Innate the activation of downstream signaling pathways including

Innate immune system imparts immunity to the body against
invading micro-organisms since birth. (1). It is the first line of defence and eliminates the pathogens by
employing various mechanisms mediated by innate cells, innate-specific
receptors (pattern recognition receptors) and proteins (1). Among pattern recognition receptors (PRRs), toll-like receptors
(TLRs) play a pivotal role in obliterating the pathogens by recognizing the
conserved structure of microbes commonly known as “Pathogen-associated
molecular patterns” (PAMPs) (2). Toll-like receptors are germline-encoded transmembrane proteins,
which sense the presence of foreign microbes and eliminate them via
extracellular leucine-rich repeat (LRR) motif and an intracellular Toll/IL-1
receptor (TIR) domain (2). 11 TLRs in human and 13 TLRs have been identified in mice till
date (3). TLRs can be divided into two types: TLR1, TLR2, TLR4, TLR5, TLR6,
and TLR11 are present on the cell surface and TLR3, TLR7/8, TLR9, and TLR10 are
prevalent in the intracellular vesicles (2). TLRs are expressed by immune cells including dendritic cells,
macrophages, B lymphocytes, neutrophils and non-immune cells such as mucosal
epithelial cells, endothelial cells, fibroblasts as well as cancer cells (4). Stimulation
of TLRs by PAMPs leads to the activation of downstream signaling pathways
including NF-?B, MAPK (JNK, p38 and
ERK) culminating in the expression and production of pro-inflammatory cytokines
such as IL-1?, TNF-? and IL-6 (5). Activation of these signaling cascades and pro-inflammatory cytokines
synthesis are extremely essential in eradicating the offending pathogens. Thus,
TLR agonists have been used as a promising therapy to treat cancer (6). However, unrestrained activation of TLR signaling pathway can lead
to dysregulation of immune balance resulting in uncontrolled production of
pro-inflammatory cytokines and predisposition to a number of  chronic inflammatory diseases including
Crohn’s disease, Ulcerative colitis, asthma, chronic obstructive pulmonary
disease, systemic lupus erythematous and many more (5, 7). Moreover,
recently the dichotomous nature of TLR activation has also been observed to
cause cancer progression (8). Dysregulated
TLR signaling has been linked to tumor promotion (8). Chronic
inflammatory conditions developed upon uncontrolled TLR signaling are known to
promote carcinogenesis in organs such as stomach, pancreas, breast, prostate,
lungs and others (8). Thus,
regulated activation of TLR signaling pathway is critical in order to prevent cancer
progression due to chronic inflammation.

Cancer is the second leading cause of death globally (8.8
million deaths in 2015) WHO|Cancer. Lung cancer is one of the most common
cancers among men and women and leads to high mortality rate (1.5 million
deaths in 2015) WHO|Cancer. Cigarette smoking, tobacco consumption and
exposure to asbestos, silica are the prime risk factors for lung cancer
progression WHO|Cancer. Numerous, anti-cancer drugs that kill cancerous cells
directly or prevent angiogenesis in tumor cells have been developed to treat
lung cancer (9).
However, no gold standard drug has been developed so far as cancer (e.g lung
cancer) cells employ various mechanisms to develop anti-cancer drug resistance such
as target bypass, wherein tumor cells utilize multiple targets to activate a
signaling pathway and promote tumor progression. As a result, blocking of one
target by a drug does not prevent cancer progression and thereby perpetuate
cell proliferation (10).
Thus, search for novel targets to treat lung cancer is imperative in order to
prevent its spread worldwide. Link between dysregulated TLR signaling and lung
cancer progression has opened up new avenues for treating lung cancer. Over
expression of TLR4 on the surface of alveolar epithelial cells is known to be
responsible for tumorigenesis in lungs (11). Additionally, dysregulated expression of TLR9 in bronchial
epithelial cells also resulted in lung cancer progression (12).
Thus, owing to the pathophysiological role of TLR4 and TLR9 in promoting lung
cancer, use of TLR4 and TLR 9 antagonists might be a promising strategy to
treat lung cancer with increased efficacy. Despite the advancements in
developing TLR inhibitors, only few TLR antagonists are available commercially (5). Hence, it is vital to develop novel TLR antagonists and new
therapeutic strategies to treat chronic-inflammation mediated lung cancer
efficiently with minimal side effects.

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Recently, with
the development of nanotechnology, nanomaterials are widely used to treat lung cancer
to overcome the limitations and side-effects of the existing therapies. Nanomaterials
are used as carriers for the delivery of a wide-range of anti-cancer drugs as
they possess desired properties including cell penetration and targeting,
biodistribution and bioavailability, enhanced permeability and retention (13). Nanoparticle-mediated drug delivery attenuates the required
dose of drugs and thereby minimizes the toxicity of anti-cancer drugs.
Moreover, owing to the role of chronic inflammation in tumor cell
proliferation, several anti-inflammatory agents are used as adjunct therapy to
the standard anti-cancer drugs 12. However, their use is limited due to
the systemic immunosuppression and associated side-effects induced by currently
available anti-inflammatory drugs. Thus, there is an unmet need to develop
novel anti-inflammatory agents that could improve the therapeutic outcome when
used as an adjunct to anti-cancer drugs. Owing to the advantages of utilizing
nanoparticles as drug delivery agents, nanoparticles possessing
immunomodulatory property would serve as immumomodulatory carriers of
anti-cancer drugs and thereby kill cancer cells as well as restrain
inflammatory responses to prevent tumor progression. Hence, the development of
nanoparticles that can regulate downregulate inflammatory responses might aid
to treat chronic inflammation induced lung cancer arising due to unrestrained
TLR signaling.

Amongst the
nanoparticles developed so far, bio-inert gold nanoparticles (metallic
nanoparticles) are widely used for drug delivery owing to their beneficial
properties such as biocompatibility, non-cytotoxicity, high surface area to
volume ratio, easy of manipulation of size and shape and surface
functionalization for the conjugation of drugs and biomolecules (13, 14). Owing to the role of organogold
compounds in treating rheumatoid arthritis, it was hypothesized that gold
nanoparticles also possess immunomodulatory properties (15). Gold nanoparticles have
been reported to attenuate the inflammatory responses in macrophages by downregulating
IL-1? and TLR signaling pathways (16-18). However, the role of gold
nanoparticles in regulating TLR signaling and downstream pro-inflammatory
pathways and cytokines in lung cancer cells has not been determined so far.