Organisms maintain homeostasis at the cellular, tissue, and systemic levels in order to survive changing physiological and environmental conditions. While maintenance mechanisms at the cellular and systemic levels are well characterized, the key cell types and signaling components controlling homeostasis in tissue compartments are undefined. Perturbations in homeostasis activate stress response pathways and result in both cell-intrinsic and cell-extrinsic responses, the latter of which can result in tissue level adaptations. Macrophages are found in almost all tissues and are known to orchestrate tissue level responses to infection and damage. Furthermore, recent evidence suggests that these innate immune cells may also perceive more general and subtle changes within the surrounding environment. We hypothesize that macrophages regulate tissue level changes to maintain homeostasis and that this feature may become dysregulated during chronic inflammatory conditions, including cancer. In order to model disrupted homeostasis, we applied a number of diverse stressors to bone marrow-derived macrophages (BMDMs) in vitro: osmotic stress, endoplasmic reticulum (ER) stress, amino acid deprivation, glucose deprivation, hypoxia, and heat shock. Next, RNA sequencing at early and late time points was performed to compare gene expression patterns between different stress conditions. We found that each stressor induces a unique transcriptional program in BMDMs, as well as a set of genes shared amongst several stress conditions. To identify potential paracrine signals originating from macrophages and acting on surrounding tissues, we focused on genes encoding secreted proteins, upregulated early after stimulation under multiple conditions, and containing known stress-associated motifs in their promoters. We found that many of the genes fitting these criteria are associated with tissue remodeling, including extracellular matrix components, cell adhesion molecules, factors involved in angiogenesis, and chemokines/cytokines. We are currently developing both in vitro and in vivo models of tissue stress to investigate these molecules as potential regulators of tissue level homeostasis.
Citation Format: Ruth A. Franklin, Scott D. Pope, Ruslan Medzhitov. The role of macrophages in tissue homeostasis [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr A127.
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