It all happens between Toll receptors and Caspase 1

Inflammation and chronic diseases of the CNS have been examined previously, with particular reference to changes in neuronal circuitry and neurotransmitters. Psychi-atrists have raised the possibility that inflammation or infection, and the subsequent immune response, may underlie or contribute to complex diseases. This concept has been considered, but was not rigorously studied and was subsequently abandoned because of the absence of convincing data regarding the production of inflammatory mediators in the brain. The fact that behaviors characteristic of illness can be elicited by both proinflammatory cytokines and major depression suggests that common molecular pathways are shared by inflammation and neuropsychiatric disorders. Furthermore, supporting data on the therapeutic effects of anti-inflammatory drugs, particularly those that penetrate the blood–brain barrier (BBB), in mental disease are lacking; therefore, studies on the inflammatory mediators in the brain, and their effect on sustained production of secondary inflammatory mediators and on the integrity of the BBB, become very important. In a recent issue of PNAS, Mastronardi et al. (1) provide evidence not only for a single inflammatory mediator being elevated in the brain, but also for up-regulation of an entire inflammatory cascade. They also describe a mechanism by which peripheral immune-competent cells are attracted to the brain, which may explain how the BBB could become compromised. These findings may contribute to an understanding of the molecular changes that take place within the CNS after LPS challenge. Caspase 1 is identified as a potential therapeutic target for such inflammatory disorders, possibly including psychiatric disorders.

The systemic inflammatory response syndrome (SIRS) involves large inflammatory changes in the brain (2), many of which are key determinants for the outcome of brain trauma. Bacterial LPS-mediated systemic inflammation has been the “workhorse” of those studying inflammatory response and, lately, of those studying innate immunity (3–5) as well. IL-1β plays a crucial role during LPS-induced inflammation, and caspase 1 appears to be a key modulator of IL-1β bioactivity and the consequent transcriptional regulation of gene expression within the brain during inflammation, as described (6–9). Mastronardi et al. (10) show that LPS-induced production of pro-IL-1β, and the subsequent cleavage of IL-1β by caspase 1 to yield the biologically active IL-1β (17 kDa), are required for full inflammatory response in the CNS.

LPS, acting at TLR4-type Toll receptors (5, 11, 12), induces multiple NF-κB-mediated transcriptional changes (13); LPS/TLR4 signaling on its own can induce COX-2, NOS2, and other enzymes that produce inflammatory mediators, such as PGE₂ and NO (14, 15). LPS also induces the transcription and synthesis of IL-1β, TNF-α, and IL-6 in many cell types and tissues. In this manner, LPS signaling subsequently regulates IL-1, TNF-α, and IL-6 signaling (16, 17), as illustrated in Fig. 1.

Fig. 1.

IL-1/IL-1RI signaling in SIRS.

For inflammatory conditions such as SIRS, the relative importance of LPS-induced cytokines and other inflammatory mediators (PGE₂, NO) is not well understood. Many inflammatory conditions show wide-ranging variation in levels of the cytokines TNF and/or IL-1β. These cytokines can induce each other's synthesis and positive feed forward of inflammatory signaling, in which IL-1β can induce its own signaling receptor as a part of the inflammatory response. It is important to note that transcriptional profiling suggests several modes by which IL-1β signaling contributes to brain inflammation: (i) the chemokines CXCL-1 and CXCL-10 may contribute to cell trafficking to the BBB, and (ii) activity of the matrix metaloprotease ADAMTS1 may be involved in the IL-1β-mediated gradual opening of the BBB. Over a longer period, opening of the BBB may become significant and may permit the infiltration of additional activated macrophages releasing inflammatory substances.

At this juncture, the importance of caspase 1 knockout (KO) mice (18), and of the caspase 1 inhibitors (19–21) now in clinical trials (21, 22), must be acknowledged (23). Caspase 1 is a key component of the inflammasome that processes and secretes IL-1β (24, 25), and thus the null mutation of caspase 1 significantly reduces (almost to zero) the concentration of IL-1β in circulation (26). If an inflammatory response to LPS depends, to an overwhelming extent, on IL-1β signaling, then caspase 1 KO mice or IL-1 RI−/− mice will have a much milder response and, consequently, a higher survival rate. When discussing inflammatory responses and the role of IL-1β in the induction of COX-2 in the brain parenchyma, the authors also cite recent double-blind, randomized studies and earlier studies in major depression (27) and schizophrenia (28) treatment, in which antidepressant or antipsychotic therapy has been successfully supplemented by inclusion of the COX-2 inhibitor celecoxib. These findings suggest that inflammatory processes may contribute to the pathophysiology of these mental diseases. Most important are the findings in the context of posttraumatic and poststroke depression (29, 30). Here it is clear that the inflammatory sequala precedes and coexists with the depression, and indeed COX-2 inhibitors have shown significant therapeutic effect, as measured by the Hamilton Depression Scale. Although some IL-1β is present, even in caspase 1 KO mice (26), it seems from the present data that, in the absence of full pro-IL-1β processing, full-blown SIRS does not occur, suggesting that even partial blockade of IL-1β signaling will be therapeutically useful.

Mastronardi et al. (31) have shown that IL-1β, and thus caspase 1, are crucially important in brain inflammatory response to systemic inflammation. The authors' transcriptional profiling and pathway analysis study clearly shows that, of the surprisingly few transcripts for which transcription is up-regulated by LPS and the up-regulation is significantly affected by the caspase 1 null mutation (10 of 152 transcripts that were up-regulated 1.8-fold by systemic LPS), most are involved with maintenance of the inflammatory response. These transcripts include COX-2, NOS2, IL-1RA, and ADAMTS.

These data highlight the potential utility of blockade of IL-1β signaling for the treatment of SIRS. Treatments may include the potent, BBB-penetrating caspase 1 inhibitors or other forms of blockade (32), such as the IL-1RA anakinra, currently approved for the treatment of rheumatic arthritis (33), and the IL-1β antibodies being used in clinical trials in Muckle–Wells syndrome (34) for the treatment of SIRS. It is noteworthy that caspase 1 inhibitors are the first orally active agents that target cytokines. Such drugs reduce not only IL-1β but also the proinflammatory actions of IL-18 and IL-33 (35). Therefore, a better understanding of the molecular events that occur during inflammation within the CNS could lead to the development of novel therapeutic strategies to treat disorders associated with the activation of inflammatory pathways in the brain. These inflammatory agents and events provide us with a set of drug targets for treating treat brain inflammation and its effect on neuropsychiatric disease.