Background/Objectives: Systemic inflammation is a known driver of neurodegenerative processes, with amyloid accumulation and neuronal loss. The Interleukin-33 (IL-33)/Suppression of Tumorigenicity 2 (ST2) signaling pathway has emerged as a critical immune regulator with dual roles in maintaining brain health. However, its role in pathological alterations in the central nervous system, and more specifically in the hippocampus during endotoxemia, is not fully elucidated. The aim of this research was to determine the role of the IL-33/ST2 axis in neurodegenerative processes in mice caused by systemic inflammation. Methods: BALB/c wild-type (WT) and ST2-deficient (ST2^−/−) mice were challenged with systemic lipopolysaccharide (LPS) for 7 days. One subgroup of WT mice also received exogenous IL-33. Expression of Iba1, myelin, and amyloid was detected by immunohistochemistry, the TUNEL assay was used for detection of apoptosis, flow cytometry was used to assess microglial phenotype, and RT PCR was used to detect the expression of cytokines. Results: LPS administration induced demyelination and amyloid deposition in the hippocampus. These pathological changes were the most pronounced in ST2^−/− mice, which exhibited an aggressive microglial phenotype, excessive production of IL-1β and massive apoptosis in the hippocampus. Conversely, exogenous IL-33 treatment in WT mice exerted a profound neuroprotective effect. IL-33 induced phagocytic morphology of Iba1-positive cells, redirected microglia toward a restorative M2 phenotype, and significantly upregulated IL-10. This immunomodulation led to the preservation of myelin integrity, a reduction in amyloid load, and the near-complete prevention of hippocampal apoptosis in IL-33 treated mice. Conclusions: This study identifies the IL-33/ST2 axis as an important defense signaling pathway in neuroinflammation induced by systemic LPS administration. By promoting a regulatory microglial state and balancing the IL-10/IL-1β ratio, IL-33 prevents neuroinflammation and neurodegeneration. Our data highlight the pharmacological potential of the IL-33/ST2 axis in counteracting amyloid-related pathologies.

Background/Objectives: Immune-mediated hepatitis, including autoimmune hepatitis, remains a formidable clinical challenge characterized by the rapid destruction of the liver parenchyma. While whey proteins are well-regarded for their anti-inflammatory properties, goat whey possesses a distinct bioactive profile, offering superior digestibility and reduced allergenicity compared to their bovine counterparts. This study investigated the hepatoprotective potential and underlying immunological mechanisms of lyophilized goat whey (LGW) in a Concanavalin A (ConA)-induced model of acute hepatitis. Methods: BALB/c and C57BL/6 mice were administered LGW orally (1 g/kg/day) for five consecutive days prior to a ConA challenge. Liver injury was quantified via serum transaminase levels and histopathological evaluation. The cytokine profiles and the phenotype of liver mononuclear cells (MNCs) were analyzed using ELISA and flow cytometry, respectively. Results: LGW pretreatment significantly attenuated ConA-induced hepatitis in both mouse strains, markedly reducing serum transaminase levels and preserving hepatic architecture. Mechanistically, LGW triggered a fundamental shift in the hepatic immune microenvironment by suppressing the pro-inflammatory Th1/Th17 axis (evidenced by decreased IFN-γ and IL-17) while concurrently upregulating the anti-inflammatory cytokine IL-10. Furthermore, LGW induced a tolerogenic phenotype in hepatic dendritic cells (CD11c⁺CD206⁺), which directly correlated with a significant expansion of regulatory T cells (Tregs). This strain-independent protection suggests that LGW modulates fundamental, early-stage immune signaling pathways within the liver. Conclusions: Our findings demonstrate that LGW exerts potent hepatoprotection by effectively reprogramming the hepatic immune microenvironment toward a tolerogenic state. These results position LGW as a promising, safe, and effective functional food candidate for the prevention and adjunct management of immune-mediated inflammatory liver diseases.