis (12,14). These same approaches may be exploited as immunotherapeutic alternatives for respiratory diseases.…”

“…To demonstrate this, we describe, for the first time, the manipulation of target gene expression at a specific time during chronic pulmonary infection. Here, we have combine our recently published noninvasive local pulmonary therapy (12,14) with the recently developed technology of gene silencing mediated by siRNA (31)(32)(33)(34) to study the role of the pulmonary XCL1/lymphotactin chemokine during chronic infection with M. tuberculosis.…”

“…Mice were treated by the intrapulmonary route following a previously described protocol (14). Briefly, mice were anesthetized by intraperitoneal injection of 100 mg/kg and 10 mg/kg body weight of ketamine and xylazine, respectively.…”

Regulation network of serum cytokines induced by tuberculosis-specific antigens reveals biomarkers for tuberculosis diagnosis

“…Some of these cytokines have been previously identified in the context of TB. For example, I-309 was shown to be upregulated in DC cells after TB-specific antigen stimulation (Jang et al, 2008;Yu et al, 2012) as were CXCL9 (MIG) (Bai et al, 2011), IL-10 (Hasan et al, 2011), IL-6 (Zhang et al, 1994, IL-7, IL-8 (Nakaya et al, 1995;Fietta et al, 2002;Boggaram et al, 2013;Huang et al, 2014), and G-CSF (Higgins et al, 2008). IL-10 is ananti-inflammatory molecule that mainly plays a negative role in immune regulation (Boussiotis et al, 2000).…”

GM-CSF Is an Essential Regulator of T Cell Activation Competence in Uterine Dendritic Cells during Early Pregnancy in Mice

“…GM-CSF influences DC and macrophage recruitment into inflammatory sites, with transgenic overexpression of Csf2 in tumor cells eliciting DC recruitment in vivo (18). GM-CSF is also important for effective Ag processing and presenting function in APCs, with in vitro experiments showing that GM-CSF facilitates Ag uptake (19) and expression of MHC class II and the costimulatory molecules CD80 and CD86 (20)(21)(22), and this is linked with increased T cell activation (18,20,23,24) and T cell-dependent Ab production (25). Experiments in Csf2-null mutant mice have demonstrated that although macrophage and DC populations are essentially intact when GM-CSF is absent (26,27), this cytokine influences mature macrophage and DC function to affect the incidence and severity of some inflammatory and autoimmune diseases, including arthritis, multiple sclerosis, glomerulonephritis, and LPS-induced lung inflammation (28).…”