published: 13 March 2013
Can microRNAs keep inflammasomes in check?
Omar Qazi, Prasanna T. Parthasarathy, Richard Lockey and Narasaiah Kolliputi*
Department of Internal Medicine, Division of Allergy and Immunology, Morsani College of Medicine, University of South Florida, Tampa, FL, USA
Ashok Sharma, Georgia Health Sciences University, USA
A commentary on
NLRP3 inflammasome activity is nega-
tively controlled by miR-223
by Bauernfeind, F., Rieger, A., Schildberg,
F. A., Knolle, P. A., Schmid-Burgk, J. L.,
and Hornung, V. (2012). J. Immunol. 189,
Inflammasomes are multi-protein sig-
naling platforms that are primed upon
patterns (PAMPs) as well as endogenous
a complex forms between the inflamma-
some sensor, an adaptor protein with
a caspase recruiter domain (ASC), and
caspase-1, which leads to the cleavage of
pro-inflammatory cytokines Interleukin-
1beta and Interleukin-18 (IL-1B, IL-18). A
specific inflammasome sensor, nucleoside-
triphosphatase domain (NACHT), leucine
rich repeat (LRR), and pyrin domain
(PYD) domains-containing protein
(NLRP3) has garnered the attention of
many secondary to its ability to func-
tion as a general sensor of cell stress,
possessing a large number of endoge-
nous and exogenous activators compared
to other inflammasome sensors such as
Interferon-inducible protein (AIM2) and
NLR family CARD domain-containing
protein 4 (NLRC4). This pathway has also
been implicated in numerous diseases like
gout, alzheimers, obesity, and diabetes
(Heneka et al., 2013; Wei et al., 2013).
Given the prevalent evidence that this
pathway is involved in many medical con-
ditions, current and further studies about
inflammasome regulation could poten-
tially allow pharmaceutical researchers to
develop drugs for currently incurable dis-
eases. TheNLRP3inflammasome complex
can be regulated in three main ways; the
degree of which the inflammasome com-
plex is expressed, the amount of NLRP3
modulation via microRNAs (miRNA).
miRNAs are defined as a class of non-
coding oligonucleotides which function
in post-transcriptional regulation of gene
expression (Bartel, 2009; Tamarapu et al.,
2012). A particular miRNAmay havemul-
tiple targets, and a given mRNA may have
several miRNAs that may exhibit regula-
tory function on itself (Krek et al., 2005;
Jalali et al., 2012). These oligonucleotide
sequences have become a hot area of
research as they are proving to become
relevant in the pathogenesis and possi-
ble cure to multiple medical conditions
(Holohan et al.,2012). In atherosclerosis it
has been shown that elevated miR-155
levels are found in pro-inflammatory
macrophages as well as in atheroscle-
rotic lesions (Wei et al., 2013). In the
September 2012 edition of the Journal
of Immunology, Bauernfeind et al. (2012)
present exciting findings on inflamma-
some sensor, NLRP3, by showing its
negative regulation via a type of miRNA,
miR-223. To investigate the potential role
of post-transcriptional regulation on the
(2012) conducted several experiments in
different cell lineages. Their initial study
involvedexamining luciferaseactivity after
transfection with a plasmid armed with
luciferaseon the 3?UTR of humanNLRP3,
as well as a genome wide miRNA precur-
sor library in 293T cells. Of the miRNA
precursor library, miR-223 showed the
greatest promise, decreasing the activity of
NLRP3. Bauernfeind et al. (2012) showed
that miR-223 levels increase during gran-
ulopoiesis and are highest in mature
neutrophils, while expression is absent in
T and B cells. They also noted an inverse
relationship with regards to miR-223 and
NLRP3 during the maturation process in
the monocyte lineage, showing a decrease
in miR-223 levels, an increase in NLRP3
transcripts, and caspase activation after
culturing with granulocyte-macrophage
colony-stimulating factor (GM-CSF).
This was also proven by Haneklaus et al.
(2012) as they showed low NLRP3 pro-
tein levels in monocytes and significantly
higher levels in macrophages, indicat-
ing that the threshold for inflammasome
activation is variable throughout gran-
ulopoiesis and different cell lines. The
work of Bauernfeind et al. (2012) has shed
light on a key mechanism in the inflam-
matory cascade, a process implicated in
numerous diseases. Finding endogenous
and exogenous mediators that can con-
trol the unchecked inflammation seen
in these conditions is an important step
to discover pharmaceutical intervention
and even possible cures. Hopefully these
studies will set the foundation for the
exploration of the regulatory effects of
miR-223 and other miRNAs in regulat-
ing inflammation in numerous medical
conditions in the near future.
National Scientist Development Grant
09SDG2260957 and National Institutes
of Health R01 HL105932 and the Joy
McCann Culverhouse Endowment to the
Division of Allergy and Immunology.
Bartel, D. P. (2009). MicroRNAs: target recognition
and regulatory functions. Cell 136, 215–233.
Bauernfeind, F., Rieger, A., Schildberg, F.A., Knolle, P.
A., Schmid-Burgk, J. L., and Hornung, V. (2012).
NLRP3 inflammasome activity is negatively con-
trolled by miR-223. J. Immunol. 189, 4175–4181.
Haneklaus, M., Gerlic, M., Kurowska-Stolarska, M.,
Rainey, A.A., Pich, D., McInnes, I. B., et al. (2012).
Cutting edge: miR-223 andEBVmiR-BART15 reg-
ulate the NLRP3 inflammasome and IL-1b pro-
duction. J. Immunol. 189, 3795–3799.
Heneka, M. T., Kummer, M. P., Stutz, A., Delekate,
A., Schwartz, S., Vieira-Saecker, A., et al. (2013).
NLRP3 is activated inAlzheimer’sdiseaseand con-
tributes to pathology in APP/PS1 mice. Nature
Holohan, K.N., Lahiri,D.K., Schneider,B. P.,Foroud,
T., and Saykin, A. J. (2012). Functional microR-
NAs in Alzheimer’s disease and cancer: differential
March 2013 | Volume 4 | Article 30 | 1
Qazi et al.Can microRNAs keep inflammasomes in check?
regulation of common mechanisms and pathway.
Front. Genet.3:323. doi: 10.3389/fgene.2012.00323
Jalali, S., Ramanathan, G. K., Parthasarathy, P. T.,
Aljubran, S., Galam, L., Yunus, A., et al. (2012).
Mir-206 regulates pulmonary artery smooth mus-
7:e46808. doi: 10.1371/journal.pone.0046808
Kolliputi, N., Galam, L., Parthasarathy, P. T.,
Tipparaju, S. M., and Lockey,R. F. (2012). NALP-3
inflammasome silencing attenuates ceramide-
Physiol. 227, 3310–3316.
Kolliputi, N., Shaik, R. S., and Waxman, A. B.
(2010). The inflammasome mediates hyperoxia-
Krek, A., Grün, D., Poy, M. N., Wolf, R., Rosenberg,
L., Epstein, E. J., et al. (2005). Combinatorial
microRNA target predictions. Nat. Genet. 37,
Tamarapu, P. P., Galam, L., Huynh, B., Yunus,
A., Abuelenen, T., Castillo, A., et al. (2012).
Wei, Y., Nazari-Jahantigh, M., Neth, P., Weber,
C.,and Schober, A.
126, -145, and -155: a therapeutic triad in
atherosclerosis? Arterioscler. Thromb. Vasc. Biol.
doi: 10.1161/ATVBAHA.112.300279. [Epub ahead
Received: 04 February 2013; accepted: 23 February
2013; published online: 13 March 2013.
Citation: Qazi O, Parthasarathy PT, Lockey R and
Kolliputi N (2013) Can microRNAs keep inflamma-
somes in check? Front. Genet. 4:30. doi: 10.3389/fgene.
This article was submitted to Frontiers in Non-Coding
RNA, a specialty of Frontiers in Genetics.
Copyright© 2013Qazi, Parthasarathy, Lockey
and Kolliputi. This is an open-access article dis-
tributed under the terms of the Creative Commons
Attribution License, which permits use, distribution
and reproduction in other forums, provided the orig-
inal authors and source are credited and subject
to any copyright notices concerning any third-party
Frontiers in Genetics | Non-Coding RNA
March 2013 | Volume 4 | Article 30 | 2