Gain-of-function Tibetan PHD2D4E;C127S variant suppresses monocyte function: A lesson in inflammatory response to inspired hypoxia
Sulagna Bhattacharya, Nishith Shrimali, Ghulam Mohammad, Parvaiz A Koul, Josef T. Prchal, Prasenjit Guchhait
Abstract
BACKGROUND: variant is associated with prevention of hypoxia-mediated inflammatory milieu in Tibetan highlanders and therefore identify a potential target to regulate inflammation. METHODS: variants post depletion of endogenous PHD2. We had also collected whole blood samples from healthy travellers and travellers afflicted with AMS and HAPE to evaluate the significance of our ex-vivo and in vitro findings. Hereafter, we also attempted to resolve hypoxia-triggered inflammation in vitro as well as in vivo by augmenting the function of PHD2 using alpha-ketoglutarate (αKG), a co-factor of PHD2. FINDINGS: and confirmed the down-modulation of the signalling molecules at protein level under hypoxia. In contrast, non-Tibetan sojourners with AMS and HAPE at high altitude (3,600 m above sea level) displayed significant increase in these inflammatory parameters. Our data henceforth underline the role of gain-of-function of PHD2 as the rate limiting factor to harness hyper-activation of monocytes in hypoxic environment. Therefore upon pre-treatment with αKG, we observed diminished inflammatory response of monocytes in vitro and reduction in leukocyte infiltration to the lungs in mice exposed to normobaric hypoxia. INTERPRETATION: variant can therefore protect against inflammation elicited by hypobaric hypoxia. Augmentation of PHD2 activity therefore may be an important method to alleviate inflammatory response to inspired hypoxia. FUNDING: This study is supported by the Department of Biotechnology, Government of India.