Limits...
Mycobacterium tuberculosis -triggered Hippo pathway orchestrates CXCL1/2 expression to modulate host immune responses

View Article: PubMed Central - PubMed

ABSTRACT

Mycobacterium tuberculosis (Mtb) pathogenesis encompasses a plethora of finely regulated alterations within the host which eventually coin the outcome of infection. Chemokines are important components in directing immune cell recruitment to the site of infection, and shaping the disease progression. Here, we demonstrate that Hippo (mammalian sterile 20–like 1 and 2 kinases, MST1/2, in mammals), is activated during mycobacterial infection in a toll-like receptor (TLR) 2-interleukin receptor-1 associated kinases (IRAK1/4)-dependent manner. Mtb-triggered Hippo signaling modulates the expression and secretion of chemokines (CXCL1 and CXCL2); as silencing MST1/2 compromised the ability of Mtb to furnish the same. Further insight into the mechanism of Hippo-mediated regulation of chemokines revealed the role for a non-canonical Hippo effector interferon (IFN) regulatory factor (IRF) 3 in the process and marked the effect to be independent of LATS1. Alongside their ability to guide directed recruitment of immune cells, we have uncovered a paracrine role for Hippo-mediated secretion of CXCL1 and CXCL2 in the production of anti-microbial peptides (beta-defensins), iNOS, NOX2 and pro-inflammatory molecules during mycobacterial infection of the host. This study highlights the involvement of TLR2-IRAK1/4-MST1/2-IRF3 axis in Mtb-triggered modulation of chemokines and identifies Hippo signaling as a novel regulator of host-mycobacterial interactions.

No MeSH data available.


Related in: MedlinePlus

Mtb activated IRF3 drives MST1/2-regulated production of CXCL1 and CXCL2.(a–d) RAW264.7 macrophages were transfected with IRF3 DN construct followed by infection with Mtb H37Ra for 12 and expression of Cxcl1 (a) or Cxcl2 (b) at mRNA level and secretion of CXCL1 (c) and CXCL2 (d) in supernatant was analyzed by qRT-PCR and ELISA respectively. All the data represent means ± SE (N = 3), *p < 0.05, **p < 0.005, ***p < 0.0001 (One way Anova). Med, medium; pg, picogram; DN, dominant negative.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC5121601&req=5

f7: Mtb activated IRF3 drives MST1/2-regulated production of CXCL1 and CXCL2.(a–d) RAW264.7 macrophages were transfected with IRF3 DN construct followed by infection with Mtb H37Ra for 12 and expression of Cxcl1 (a) or Cxcl2 (b) at mRNA level and secretion of CXCL1 (c) and CXCL2 (d) in supernatant was analyzed by qRT-PCR and ELISA respectively. All the data represent means ± SE (N = 3), *p < 0.05, **p < 0.005, ***p < 0.0001 (One way Anova). Med, medium; pg, picogram; DN, dominant negative.

Mentions: With the premise that IRF3 regulates the expression of several chemokines during infection with viruses and certain bacteria5051 led us to explore the role of IRF3 in mycobacteria-induced production of chemokines. To this end, dominant negative form of IRF3 (lacking DNA binding domain) was over expressed in macrophages, followed by infection with mycobacteria (Fig. 7a–d); which rendered Mtb sufficiently incapable of inducing the expression of the concerned chemokines. These results explicitly bespeak the role for MST1/2-regulated IRF3 in the production of CXCL1 and CXCL2 during mycobacterial pathogenesis.


Mycobacterium tuberculosis -triggered Hippo pathway orchestrates CXCL1/2 expression to modulate host immune responses
Mtb activated IRF3 drives MST1/2-regulated production of CXCL1 and CXCL2.(a–d) RAW264.7 macrophages were transfected with IRF3 DN construct followed by infection with Mtb H37Ra for 12 and expression of Cxcl1 (a) or Cxcl2 (b) at mRNA level and secretion of CXCL1 (c) and CXCL2 (d) in supernatant was analyzed by qRT-PCR and ELISA respectively. All the data represent means ± SE (N = 3), *p < 0.05, **p < 0.005, ***p < 0.0001 (One way Anova). Med, medium; pg, picogram; DN, dominant negative.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5121601&req=5

f7: Mtb activated IRF3 drives MST1/2-regulated production of CXCL1 and CXCL2.(a–d) RAW264.7 macrophages were transfected with IRF3 DN construct followed by infection with Mtb H37Ra for 12 and expression of Cxcl1 (a) or Cxcl2 (b) at mRNA level and secretion of CXCL1 (c) and CXCL2 (d) in supernatant was analyzed by qRT-PCR and ELISA respectively. All the data represent means ± SE (N = 3), *p < 0.05, **p < 0.005, ***p < 0.0001 (One way Anova). Med, medium; pg, picogram; DN, dominant negative.
Mentions: With the premise that IRF3 regulates the expression of several chemokines during infection with viruses and certain bacteria5051 led us to explore the role of IRF3 in mycobacteria-induced production of chemokines. To this end, dominant negative form of IRF3 (lacking DNA binding domain) was over expressed in macrophages, followed by infection with mycobacteria (Fig. 7a–d); which rendered Mtb sufficiently incapable of inducing the expression of the concerned chemokines. These results explicitly bespeak the role for MST1/2-regulated IRF3 in the production of CXCL1 and CXCL2 during mycobacterial pathogenesis.

View Article: PubMed Central - PubMed

ABSTRACT

Mycobacterium tuberculosis (Mtb) pathogenesis encompasses a plethora of finely regulated alterations within the host which eventually coin the outcome of infection. Chemokines are important components in directing immune cell recruitment to the site of infection, and shaping the disease progression. Here, we demonstrate that Hippo (mammalian sterile 20&ndash;like 1 and 2 kinases, MST1/2, in mammals), is activated during mycobacterial infection in a toll-like receptor (TLR) 2-interleukin receptor-1 associated kinases (IRAK1/4)-dependent manner. Mtb-triggered Hippo signaling modulates the expression and secretion of chemokines (CXCL1 and CXCL2); as silencing MST1/2 compromised the ability of Mtb to furnish the same. Further insight into the mechanism of Hippo-mediated regulation of chemokines revealed the role for a non-canonical Hippo effector interferon (IFN) regulatory factor (IRF) 3 in the process and marked the effect to be independent of LATS1. Alongside their ability to guide directed recruitment of immune cells, we have uncovered a paracrine role for Hippo-mediated secretion of CXCL1 and CXCL2 in the production of anti-microbial peptides (beta-defensins), iNOS, NOX2 and pro-inflammatory molecules during mycobacterial infection of the host. This study highlights the involvement of TLR2-IRAK1/4-MST1/2-IRF3 axis in Mtb-triggered modulation of chemokines and identifies Hippo signaling as a novel regulator of host-mycobacterial interactions.

No MeSH data available.


Related in: MedlinePlus