Macrophage-mediated inflammatory response decreases mycobacterial survival in mouse MSCs by augmenting NO production

Abstract

Mycobacterium tuberculosis (MTB) is a hard-to-eradicate intracellular microbe, which escapes host immune attack during latent infection. Recent studies reveal that mesenchymal stem cells (MSCs) provide a protective niche for MTB to maintain latency. However, the regulation of mycobacterial residency in MSCs in the infectious microenvironment remains largely unknown. Here, we found that macrophage-mediated inflammatory response during MTB infection facilitated the clearance of bacilli residing in mouse MSCs. Higher inducible nitric oxide synthase (iNOS) expression and nitric oxide (NO) production were observed in mouse MSCs under macrophage-mediated inflammatory circumstance. Blocking NO production in MSCs increased the survival of intracellular mycobacteria, indicating NO-mediated antimycobacterial activity. Moreover, both nuclear factor κB (NF-κB) and Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathways were involved in iNOS expression and NO production in inflammatory microenvironment. Furthermore, pro-inflammatory cytokine interleukin-1β could trigger NO production in MSCs and exert anti-mycobacterial activity via NF-κB signaling pathway. Neutralization of interleukin-1β in macrophage-mediated inflammatory microenvironment dampened the ability of mouse MSCs to produce NO. Together, our findings demonstrated that macrophage-mediated inflammatory response during mycobacterial infection promotes the clearance of bacilli in mouse MSCs by increasing NO production, which may provide a better understanding of latent MTB infection.

Anatomic and Cellular Niches for Mycobacterium tuberculosis in Latent Tuberculosis Infection

“…Moreover, CD271 + bone marrow mesenchymal stem cells harboring MTB are localized in the hypoxic niche in both mice and humans, a critical microenvironmental factor that is known to induce dormancy [74]. The ability of mesenchymal stem cells to maintain MTB depends on the inflammatory milieu: Yang et al [75] reported that murine macrophages produced cytokines during mycobacterial infection that promoted clearance of MTB from mesenchymal stem cells by increasing production of nitric oxide in an IL-1β-dependent manner.…”

HMGN2 regulates non‐tuberculous mycobacteria survival via modulation of M1 macrophage polarization

“…It has been well noted that macrophages are the host primary cells, macrophage can destroy mycobacteria or be a reservoir for intracellular non‐tuberculous mycobacteria replication . In general, to fight against non‐tuberculous mycobacteria infection, macrophage can initiate innate immunity though recognition of pathogen‐associated molecular patterns (PAMP) by pattern‐recognition receptors (PRRs), such as activation of phagocytic pathway, production of nitric oxide (NO) and antibacterial peptide, release of pro‐inflammatory cytokines and chemokines, which was conceptually introduced as classical activation of macrophage, also termed as M1 polarization . Following the acute inflammatory burst, however, macrophages can remove cell debris and apoptotic inflammatory cells by so‐called efferocytosis and polarize into alternatively activated, M2 macrophages …”

Mycobacterium tuberculosis-Infected Hematopoietic Stem and Progenitor Cells Unable to Express Inducible Nitric Oxide Synthase Propagate Tuberculosis in Mice

“…NOS2 is not expressed in resting cells [ 13 ] and thus NOS2 is not active in HSCs. NOS2 is induced by inflammatory cytokines in MSCs and controls growth of intracellular M. tuberculosis in vitro [ 14 ] and, similarly, could also be induced in more mature hematopoietic progenitors to kill intracellular M. tuberculosis , as they develop from HSC. Thus, wild-type bone marrow would retain M. tuberculosis only in the resting LT-HSC, as we have seen previously in M. tuberculosis -infected wild-type bone marrow cells [ 5 ].…”