Nitric Oxide Is Involved in Mycobacterium bovis Bacillus Calmette-Guérin–Activated Jagged1 and Notch1 Signaling

Abstract

Pathogenic mycobacteria have evolved unique strategies to survive within the hostile environment of macrophages. Modulation of key signaling cascades by NO, generated by the host during infection, assumes critical importance in overall cell-fate decisions. We show that NO is a critical factor in Mycobacterium bovis bacillus Calmette-Guérin–mediated Notch1 activation, as the generation of activated Notch1 or expression of Notch1 target genes matrix metalloproteinase-9 (MMP-9) or Hes1 was abrogated in macrophages derived from inducible NO synthase (iNOS) knockout (iNOS−/−), but not from wild-type, mice. Interestingly, expression of the Notch1 ligand Jagged1 was compromised in M. bovis bacillus Calmette-Guérin–stimulated iNOS−/− macrophages, and loss of Jagged1 expression or Notch1 signaling could be rescued by NO donors. Signaling perturbations or genetic approaches implicated that robust expression of MMP-9 or Hes1 required synergy and cross talk between TLR2 and canonical Notch1-PI3K cascade. Further, CSL/RBP-Jk contributed to TLR2-mediated expression of MMP-9 or Hes1. Correlative evidence shows that, in a murine model for CNS tuberculosis, this mechanism operates in vivo only in brains derived from WT but not from iNOS−/− mice. Importantly, we demonstrate the activation of Notch1 signaling in vivo in granulomatous lesions in the brains of Mycobacterium tuberculosis-infected human patients with tuberculous meningitis. Current investigation identifies NO as a pathological link that modulates direct cooperation of TLR2 with Notch1-PI3K signaling or Jagged1 to regulate specific components of TLR2 responses. These findings provide new insights into mechanisms by which Notch1, TLR2, and NO signals are integrated in a cross talk that modulates a defined set of effector functions in macrophages.

The WNT Signaling Pathway Contributes to Dectin-1-Dependent Inhibition of Toll-Like Receptor-Induced Inflammatory Signature

“…Activation of host signaling pathways upon engagement of surface-or intracellular-expressed PRRs is shown to dictate the immune cell fate. Contribution of signaling pathways like Sonic Hedgehog (30), WNT (31), and NOTCH (41,42) has been deciphered during various bacterial infections as well as during derailed inflammation (43)(44)(45). Here, we found significant contribution of WNT5A during dectin-1-mediated immune responses.…”

“…Our data clearly suggest the involvement of crucial kinases, like TAK1 and Pyk2, in mediating dectin-1-induced WNT5A-Ca 2ϩ / CAMKII signaling. NF-B, a unique transcription factor, is shown to regulate numerous immune cell functions under various pathological conditions (42,48). Regulation of NF-B nuclear translocation by TAK1 has been reported in T-cell-mediated functions (49).…”

Src Homology 3-interacting Domain of Rv1917c of Mycobacterium tuberculosis Induces Selective Maturation of Human Dendritic Cells by Regulating PI3K-MAPK-NF-κB Signaling and Drives Th2 Immune Responses

“…Among the transcription factors, the active heterodimer p50/p65 forms of nuclear factor-B (NF-B) has been suggested to play a central role in immunological processes by inducing expression of a variety of genes involved in inflammatory responses (50,51,54,57,58). In this regard, Rv1917c triggered the activation of Akt as well as MAPKs, ERK1/2, and p38 MAPK (Fig.…”

Nitric oxide in cerebrospinal fluid of central nervous system tuberculosis: correlations with culture, antibody response, and cell count

“…NO is found to play a role in TBM in mouse models, but there are few studies with human subjects. The role of NO has been established in disease processes over the years (14). It is shown that NO plays a role similar to cytokines in the disease process.…”