Macrophage phosphoinositide 3-kinase p110delta regulates intestinal homeostasis by directing adaptive immunity and enhancing microbial clearance

The human inflammatory bowel diseases (IBDs), Crohn's disease (CD) and ulcerative colitis, result from an inappropriately directed immune response to enteric microbiota in a genetically susceptible host. IBDs represent an increasing burden on the global health care system, as incidence is increasing and effective therapies remain elusive. Genome-wide association studies highlight the importance of host innate immune cell-microbial interactions in the pathogenesis of IBDs.;PI3K signaling regulates diverse functions, including cell growth, differentiation, proliferation and survival. The Class IA PI3K catalytic subunit p110delta negatively regulates toll-like receptor signaling in innate immune cells. The importance of p110delta in intestinal homeostasis is shown in a mouse harboring a kinase-dead p110delta (p110deltaKD) that develops spontaneous Th1/Th17-skewed colitis. We describe a requirement for the enteric microbiota to drive intestinal inflammation in p110delta KD mice. Microbial-innate immune interactions maintain homeostasis through regulation of both protective (IL-10) and inflammatory (IL-12p40) cytokines, and p110delta is a central regulator of this balance. Additionally, p110delta positively regulates eradication of intracellular bacteria in macrophages. Persistence of intracellular bacteria and chronic stimulation in intestinal p110deltaKD macrophages propagates the cytokine imbalance. Furthermore, p110delta orchestrates innate immune cell regulation of pathogenic adaptive immune responses. Importantly, in human CD, decreased intestinal PIK3CD gene expression and an inverse correlation with intestinal IL12B:IL10 ratios are demonstrated. Thus, p110delta appears to be a central homeostatic switch in the intestine, governing the critical balance between IL-12/23 and IL-10 induced by the microbiota that determines the subsequent T cell response. Counter to prevailing paradigms where p110delta inhibition is a strategic approach in inflammatory diseases, strategies to induce p110delta gene expression could be a potential therapeutic approach in human IBDs.