Uveitis can arise from infection but is also a manifestation of many autoinflammatory diseases. IL-1 is one of the most studied cytokines in infection and inflammatory disease, yet very little work has investigated the extent to which the inflammasome contributes to uveitis. The data presented here demonstrate the presence of three NLRP3 inflammasome constituents within eye tissue and the capacity of caspase-1 and NLRP3 to regulate IL-1β production during EIU.
These studies show that deficiency in NLRP3 or cas-pase-1 did not significantly alter the severity of EIU. IL-1β
can play an important role in leukocyte recruitment by its ability to trigger endothelial cells to produce chemokines, e.g., monocyte chemotactic protein-1 (MCP-1) and IL-8, and adhesion molecules, e.g., intercellular adhesion molecule-1 (ICAM-1), that are known to be critical for EIU [23
]. Our finding that abrogated IL-1β
production in the caspase-1 KO or NLRP3 KO mice did not alter LPS-triggered leukocyte recruitment was somewhat unexpected. KO and WT mice exhibited similar cellular trafficking responses within the iris, which coincided with increased leukocyte accumulation in the aqueous humor. Akin to the traditional model of EIU in WT mice, neutrophils appear to represent the predominant cell type. The lack of a role for IL-1β
in uveitis is, however, consistent with prior reports investigating uveitis induced by LPS [26
], as well as NOD1- or NOD2-dependent models of uveitis [18
]. NOD2 and NOD1 are NLRs associated with the autoin-flammatory diseases, Blau syndrome and sarcoidosis, wherein uveitis and arthritis are dominant clinical manifestations. In experimental forms of uveitis, caspase-1 was required for IL-1β
production in the eye, yet IL-1 signaling was not essential for development of uveitis. These experimental data are consistent with clinical reports of the ineffectiveness of anakinra in treating uveitis in patients with Blau syndrome [28
]. The apparent lack of a pathologic role for IL-1β
in acute inflammatory uveitis driven by innate immune signals might reflect functional redundancy with a yet to be determined cytokine. These findings do not rule out the potential of the inflammasome in other experimental uveitis models such as experimental autoimmune uveitis (EAU), wherein IL-1 has been implicated [30
]. It is interesting to conjecture whether involvement of a T cell component as in EAU or the chronicity of uveitis may alter the inflammatory pathways involved in the pathogenesis of experimental uveitis.
There is precedent for caspase-1 mediating inflamma-tory responses to LPS. Indeed, resistance of caspase-1 deficient mice to endotoxin shock induced by LPS has long been known [32
]. This leads us to consider how the ocular environment may alter the extent to which the caspase-1 inflammasome is required for inflammatory responses. The eye has an immunosuppressive milieu believed to protect its nonregenerating tissues that can suffer irreversible destruction in the face of inflammation, hence its immune-privileged state. The increased production of IL-1β
in a caspase-1- and NLRP3-dependent mechanism indicates adequate mRNA synthesis, which has been previously reported [26
], as well as inflam-masome activity. This would lead us to believe that intraocular injection of LPS might result in endogenous release of adenosine triphosphate (ATP) sufficient for activation of the inflammasome, as has been reported to occur in human monocytes [37
It is interesting to consider that the activities of secreted IL-1β
are impeded in some way as an underlying mechanism of the immune-privileged state within the eye. The immunosuppressive milieu that exists within the eye [for example, increased presence of anti-inflammatory factors such as transforming growth factor-beta (TGF-β
), neuropeptides, or IL-1Ra] may enhance the eye’s resistance to certain inflammatory cytokines such as IL-1β
. Future investigation into how the actions of IL-1β
may be controlled within the eye will be important for our understanding of uveitis. We have recently examined the extent to which IL-1R contributes to EIU. Consistent with our findings here, deletion of IL-1R had no effect on EIU severity. However, IL-1Ra had a profound impact on controlling the severity of EIU as the uveitis was markedly exacerbated in mice deficient for IL-1Ra (Planck, Woods, Clowers, Nicklin, Rosenbaum, and Rosenzweig, submitted). Thus, there may be a threshold below which IL-1β
activity is successfully blocked by IL-1Ra and above which IL-1β
potentiates uveitis. This may be especially relevant to diseases characterized by high systemic IL-1β
levels. Anakinra successfully ameliorated uveitis in a patient with the CAPS disease, NOMID (also referred to as CINCA) [39
]. Emerging data support a beneficial effect for anti-IL-1 therapy in uveitis in patients with Behçet’s disease as well [40
]. Thus, dysregulation of IL-1 signaling has the potential to impact uveitis, and the extent to which targeting IL-1β
therapeutically is beneficial likely varies depending on the pathogenesis of a particular disease.
The importance of IL-1β processing by the inflamma-some is being increasingly realized in a wide spectrum of host defense responses and diseases, yet its role in uveitis is poorly understood. The present study demonstrates the presence of inflammasome components ASC, caspase-1, and NLRP3 in murine eye tissue. Caspase-1 is activated during EIU, and both caspase-1 and NLRP3 are required for the ensuing IL-1β production. Somewhat surprisingly, absence of NLRP3 or caspase-1 did not profoundly alter EIU. These data indicate that the NLRP3 inflammasome is dispensable in EIU.