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Review
. 2017 Jun 1;127(6):2022-2029.
doi: 10.1172/JCI93537. Epub 2017 Jun 1.

Inflammasomes and IL-1 biology in the pathogenesis of allograft dysfunction

S Samuel Weigt, Vyacheslav Palchevskiy, John A Belperio
Review

Inflammasomes and IL-1 biology in the pathogenesis of allograft dysfunction

S Samuel Weigt et al. J Clin Invest. .

Abstract

Inflammasomes are high-molecular-weight cytosolic complexes that mediate the activation of caspases. There are many inflammasomes, and each is influenced by a unique pattern-recognition receptor response. Two signals are typically involved in the inflammasome pathways. Signal one involves recognition of pathogen-associated molecular patterns (PAMPs), such as LPS or other colonizing/invading microbes, that interact with TLRs, which induce the downstream production of pro-IL-1β. This is followed by signal two, which involves recognition of PAMPs or damage-associated molecular patterns (DAMPs), such as uric acid or ATP, via NLRP3, which leads to caspase-1-dependent cleavage of pro-IL-1β to active IL-1β and pyroptosis. Ultimately, these two signals cause the release of multiple proinflammatory cytokines. Both PAMPs and DAMPs can be liberated by early insults to the allograft, including ischemia/reperfusion injury, infections, and rejection. The consequence of inflammasome activation and IL-1 expression is the upregulation of adhesion molecules and chemokines, which leads to allograft neutrophil sequestration, mononuclear phagocyte recruitment, and T cell activation, all of which are key steps in the continuum from allograft insult to chronic allograft dysfunction.

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Conflict of interest statement

Conflict of interest: The authors have declared that no conflict of interest exists.

Figures

Figure 1
Figure 1. Allograft airway with an adjacent vessel.
The allograft airway is prone to colonization and infection with E. coli due to transplant immunosuppression and gastroesophageal reflux. The E. coli stimulate TLRs via LPS, leading to MyD88 and NF-κB signaling that generates pro–IL-1β. Allograft injury from invading E. coli can lead to increased levels of uric acid (UA) that are detected by the cytosolic sensor NLRP3, which contains a pyrin domain (PYD), NACHT, and LLR. This monomeric sensor becomes activated, resulting in oligomerization via PYD homotypic interactions. Next, the ASC adaptor protein, which contains two death-fold domains that include the PYD and the caspase recruitment domain (CARD), is recruited. The ASC adaptor CARD domain allows for binding to the effector caspase via induced proximity, which creates a seven–NLRP3/ASC adaptor protein called the NLRP3 inflammasome. The NLRP3 inflammasome mediates proteolytic cleavage of pro–caspase-1 to caspase-1, resulting in pyroptosis, as well as the processing of pro–IL-1β to IL-1β. It should be noted that cytoplasmic LPS can be sensed by rodent caspase-11 or human caspase-4 or caspase-5, leading to pyroptosis, and can activate NLRP3. This complex is termed the noncanonical inflammasome.
Figure 2
Figure 2. IL-1 and allograft endothelial cells.
During normal endothelial cell turnover, the precursor IL-1α stays bound to IL-1R2 and, when released, is less biologically active than mature IL-1α; thus, there is minimal inflammation that perturbs adjacent endothelial cells. However, when CD4+ memory T cells (CD4+ Tm) interact with the allograft endothelium, there is an induction of CD4+ Tm–secreted TNF-α. In turn, TNF-α activates the endothelial cells, allowing caspase to cleave IL-1R2 away from precursor IL-1α, which is then cleaved by calpain to the mature, biologically active IL-1α. IL-1α skews naive CD4+ T cells (CD4+ Tn) toward a Th17 phenotype. The Th17 cells secrete IL-17, which interacts with smooth muscle cells, augmenting their expression of chemokines that recruit injurious leukocytes. IL-1 also interacts with adjacent endothelial cells, upregulating adhesion molecules, cytokines, and chemokines that allow for the recruitment of more injurious alloreactive cells as well as other mononuclear cells.
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