Mycobacterium tuberculosis (Mtb) kills 1.7 million people annually. The Th1 paradigm does
not explain TB-driven cavitation. Current treatment is lengthy with many adverse effects. The
IL-23/Th17 axis plays a critical role in early Mtb containment. Respiratory stromal cells are
important first-line defence and secrete MMPs. Regulation of Matrix metalloproteinases
(MMPs), which are substrate-specific proteases causing extracellular matrix (ECM)
degradation/ remodelling, was investigated in the context of TB.
Human bronchoalveolar lavage (BAL) samples from 35 well-characterised TB and control
patients were analysed for MMPs and Th17 cytokines. TB/Control lung biopsies were stained
for MMPs/IL-17. Primary normal human bronchial epithelial cells (NHBEs) and MRC-5
fibroblasts were stimulated with IL-17/IL-22/IL-23, alone and in combination with
conditioned medium from Mtb-infected monocytes (CoMTb). Secretion, gene expression,
gene silencing and intracellular signalling were investigated by luminex, ELISA,
zymography, dual-luciferase promoter-reporter, real time RT-PCR and siRNA transfection.
MMPs were up-regulated in Human TB BALs (p<0.0001). This positively correlated with
cavitation score on CXRs. IL-17 and MMP-3 were co-expressed in pneumocytes around
granulomas in TB lung biopsies.
CoMTb (but not direct infection) up-regulated secretion and gene expression of MMP-1
(collagenase, p<0.0001), MMP-3 (stromelysin, p<0.001) and MMP-9 (gelatinase, p<0.0001)
from NHBEs. MMP-3 protein and promoter activity in MRC-5 fibroblasts was also increased
by CoMTb. AKT inhibition suppressed all MMPs (p<0.01) whereas siRNA and chemical
inhibition of the proximal PI3Kp110α subunit abrogated MMP-3 only (p<0.001). Distally,
p70S6K(mTOR) blockade with rapamycin abrogated TB-driven MMP-1 and MMP-3
(p<0.001). MMP-9 regulation was more complex.
IL-17 independently and also synergistically with CoMTb, augmented MMP-3 secretion/
gene expression from NHBEs and MRC-5 fibroblasts in a concentration-dependent manner
(peak 8ng/ml, p<0.0001). This was p38-dependent, confirmed by p38-specific siRNA. In
contrast, IL-17 down-regulated CoMTb-driven MMP-9 to baseline (p<0.01). Interleukin-22
augmented MMP-3 from fibroblasts in a TB network, but not from NHBEs. IL-23 did not
drive MMPs.
MMP-1, MMP-3 and MMP-9 production was also affected by anti-mycobacterial agents in a
TB network.
In summary, MMPs are key mediators of tissue damage in human pulmonary TB and are
regulated in a cell- and stimulus-specific manner. IL-17 and IL-22 drive MMP-3 from human
airway stromal cells. The PI3Kinase/p110α/p70S6K is a crucial target and its immunomodulation
(e.g. with rapamycin) has potential as adjunctive therapy to limit tissue
destruction and shorten chemotherapy in TB.