Innate Immune Response in Bovine Tuberculosis 147
the one hand, they help innate immunity to
increase pro-inflammatory signals with the
purpose to identify and eliminate pathogens,
but on the other hand they promote develop-
ment of immunopathology. A fine balance is
required in order to favour host survival. The
AIM2 cytosolic DNA sensor may conjugate
competitively with cytosolic M. bovis DNA
to restrict M. bovis-induced STING-TBK1-
dependent autophagy activation and IFN-β
secretion (Liu et al., 2016).
10.6 Role of Interferon-b in Infection
of M. bovisUntil now, several cytokines have been shown to
participate in the innate host response against
M. tuberculosis, where they can either function
to enhance host resistance or may play a role in
aggravating the infection (O’ Garra et al., 2013).
The critical role of inflammatory cytokines such
as IL-1β has been established in the control of
M. tuberculosis activity by augmenting the anti-
microbial function of macrophages (Fremond
et al., 2007). On the other hand, an important
cytokine IFN-β has been reported to have pro-
bacterial activity and is associated with the
development of tuberculosis in many studies
on animal models and humans (Manca et al.,
2005; Stanley et al., 2006; Berry et al., 2010;
Trinchieri, 2010). Recent studies showed that
this pro- bacterial activity of IFN-β is correlated
with its anti-inflammatory characteristics as it
antagonizes the production and function of
IL-1β and IL-18 through increased IL-10 pro-
duction and also inhibits the NLRP3 inflamma-
some. Furthermore, IFN-β also fails to initiate
an appropriate Th1 response with reduced
expression of MHC-II and IFN-γ receptors
(IFNGR).
IL-1 is an important and extensively stud-
ied cytokine. It plays a pivotal role in the induc-
tion of the inflammatory and immune response
against virulent mycobacterial strains, but it is
suppressed by type I IFN (Mayer-Barber et al.,
2011; Novikov et al., 2011). IFN-β–induced
inhibition of IL-1 production has been reported
by Guarda et al. (2011) and Ma et al. (2014)
through two distinct pathways. IFN-β signal-
ling, via the STAT1 transcription factor,
repressed the activity of nucleotide-binding
domain and leucine-rich repeat containing
proteins 1 and 3 (NLRP1 and NLRP3) inflam-
masomes, hence suppressing the caspase-1-
dependent IL-1β maturation. In addition, IFN-β
induced IL-10 in a STAT1-dependent manner,
and then IL-10, via autocrine action, led to
reduced production of pro-IL-1α and pro-IL-1β
through STAT3 signalling. Mayer-Barber et al.
(2011) reported that IFN-β inhibited IL-1 pro-
duction by both subsets, whereas CD4+ T-cell–
derived IFN-γ suppressed IL-1 expression
selectively in inflammatory monocytes. The
data provided cellular evidence for the anti-
inflammatory effects of IFN-β as well as pro-
bacterial functions during mycobacterial
infection. In another report by the same group
(Mayer- Barber et al., 2014), it was revealed that
IL-1β prostaglandin E2 (PGE2) is another
important pathway by which IFN-β antago-
nizes IL-1 production during mycobacterial
infection. The absence of IFN-β signalling
resulted in increased PGE2 and IL-1β and
decreased IL-1Ra. M. tuberculosis-infected wild-
type bone marrow-derived macrophages pro-
duced significantly less PGE2 when exogenous
IFN-β was present. Novikov et al. (2011) dem-
onstrated that IFN-β selectively limits the pro-
duction of IL-1β. This regulation occurs at the
level of IL-1β mRNA expression, rather than
caspase-1 activation or autocrine IL-1 amplifi-
cation, and this regulation is only evident in the
virulent mycobacterial strains as avirulent
strains fail to trigger the same response. Recip-
rocal control of type 1 IFNs by IL-1β PGE2-
mediated pathway has also been reported, and
PGE2 treatment led to reduced production of
type 1 IFNs and increased protection against
M. tuberculosis infection (Xu et al., 1998; Mayer-
Barber et al., 2014). Briken et al. (2013)
reviewed the role of IFN-β after its induction by
myco bacterial infection, showing it could sup-
press NLRP3-inflammasome activation while
increasing the action of AIM2 (absent in
melanoma)-inflammasome. In contrast, a
recent study reported the AIM2 cytosolic DNA
sensor may conjugate competitively with cyto-
solic M. bovis DNA to restrict M. bovis-induced
STING-TBK1-dependent IFN-β secretion (Liu
et al., 2016). IFN-β release increases in macro-
phages exposed to M. bovis and this requires the
activation of the DNA sensor of IFN-γ inducible