Journal
AUTOPHAGY
Volume 11, Issue 9, Pages 1688-1699Publisher
TAYLOR & FRANCIS INC
DOI: 10.1080/15548627.2015.1075110
Keywords
antimicrobial peptides; cathelicidin; innate immunity; P2RX7; tuberculosis; vitamin D
Categories
Funding
- Swedish Foundation for Strategic Research (SSF) [RBd08-0014]
- Swedish Heart-Lung Foundation [2013-0366]
- Karolinska Institutet (KID)
- Swedish Research Council [K2014-67X-11217-20-3, 2011-3455, 2013-2709]
- Stockholm County Council (ALF) [2013-0317]
- Swedish International Development Cooperation Agency (Sida) [384, SWE-2008-065]
- Swedish Civil Contingencies Agency (MSB) [Sida-MSB 2010-7938]
- Icelandic Centre for Research (RANNIS)
- Wenner-Gren Foundation
- Swedish Foundation for Strategic Research (SSF) [RBd08-0014] Funding Source: Swedish Foundation for Strategic Research (SSF)
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LL-37 is a human antimicrobial peptide (AMP) of the cathelicidin family with multiple activities including a mediator of vitamin D-induced autophagy in human macrophages, resulting in intracellular killing of Mycobacterium tuberculosis (Mtb). In a previous trial in healthy volunteers, we have shown that LL-37 expression and subsequent Mtb-killing can be further enhanced by 4-phenylbutyrate (PBA), also an inducer of LL-37 expression. Here, we explore a potential mechanism(s) behind PBA and LL-37-induced autophagy and intracellular killing of Mtb. Mtb infection of macrophages downregulated the expression of both the CAMP transcript and LL-37 peptide as well as certain autophagy-related genes (BECN1 and ATG5) at both the mRNA and protein levels. In addition, activation of LC3-II in primary macrophages and THP-1 cells was not detected. PBA and the active form of vitamin D-3 (1,25[OH](2)D-3), separately or particularly in combination, were able to overcome Mtb-induced suppression of LL-37 expression. Notably, reactivation of autophagy occurred by stimulation of macrophages with PBA and promoted colocalization of LL-37 and LC3-II in autophagosomes. Importantly, PBA treatment failed to induce autophagy in Mtb-infected THP-1 cells, when the expression of LL-37 was silenced. However, PBA-induced autophagy was restored when the LL-37 knockdown cells were supplemented with synthetic LL-37. Interestingly, we have found that LL-37-induced autophagy was mediated via P2RX7 receptor followed by enhanced cytosolic free Ca2+, and activation of AMPK and PtdIns3K pathways. Altogether, these results suggest a novel activity for PBA as an inducer of autophagy, which is LL-37-dependent and promotes intracellular killing of Mtb in human macrophages.
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