HIF-1α promotes hypoxia tolerance by restraining excess cytokine signaling
Authors: Kate Ding 1,2,3; Danielle Polan 1,2,3; Byoungchun Lee 1,2,3; Tiffany Cheung 1; Elizabeth Barretto 1; Savraj Grewal 1,2,3
Affiliations: 1) University of Calgary, Calgary, AB; 2) Arnie Charbonneau Cancer Institute; 3) Department of Biochemistry and Molecular Biology
Keywords: a. stress responses; f. JAK-STAT signaling
Our cells and organs need oxygen from the air we breathe in order to function normally. In conditions of low oxygen, also known as hypoxia, animals experience tissue damage and deregulation of metabolic homeostasis which are characteristic of diseases such as stroke and ischemia. Tumors are also associated with hypoxia, which is thought to trigger enhanced cell proliferation and metastasis. Furthermore, diseases that obstruct proper oxygen intake such as chronic lung disease and sleep apnea can result in intermittent, but chronic, whole-body hypoxia that can have long-term deleterious effects on health.
Although the air we breathe is made up of ~20% oxygen, our cells and tissues experience much lower levels than this, ranging from 1-10%. This aspect of normal physiology is often overlooked in cell culture experiments where the cells are typically maintained in 20% oxygen. Understanding how tissues and organs respond to low oxygen is therefore an important question in biology. Drosophila experience sustained conditions of hypoxia as they bury in rotting fruit they forage through during the larval stages. They have therefore evolved to tolerate hypoxia. Trachea deliver oxygen directly to tissues, hence by modulating environmental oxygen we can trigger hypoxia in cells and tissue. As such, Drosophila have emerged as an ideal in vivo model for studying how organisms tolerate hypoxia. Recent studies have revealed an adaptive role for Upd/JAK/STAT signaling in response to conditions of low oxygen that involve tissue-tissue crosstalk to promote differentiation of specific immune cells.
In our lab, we have demonstrated a role for cytokine signaling mechanisms - involving the fly interleukin-6 homolog upd3- which is important for whole-body hypoxia tolerance. We found that expression of upd3 is strongly upregulated (>20-fold) in hypoxia and that upd3 mutants show reduced survival in low oxygen. Interestingly, we also found that knockdown of HIF-1 alpha, the classic hypoxia-induced factor required for survival in low oxygen, lead to a further enhancement of upd3 expression. Further, when we genetically mimicked this enhancement in upd3 levels, we found animals also had reduced survival in low oxygen. Previous studies have demonstrated a link between HIF-1α and immune system modulation, thereby already implicating a role of hypoxia in immunity. However, with our recent discovery that upd3 is modulated in hypoxia and may be regulated in part by HIF-1α, this leaves open the question of what role upd3 is playing and how it promotes hypoxia tolerance. Using the versatility of Drosophila genetics, we have begun to tease apart what tissues may be producing upd3 and where the cytokines may be acting.