Research Publications | Overview
Although immune cells are well-known for their mobility, it’s becoming clear that tissue resident immune cells, such as macrophages, are organized into unique spatial patterns within tissues. We are interested in uncovering cellular mechanisms that organize immune cells spatially and temporally, and how such organization dictates their homeostatic and inflammatory functions.
Appropriate numbers and ratios of different cell types are ensured throughout tissue development. Sustained changes in tissue composition often underlie pathological transition in inflammatory diseases. How is the compartment size of immune & non-immune cells maintained, regulated and altered at homeostasis and inflammatory conditions? We are interested in identifying molecular and cellular principles defining tissue composition, with the goal of creating synthetic modules to control cell numbers and restore tissue homeostasis.
Immune cells are specialized into sensing infections and injuries. They also express diverse receptors that monitor tissue microenvironment, such pH, oxygen, osmolarity, pressure, etc. These variables are often impacted by inflammatory response, as a consequence of host defense mechanisms. A good example is extravasation. Recruitment of neutrophils and monocytes to the site of infection helps clear pathogens, at the cost of perturbing microenvironment variables. We are interested in dissecting how changes in tissue microenvironment modulate immune functions as a potential strategy to control inflammation.
Programming immune functions
Macrophages have recently gained attractions in immune engineering and cancer immunotherapy. They are present in almost all tissues and possess diverse functions. We are interested in engineering macrophages to control their population size, interaction partner, location, and response to given environmental cues, as cellular vehicles to treat inflammatory disorders, cancer and fibrotic disease.
Zhou X*, Franklin RA*, Adler M, Condiff E, Adams TS, Pope SD, Philip NH, Meizlish ML, Kaminski N, and Medzhitov R. Sensing of microenvironment by fibroblasts controls tissue composition. In submission. Sensing tissue microenvironment through fibroblast controls population size of macrophages through Hippo-Yap signaling.
Meizlish M*, Franklin R*, Zhou X*, Medzhitov R. Tissue Homeostasis and Inflammation. Annual Review Immunology. 2021 Apr 26;39:557-581. We discuss how tissues are organized from a functional perspective and how this helps understand homeostasis, stress and inflammation at tissue level.
Adler M, Mayo A, Zhou X, Franklin R, Meizlish M, Medzhitov R, Kallenberger S, Alon U. Principles of Cell Circuits for Tissue Repair and Fibrosis. iScience. 2020 Feb 21; 23(2). Myeloid and stromal communication circuitry drives irreversible switch between homeostatic and fibrotic states.
Wang J, Sun JW, Liu L, Flies D, Nie XX, Zhang JP, Song C, Zarr M, Zhou X, Han X, Archer K, O’Neill T, Boto A, Chen LP. Siglec-15 As an Immune Suppressor and Potential Target for Normalization Cancer Immunotherapy. Nature Medicine. 2019 Apr; 25(4):565-666. Myeloid expression of Siglec15 is a immune suppressor and provides a novel target for cancer immunotherapy.
Allen NC, Philip NH, Hui L, Zhou X, Franklin RA, Kong Y, Medzhitov R. Desynchronization of the Molecular Clock Contributes to the Heterogeneity of the Inflammatory Response. Science Signaling. 2019 Mar 5; 12(571). Mammalian circadian clock regulates the the heterogeneity of an inflammatory response at single cell level.
Li MD, Vera NB, Yang YF, Zhang BC, Ni WM, Ziso-Qejvanaj E, Ding S, Zhang KS, Yin RN, Wang SM, Zhou X, Fang EX, Xu T, Erion DM, Yang XY. Adipocyte OGT Governs Diet-Induced Hyperphagia and Obesity. Nature Communications. 2018 Nov 30; 9(1):5103. O-GlcNAc transferase promotes transcriptional activation of de novo lipid desaturation in adipose tissue.
Zhou X*, Franklin RA*, Adler M*, Jacox JB, Bailis W, Shyer JA, Flavell RA, Mayo A, Alon U#, Medzhitov R#. Circuit Design Features of a Stable Two-cell System. Cell. 2018 Feb 8; 172(4):744-757. Growth factor communication cell circuit between macrophages and fibroblast can maintain proper population ratios through feedback mechanisms. Read preview by Nicholas Frankel and Windell Lim.
Adler M, Mayo A, Zhou X, Franklin RA, Jacox JB, Medzhitov R, Alon U. Circuits for Homeostasis of Cell-type Ratios Using Growth-factor Endocytosis as a Feedback Mechanism. PNAS. 2018 Feb 20; 115(8):E1926-E1935. Circuit modeling reveals endocytosis as a general strategy to achieve a stable two-cell system.
Karimy JK, Zhang J, Kurland DB, Theriault BC, Duran D, Stokum JA, Furey CG, Zhou X, Mansuri MS, Montejo J, Vera A, DiLuna ML, Delpire E, Alper SL, Gunel M, Gerzanich V, Medzhitov R, Simard JM, Kahle KT. Inflammation-dependent Cerebrospinal Fluid Hypersecretion by the Choroid Plexus Epithelium in Posthemorrhagic Hydrocephalus. Nature Medicine. 2017 Aug; 23(8):997-1003. Intraventricular hemorrhage triggers Toll-like receptor 4-dependent inflammatory response in choroid plexus epithelium.
He B, Zhou X, O’Shea EK. Evolution of Reduced Co-Activator Dependence Led to Target Expansion of a Starvation Response Pathway. eLife. 2017 May 9;6:e25157. Rewiring of transcriptional network markedly altered the spectrum of a cellular response.
Zhou X*, Blocker AW*, Airoldi EM#, O'Shea EK#. A Computational Approach to Map Nucleosome Positions and Alternative Chromatin States with Base Pair Resolution. eLife. 2016 Sep 13;5:e16970. A bayesian template-based model reveals eukaryotic chromatin landscape at base-pair resolution.
Su T*, Bondar T*, Zhou X, Zhang C, He H, Medzhitov R. Two-signal Requirement for Growth-promoting Function of Yap in Hepatocytes. eLife. 2015 Feb 10;4:e02948. Inflammatory signals synergize with the Hippo-signaling pathway to drive liver cancer.
Zhou X, O’Shea EK. Integrated Approaches Reveal Determinants of Genome-wide Binding and Function of the Transcription Factor Pho4. Molecular Cell. 2011 Jun 1;52(3):318-27. Specificity of transcription program not only requires DNA sequence, but also involves combinatorial epigenetic mechanisms that include restriction by chromatin, competitive and cooperative binding transcription factors.