RESUMO
Over the past two decades, new insights have positioned phosphoinositide 3-kinase-γ (PI3Kγ) as a context-dependent modulator of immunity and inflammation. Recent advances in protein structure determination and drug development have allowed for generation of highly specific PI3Kγ inhibitors, with the first now in clinical trials for several oncology indications. Recently, a monogenic immune disorder caused by PI3Kγ deficiency was discovered in humans and modelled in mice. Human inactivated PI3Kγ syndrome confirms the immunomodulatory roles of PI3Kγ and strengthens newly defined roles of this molecule in modulating inflammatory cytokine release in macrophages. Here, we review the functions of PI3Kγ in the immune system and discuss how our understanding of its potential as a therapeutic target has evolved.
Assuntos
Classe Ib de Fosfatidilinositol 3-Quinase , Fosfatidilinositol 3-Quinases , Humanos , Camundongos , Animais , Classe Ib de Fosfatidilinositol 3-Quinase/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Fosfatidilinositol 3-Quinase , Inibidores de Fosfoinositídeo-3 Quinase , Macrófagos/metabolismoAssuntos
Adenosina Desaminase/deficiência , Infecções por Vírus Epstein-Barr/diagnóstico , Infecções por Vírus Epstein-Barr/etiologia , Peptídeos e Proteínas de Sinalização Intercelular/deficiência , Imunodeficiência Combinada Severa/complicações , Imunodeficiência Combinada Severa/genética , Adenosina Desaminase/sangue , Antivirais/uso terapêutico , Biomarcadores , Biópsia , Criança , Análise Mutacional de DNA , Gerenciamento Clínico , Suscetibilidade a Doenças , Infecções por Vírus Epstein-Barr/tratamento farmacológico , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/sangue , Imunodeficiência Combinada Severa/diagnóstico , Imunodeficiência Combinada Severa/terapia , Irmãos , Avaliação de Sintomas , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Sequenciamento do ExomaRESUMO
Phosphatidylinositol 3-kinase-gamma (PI3Kγ) is highly expressed in leukocytes and is an attractive drug target for immune modulation. Different experimental systems have led to conflicting conclusions regarding inflammatory and anti-inflammatory functions of PI3Kγ. Here, we report a human patient with bi-allelic, loss-of-function mutations in PIK3CG resulting in absence of the p110γ catalytic subunit of PI3Kγ. She has a history of childhood-onset antibody defects, cytopenias, and T lymphocytic pneumonitis and colitis, with reduced peripheral blood memory B, memory CD8+ T, and regulatory T cells and increased CXCR3+ tissue-homing CD4 T cells. PI3Kγ-deficient macrophages and monocytes produce elevated inflammatory IL-12 and IL-23 in a GSK3α/ß-dependent manner upon TLR stimulation. Pik3cg-deficient mice recapitulate major features of human disease after exposure to natural microbiota through co-housing with pet-store mice. Together, our results emphasize the physiological importance of PI3Kγ in restraining inflammation and promoting appropriate adaptive immune responses in both humans and mice.
