Role of the MIF/CD74 pathway in ILC2-driven airway hyperreactivity - PROJECT SUMMARY The long-term goal of this study is to increase our understanding of the immune mechanisms involved in the pathogenesis of allergic disease and asthma. Despite the identification of elevated Macrophage migration inhibitory factor (MIF) levels in asthmatic patients, the contribution of MIF to the pathogenesis of asthma remains elusive due in parts to the considerable heterogeneity of asthma endotypes and lack of mechanistic insights on the signaling of MIF in immune cells. Group 2 innate lymphoid cells (ILC2) are innate lymphocytes crucial in asthma, with their activation influenced by various external factors, including cytokines. Our pilot studies using acute and chronic allergen-induced models of airway hyperreactivity (AHR) show that MIF is induced in the lungs during inflammation, with activated lung ILC2s rapidly upregulating MIF receptor CD74. Our protein and transcriptomic analysis further suggest that MIF induces higher ILC2 activation, expansion and metabolic activity in the lungs through receptor CD74. Understanding how MIF controls ILC2 function can therefore provide a molecular and cellular framework for appropriate therapeutic approaches to target the pathophysiological root of asthma rather than symptom relief, meeting the pressing demand for innovative, mechanism-based therapies. Based on existing evidence and preliminary data, we hypothesize that the modulation of the MIF/CD74 axis in ILC2s has the potential to reprogram the intrinsic metabolic activities of ILC2s. This, in turn, could directly influence cellular function and contribute to the subsequent development of AHR. In the first part, we will identify the role of MIF on ILC2 function. Aim 1 will assess the expression patterns of CD74 in the lungs and measure the effects of MIF or CD74 inhibition on ILC2 activation and development of AHR in different in vivo acute and chronic models of AHR where a pathogenic role for ILC2s is well described. The role of MIF on ILC2 metabolism will be characterized in the second part. Aim 2 will analyze how MIF affects ILC2 metabolic pathways fueling the activity of the mitochondria and provide potential metabolic approaches for the modulation of ILC2 activity. The proposed studies are conceptually and technically innovative because we will be the first to test the effects of the MIF/CD74 pathway in ILC2-driven AHR and lung inflammation. In particular, our comprehensive combined cellular, molecular and metabolism approach utilizing 3 different MIF/CD74 inhibitors and genetically modified mice was not addressed in any other immune cell population. Our studies will therefore provide pre- clinical novel data on a previously unrecognized role of this pathway in ILC2 regulation. To conduct these studies, we have assembled an outstanding team including experts in the fields of asthma and immunometabolism, as the two aims of the project come together to address the mechanisms through which MIF regulates ILC2-driven immune responses. Overall, the proposed project therefore holds the promise of uncovering new regulatory mechanisms in ILC2s that could significantly advance our understanding of the immunomodulatory mechanisms driving the magnitude of lung inflammation and offer therapeutic options for allergic diseases like asthma.
