Mast cells are necessary for the hypothermic response to LPS-induced sepsis

Abstract

As central nervous system residents, mast cells contain many cytokines and are localized primarily near large blood vessels in the diencephalon and within the leptomeninges, making them candidates for immune to neural “cross talk.” Using mast cell-deficient Kit^W-sh/W-sh mice, we assessed the role of these cells in the thermoregulatory component of the immune response to lipopolysaccharide (LPS). Kit^W-sh/W-sh and wild-type (WT) mice differed in several respects in response to injection of a high dose of LPS (1 mg/kg ip). Core temperature (T_c) of WT mice decreased by ∼3°C, whereas Kit^W-sh/W-sh mice did not become hypothermic but instead exhibited pronounced low-frequency T_c oscillations around their baseline temperature. In addition, Kit^W-sh/W-sh mice had lower levels of whole brain TNF-α but no differences in IL-1β, IL-6, IFN-γ, or histamine compared with WT mice following injection of the high dose of LPS, consistent with the role of TNF-α in sepsis. Kit^W-sh/W-sh mice had increased resistance to LPS, and some survived a dose of LPS that was lethal in littermate controls. In contrast, Kit^W-sh/W-sh and WT mice were similar in other aspects, namely, in the hyperthermia following injection of TNF-α (1.5 μg icv), reduced nighttime T_c and locomotor activity (to 1 mg/kg LPS), response to a low dose of LPS (10 μg/kg ip), and response to subcutaneous turpentine injection. These results indicate that mast cells play a role in the regulation of thermoregulatory responses and survival following sepsis induction and suggest a brain site of action.