Biology Reference
In-Depth Information
Consistent with the above demonstrating a lack of a role for TLR3, a previous
study demonstrated that CD8- and CD4-mediated GVHD were similar
whether host APCs were wild-type or deficient in MyD88, TRIF, or MyD88
and TRIF
[74]
. These data demonstrated that, in the context of a minor anti-
gen-mismatched BMT, the intra- (and extra-)cellular TLR sensors have no
direct impact on GVHD. Alternatively, this could represent the impact of the
quality and quantity of the host and donor microbiota before BMT and the
subsequent dysbiosis. Nevertheless, they suggest considerable redundancy
in the requirements for APC activation from endogenous stimuli for directly
affecting alloreactivity. However, excess stimulation of these pathways from
exogenous stimuli with CpG or TLR7/8 ligands aggravates GVHD in the
presence of intact signaling.
Nucleotide-binding and oligomerization domain-like
receptors
NLRs are another class of cytoplasmic receptors that recognize molecu-
lar patterns associated with microbes, danger, or damage
[75]
. They are
evolutionarily similar to a large set of cytosolic proteins referred to as dis-
ease resistance or “R” proteins, which directly or indirectly sense patho-
gen virulence proteins in plants. In the animal kingdom, homologs of the
NLRs are present in vertebrates and phylogenetically more primitive organ-
isms, such as the sea urchin
[76]
. Twenty-three members in humans and
34 members in mice make up this family of intracellular sensors
[77,78]
.
All NLRs are intracellular and are defined by a tripartite structure compris-
ing the following: a CARD, a pyrin domain (PYD), an acidic transactivating
domain or baculovirus inhibitor repeat (BIR) that mediates downstream
protein-protein interactions, a central NOD that mediates self-oligomer-
ization, and carboxy-terminal leucine-rich repeats (LRRs) that are thought
to sense various microbial and endogenous damages
[77,79]
. Each LRR
consists of 20-29 amino acids and the number of LRRs varies in each NLR.
The NACHT domain is required for ATP-dependent oligomerization, which
culminates in release of IL-1β and IL-18, while LRRs are crucial for inter-
action with a variety of inter- and intramolecular domains
[79,80]
. These
proteins thus can form a multiprotein complex termed the inflammasome,
whose hallmark
[80]
activity is the activation of caspase 1 and the secre-
tion of IL-1. The NLR family is divided into five subfamilies based on the
class of N-terminal effector domain that have been proposed and approved
by the Human Genome Organization Gene Nomenclature Committee
[81]
.
Four subfamilies are defined by the presence of the N-terminal CARD, PYD,
BIR, and acidic domains. An additional subfamily, NLRX, characterized by
the presence of an N-terminal domain without significant homology to any
known domains, is localized to the mitochondria
[80]
. Members of the NLR
family include NODs (NOD1 and NOD2) and NLRPs (NLRP1, NLRP3, and
NLRC4) and the cytosolic receptor AIM2
[82]
.
433
NOD1 AND NOD2
The NLRs NOD1 and NOD2 were first discovered as mammalian mem-
bers of the Ced4/Apaf-1 family of apoptosis regulators. NOD1 is widely
expressed in many cell types and organs, while expression of NOD2
is more restricted to macrophages, dendritic cells, Paneth cells, and
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