253 : IL-36 induces inflammation and collagen deposition in the lung

Abstract

IL-36 α , IL-36β and IL-36g are members of the IL-1 family of cytokines which bind to the IL-36R leading to recruitment of the IL-1 receptor accessory protein (IL-1RAcP) to initiate signal transduction. IL-36Ra is a natural antagonist of IL-36 and mutations in the IL-36Ra gene have been shown to be causative for a severe form of psoriasis, generalized pustular psoriasis. IL-36 is believed to initiate an inflammatory loop in the skin and drive psoriasis pathogenesis. In addition to the skin, IL-36 and IL-36R are expressed in the lung. Intranasal delivery of IL-36 leads to rapid recruitment of neutrophils into the bronchoalveolar lavage fluid. Upon longer term exposure, IL-36 administration leads to an accumulation of lymphocytes in addition to neutrophils and collagen deposition. To address which cell types are responsive to IL-36, we administered IL-36 intranasally and examined lungs for nuclear translocation of the NF-kB subunit p65. Intranasal IL-36 delivery results in NF-kB nuclear translocation in the bronchiolar epithelium, endothelium, and alveolar macrophages. In humans, the IL-36R is expressed by a number of cell types of interest in respiratory diseases including macrophages of the M0 and M2 subtype, but not M1, fibrocytes, bronchial epithelial cells and lung fibroblasts. IL-36 stimulation of these cells produces inflammatory cytokines and chemokines, including IL-1β, IL-6, IL-8, IL-23 and TNF and upregulates expression of fibrotic pathway genes such as BMP2 and WNT5A from fibrocytes. Expression of IL-36 is induced in bronchial epithelial cells upon exposure to a number of stimuli including TGFβ, rhinovirus and smoke exposure which are highly relevant to pulmonary fibrosis, asthma and chronic obstructive pulmonary diseases, respectively. IL-36 can then act on fibroblasts, fibrocytes and macrophages to induce cytokines, chemokines and extracellular matrix proteins leading to recruitment of additional immune cells such as neutrophils and lymphocytes thereby amplifying the immune and fibrotic responses.