Maintaining structural and functional homeostasis of theDrosophilarespiratory epithelia requires stress-modulated JAK/STAT activity

Abstract

11 12 13 14 15 47 The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling 48 system is of central importance for several critical physiological processes including 49 development, tissue homeostasis, and immune responses [1]. Various cytokines, growth 50 factors, and related signaling compounds signal via this evolutionarily conserved system 51 [2]. The JAK/STAT signaling pathway effectively transduces external signals into desired 52 cellular responses despite having relatively few essential components. Signaling via this 53 pathway is therefore straightforward and allows environmental factors to directly 54 influence transcriptional activity in cells, thereby linking important biological processes 55 with environmental cues [3]. Moreover, JAK/STAT signaling is tightly associated with a 56 great variety of immune responses. JAK/STAT signaling acts downstream of a plethora of 57 cytokines that transmit immune-related information and is, therefore, a central hub in 58 various immunocompetent cells [4-7]. Deregulation of this signaling pathway is directly 59 linked with numerous human diseases, including cancer and inflammatory diseases [5, 8, 60 9]. 61 Lung diseases are often associated with deregulated JAK/STAT signaling. Such 62 deregulation can arise due to mutations and polymorphisms in genes associated with 63 JAK/STAT signaling. In addition, this signaling is activated by stressors, infections, and 64 injuries. This might cause sustained chronic inflammation of the airways and/or alveoli, 65 which is closely associated with the onset and chronification of various lung diseases.66 Niu et al. JAK/STAT signaling in the larval trachea of Drosophila 5 Chronic obstructive pulmonary disease (COPD), asthma, idiopathic pulmonary fibrosis, 67 and lung cancer are causally associated with deregulated JAK/STAT signaling [10]. This 68 signaling is not only of great importance during organ development, but also plays a 69 central role in maintaining tissue and immune homeostasis, especially in response to 70 stressors, infection, and damage [11, 12]. Functional JAK/STAT signaling is required to 71 cope with stressful stimuli such as hyperoxia in the airway epithelium [10]. Deregulation 72 of this signaling in the airways is associated with pathological states. Specifically, 73 chronically reduced JAK/STAT signaling is associated with impaired repair capacities [11], 74 while increased JAK/STAT signaling leads to cell proliferation that can cause cancer [13]. 75 Despite its simple general organization, the JAK/STAT signaling pathway is characterized 76 by multiple redundancies in vertebrates. A multitude of elements function at each level 77 of the JAK/STAT signaling pathway; for example, more than 50 cytokines can activate this 78 pathway [6]. Moreover, deregulation of JAK/STAT signaling in different motile and 79 resident cell types found in the lungs is associated with chronic lung diseases. Therefore, 80 models with a much simpler JAK/STAT pathway and a less complicated cellular 81 compo...