IL-1 type I receptor plays a key role in mediating the recruitment of leukocytes into the central nervous system
Introduction
Recruitment of leukocytes into the CNS through the blood-brain barrier (BBB) is involved in host defense against CNS infection (Borges, 1992; Liu et al., 2000; Patterson et al., 2002) and in CNS injuries resulting from immune activity inside the nervous tissue. This process plays important roles in cerebral meningitis (Ostergaard et al., 2000), traumatic brain injury (McKeating et al., 1998), and multiple sclerosis (Schiffenbauer et al., 2000). The recruitment of leukocytes across the BBB involves more than the regulation of the permeability of the BBB, as this process does not simply occur by infiltration of leukocytes through gaps in the BBB. It has been shown that infiltration of leukocytes occurs where the BBB is intact [see Perry for review (Perry et al., 1997)]. Thus, diapedesis, rather than passive diffusion, of leukocytes across the BBB appears to be the mechanism of leukocyte recruitment in CNS tissues. Several studies have now shown that cytokines, chemokines, and selectins are directly involved in orchestrating this intricate process (Bernardes-Silva et al., 2001; Betmouni et al., 1996; Minghetti et al., 1999; Proescholdt et al., 2002).
Selectins and chemokines mediate rolling, arrest, and subsequent extravasation of leukocytes through the blood vessels (Alon and Feigelson, 2002; Ebnet and Vestweber, 1999) in both peripheral and in CNS tissues. Because inflammatory cytokines have the ability to induce the production of selectins and chemokines, cytokines may be the initiators of leukocyte transmigration (Read et al., 1995). In the periphery, extravasation of leukocytes can be induced by several cytokines including IL-1 (Mantovani et al., 1992; Movat et al., 1987; Nourshargh et al., 1995), TNF-α (Koizumi et al., 2003; Lukacs et al., 1995; Vaday et al., 2001), and IFN-γ (Issekutz, 1995). These cytokines have been shown to act synergistically or independently (Vaday et al., 2001). In the CNS, however, a study by Schiffenbauer et al. showed that the presence of the type I IL-1 receptor, but not the receptor for TNF-α, was required for the recruitment of leukocytes in CNS tissue in a mouse model of EAE (Schiffenbauer et al., 2000), suggesting that IL-1R1 may be required for leukocyte recruitment in CNS tissue. Although several other studies found that injection of inflammatory cytokines other than IL-1 can induce the infiltration of leukocytes into the CNS (Peng et al., 1998; Sethna and Lampson, 1991; Simmons and Willenborg, 1990), it is not clear whether they do so by inducing the expression of IL-1. Therefore, this study was designed to test the hypothesis that IL-1R1 is critical for mediating leukocyte recruitment into the CNS.
Section snippets
Animals and cytokines injection
Control male mice and IL-1R1, IL-6, TNFR1, IFN-γR1, and LTα knockout mice, weighing 20–30 g at the age of 6–10 weeks, were purchased from The Jackson Laboratory (Bar Harbor, Maine). Mice were used 1 week after acclimation to the animal facility. All mice were anesthetized by ip injection of 2 mg/20 g Nembutal (Abbott Laboratories, North Chicago, IL) and then securely fixed on the small animal stereotaxic (David Kopf Instrument, Tujunga, CA) for cytokines injection. After surgically opening a small
Results
The presence of leukocytes in the brain parenchyma was detected by anti-CD45. ICV injection of 20 ng of IL-1β induced infiltration of CD45 positive (CD45+) cells into the brain (Fig. 1). No CD45+ leukocytes were found in the brain parenchyma at any time points after icv injection of saline. Fig. 1A shows that no CD45+ cells were found in the brain parenchyma 16 h after the saline injection. The few positively labeled cells in Fig. 1A were clearly cells that were trapped in the blood vessels, not
Discussion
The salient finding of this study is that IL-1R1 plays a key role in mediating the recruitment of leukocytes into the CNS. Similar to previous reports, we found that direct injection of IL-1β into the cerebral ventricles results in infiltration of leukocytes into the brain parenchyma (Bernardes-Silva et al., 2001; Proescholdt et al., 2002). This study established that IL-1-induced infiltrating leukocytes were neutrophils by excluding monocytes, T-cells, B-cells, and NK cells and by double
Acknowledgements
This study was supported by a grant from the National Institute of Health (R01 NS40098) to N.Q.
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