Abstract
The class IB phosphoinositide 3-kinase gamma enzyme complex (PI3Kγ) functions in multiple signaling pathways involved in leukocyte activation and migration, making it an attractive target in complex human inflammatory diseases including MS. Here, using pik3cg −/− mice and a selective PI3Kγ inhibitor, we show that PI3Kγ promotes development of experimental autoimmune encephalomyelitis (EAE). In pik3cg−/− mice, EAE is markedly suppressed and fewer leukocytes including CD4+ and CD8+ T cells, granulocytes and mononuclear phagocytes infiltrate the CNS. CD4+ T cell priming in secondary lymphoid organs is reduced in pik3cg−/− mice following immunisation. This is attributable to defects in DC migration concomitant with a failure of full T cell activation following TCR ligation in the absence of p110γ. Together, this results in suppressed autoreactive T cell responses in pik3cg−/− mice, with more CD4+ T cells undergoing apoptosis and fewer cytokine-producing Th1 and Th17 cells in lymphoid organs and the CNS. When administered from onset of EAE, the orally active PI3Kγ inhibitor AS605240 caused inhibition and reversal of clinical disease, and demyelination and cellular pathology in the CNS was reduced. These results strongly suggest that inhibitors of PI3Kγ may be useful therapeutics for MS.
Highlights
Multiple Sclerosis (MS) is the most common inflammatory disorder of the central nervous system (CNS) and is a chronic, debilitating and demyelinating disease
To investigate the role of phosphoinositide 3-kinase gamma enzyme complex (PI3Kc) in CNS autoimmune disease, EAE was induced in WT and pik3cg2/2 mice, which lack the catalytic subunit of PI3Kc, p110c
Histological analyses of spinal cord tissue taken on day 15 post-immunisation when peak disease was apparent in WT mice revealed that pik3cg2/2 mice lacked the characteristic lesions containing infiltrating leukocytes, while these were clearly apparent in WT spinal cord sections (Figure 1C)
Summary
Multiple Sclerosis (MS) is the most common inflammatory disorder of the central nervous system (CNS) and is a chronic, debilitating and demyelinating disease. In active EAE, autoreactive encephalitogenic Th1 and Th17 CD4+ T cells are activated through immunisation, invade the CNS and subsequently promote the recruitment of immune effector cells such as monocytes and neutrophils, resulting in demyelinating autoimmune inflammation that resembles human MS in many clinical and histopathological features. This model is commonly used to assess the importance of molecular and cellular components in CNS autoimmunity and provide proof-of-concept for novel therapeutics for human MS [2,3]. We have used pik3cg2/2 mice, which lack expression of p110c, and a highly selective PI3Kc inhibitor to conduct a detailed investigation of the role of this protein in CNS autoimmune disease and we show that PI3Kc plays a critical role in EAE by controlling CD4+ T cell activation and survival
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