Role of the phosphoinositide 3‐kinase p110δ in generation of type 2 cytokine responses and allergic airway inflammation

Abstract

Phosphoinositide 3-kinases (PI3K) regulate immune activation via their roles in signal transduction of multiple classes of receptors. Here, we examined the effect of genetic inactivation of the hemopoietic cell-restricted PI3K isoform p110d on systemic cytokine and chemokine responses and allergic airway inflammation. We found that type 2 cytokine responses (IL-4, IL-5 and IL-13) are significantly decreased in p110d mutants, whereas type 1 cytokine responses (IFN-c and CXCL10) were robust. Elevated IFN-c production during the primary response to ovalbumin (OVA) was associated with reduced production of the regulatory cytokine IL-10. IFN-c and IL-10 production normalized after secondary OVA immunization; however, type 2 cytokine production was persistently reduced. Type 2 cytokine-dependent airway inflammation elicited by intranasal challenge with OVA was dramatically reduced, with reduced levels of eosinophil recruitment and mucus production observed in the lungs. Induction of respiratory hyper-responsiveness to inhaled methacholine, a hallmark of asthma, was markedly attenuated in p110d-inactivated mice. Adoptive transfer of OVA-primed splenocytes from normal but not p110d-inactivated mice could induce airway eosinophilia in naive, airway-challenged recipient mice. These data demonstrate a novel functional role for p110d signaling in induction of type 2 responses in vivo and may offer a new therapeutic target for Th2-mediated airway disease. IntroductionPhosphoinositide 3-kinases (PI3K) are key signaling enzymes regulating immune function [1,2]. PI3K are activated by stimulation through a variety of receptor types, including antigen receptors, costimulatory receptors and certain cytokine receptors. PI3K function by phosphorylating specific plasma membrane phospholipids to generate short-lived, membrane-integral lipid [3,4]. Effects of regulatory subunit deficiencies on T cells are less clear: deficiency of the p85a regulatory subunit for class 1A PI3K was reported to have no effect on T cell activation in vitro, while deficiency in the p85b regulatory subunit increased T cell proliferation in vitro [5]. One group found that p85-deficient mice have enhanced responses to Leishmania infection [6], but reduced immunity to nematode infection [7], suggesting that impaired class IA PI3K signaling leads to an immune dysregulation rather than a general immunodeficiency. However, the interpretation of these studies is complicated because regulatory subunits each affect the stability and activity of multiple catalytic subunits and may have adaptor functions in signaling independent of PI3K catalytic subunits.Recent work has begun to explore the specific roles of different PI3K catalytic subunit isoforms in immune function. Analysis of p110a and p110b deficiency has been hindered by the lethality of these mutations [8,9]. Mice deficient in the class IB subunit p110c are viable and have defects in T cell development and activation, as well as severe defects in neutrophil function, while B cell activation appears normal [1...

PI3Kγ-deficient mice have reduced levels of allergen-induced eosinophilic inflammation and airway remodeling

“…While this study has demonstrated an important role for PI3K␥ (a class Ib PI3K) in airway remodeling and eosinophil recruitment to the airway, previous studies have examined the importance of class Ia PI3K (such as PI3K␦ as well as the p85 regulatory subunit of class Ia PI3K) (9,15,20,25,26) in models of asthma. Studies of PI3K␦-deficient mice acutely challenged with OVA exhibit reduced eosinophilic inflammation and mucus expression (26).…”

“…Studies of PI3K␦-deficient mice acutely challenged with OVA exhibit reduced eosinophilic inflammation and mucus expression (26). In addition to studies using PI3K-deficient mice, studies have also targeted PI3K using pharmacological or adenoviral construct inhibitors of PI3K in animal models of asthma (16,25).…”

“…In contrast, class Ia regulatory subunits associate with activated tyrosine kinase receptors resulting in activation of class Ia PI3K by many cytokines (27). Studies investigating the role of PI3K in airway inflammation in asthma have identified an important role for class Ia PI3K (such as PI3K␦ as well as the p85 regulatory subunit of class Ia PI3K) (25,26), but have not investigated the role of the class Ib PI3K (i.e., PI3K␥) in airway inflammation in asthma. Therefore, in this study, we have investigated whether targeting PI3K␥ (a class Ib PI3K activated by G protein-coupled receptors rather than receptor tyrosine cytokine receptors) would not only reduce airway inflammation and airway responsiveness (as has been demonstrated for class Ia PI3K activated by receptor tyrosine cytokine receptors) but also reduce levels of airway remodeling, which has not been reported in studies targeting any PI3K.…”

PI3Kδ inhibition reduces TNF secretion and neuroinflammation in a mouse cerebral stroke model

“…We have recently shown that PI3Kd activity regulates post-Golgi transport and secretion of TNF in macrophages 18,19 . PI3Kd is similarly implicated in the release of cytokines from other immune cells [20][21][22][23][24] , and PI3Kd-selective inhibitors have significant anti-inflammatory efficacy [24][25][26] . A dual PI3Kg/d inhibitor has been shown to reduce damage in myocardial infarction 27 .…”

p110δ Phosphoinositide 3-Kinase Represses IgE Switch by Potentiating BCL6 Expression

“…Extensive studies have been carried out to target these enzymes, especially p110d, for the treatment of immune cell-mediated diseases (3). Human allergy and asthma are among those diseases that may benefit from p110d inhibition, and it was shown that in vivo inactivation of the class IA isoform p110d is able to reduce AgR function, Th2 cytokine production, Th2-mediated inflammatory reactions, and airway hyperresponsiveness (4,5).…”