Abstract
The incidence of nontuberculous mycobacteria lung disease (NTM-LD) is increasing in patients without human immunodeficiency virus. Mycobacterium avium complex (MAC) is one of the most common pathogenic species. The presence of MAC has a clinical relevance of around 35~42%, indicating the possibility of host susceptibility. Previous studies have shown that interleukin (IL)-1β and IL-1-receptor knock-out mice are susceptible to mycobacterial infections; however, the role of inflammasome-driven interleukin (IL)-1β has not been studied in MAC-LD. We enrolled patients with MAC-LD and healthy controls. Peripheral blood mononuclear cells (PBMCs), monocytes, and monocyte-derived macrophages were stimulated by MAC bacilli. The responses of interleukin(IL)-1β and the expression of inflammasome and toll-like receptors (TLRs) were measured. Single nucleotide polymorphisms (SNPs) were also examined for NLRP3 and TLR2 genes. In the patients with MAC-LD, the IL-1β responses decreased in PBMCs, monocytes, and macrophages assayed by MAC bacilli in comparison to the healthy controls. In addition, the level of caspase-1 after stimulation was lower in the MAC-LD group, although the mRNA level of IL-1β was not significantly lower. In surveying the activation of IL-1β, the MAC-LD group had an attenuated mRNA level of NLRP3 but similar levels of AIM2 and ASC compared with the controls. The SNPs rs3806268 and rs34298354 in NLRP3 for females and rs3804100 in TLR2 for males were associated with MAC-LD. In conclusion, our patients with MAC-LD had attenuated IL-1β production, which may have been due to lower activation of the NLRP3-caspase-1 axis. Two SNPs of NLRP3 and one of TLR2 were correlated with MAC-LD, possibly indicating host susceptibility.
Highlights
Lung disease (LD) due to nontuberculous mycobacteria (NTM) has become an important clinical concern[1] because the incidence and prevalence of nontuberculous mycobacteria lung disease (NTM-LD) has increased over the last 10 years in patients without human immunodeficiency virus[2,3]
They did not have underlying disease of malignancy or cirrhosis, and of the MACLD patients, 75% (n = 15) had the nodular-bronchiectasis pattern and 20%, the fibro-cavitary pattern. These results suggested that in contrast to healthy controls, a defective inflammasome platform exists in the Peripheral blood mononuclear cells (PBMCs) of patients with Mycobacterium avium complex (MAC)-LD
We found that MAC stimulation caused IL-1β synthesis in CD14+ monocytes in both populations, but a lower IL-1β signal in the patients with MAC-LD than in the healthy controls (14.09% vs 2.23%, MOI = 100) (Fig. 1B, upper panel)
Summary
Lung disease (LD) due to nontuberculous mycobacteria (NTM) has become an important clinical concern[1] because the incidence and prevalence of NTM-LD has increased over the last 10 years in patients without human immunodeficiency virus[2,3]. Www.nature.com/scientificreports associated with NTM-LD in the USA and South East Asia[2]. The reasons for this increase are not clear; it could be related to the increase in patients with acquired compromised immunity and advances in mycobacterial culture techniques[4,5,6,7]. Because MAC exists ubiquitously in the environment, the relevance of sputum growing NTM (the number of patients with true disease over the number of isolated patients) is around 35–42%8,9. This indicates host vulnerability; the mechanism for it is unknown. We conducted this study to investigate the role of the NLRP3 inflammasome-driven IL1β axis in MAC-LD
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