Alveolar Macrophages as Age-Related Drivers of Disordered Tissue Repair

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Abstract One of the most important clinical manifestations of age-related immune dysfunction is an enhanced susceptibility to and mortality from pneumonia, the most common cause of death from an infectious disease worldwide. In the year after hospital discharge older pneumonia survivors have an increased risk of developing age-related disorders including persistent lung injury, skeletal muscle dysfunction leading to immobility, myocardial infarction, chronic kidney disease, dementia and cognitive impairment. As such, pneumonia is a gateway for the compounding morbidity that limits healthspan at the end of life. Alveolar macrophages are the most abundant resident immune population in the alveolar space, where they serve as sentinel and effector cells that respond to inhaled particles, toxins and pathogens in the ambient air. We used a combination of causal genetic experiments targeting macrophages and unbiased transcriptomic and proteomic analyses of flow-sorted cell populations from the lungs of influenza A infected mice to suggest that the reparative function of alveolar macrophages is reduced during aging. These findings converge with the concept of mitochondrial hormesis that emerged from Dr. Morimoto and Dr. Chandel's work (Project 2). They found that low level inhibition of mitochondrial electron transport in C. elegans induced a proteostasis-protective response that enhanced the resilience of aging animals, while more dramatic inhibition of electron transport was toxic. In mice, we found that metformin inhibits mitochondrial electron transport at complex I in alveolar macrophages to induce the expression of proteostasis protective genes in response to environmental stress. Mitochondrial electron transport is linked with proteostasis through the integrated stress response and activation of the transcription factor ATF4. Consistently, we found a small molecule inhibitor of the integrated stress response, ISRIB, accelerated lung repair after influenza A infection in aged mice. These data support our hypothesis that age- related impairments in the reparative function of alveolar macrophages can be reversed by transient low level inhibition of electron transport with complex I inhibitors via the ISR and ATF4, while smoldering activation of these pathways during aging precludes normal repair. We will test this hypothesis in three interrelated Specific Aims: Aim 1. To determine whether deficiency of the scavenger receptor Mertk in aged alveolar macrophages impairs lung repair after influenza A-induced injury. Aim 2. To determine whether metformin can restore the reparative function of alveolar macrophages via inhibition of complex I of mitochondrial electron transport during aging. Aim 3. To determine whether mitochondrial activation of proteostasis through eIF2?-mediated translational inhibition and/or ATF4 improves lung repair after injury during aging.