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The inflammation-associated innate immune response has two major functions: the early recognition and response to pathogen invaders of all varieties and the subsequent and ongoing optimization of the adaptive (T and B cell-mediated) immunity ultimately responsible for the elimination of pathogens, and the development of memory. The innate immune response is subject to an extraordinarily complex series of regulatory events to maximize anti-pathogen responses but also to constrain the deleterious effects of innate immune response-driven inflammation. We study the regulatory events controlling immune responses in inflammatory settings.
Persistent inflammation in chronic diseases is non-resolving inflammation because the insulting agents (i.e. malignant cells, cholesterol crystals in atherosclerosis, excess fat in obesity, bacteria such as Mycobacterium tuberculosis) are not cleared. While the ‘rules’ governing immune cell behavior in resolving inflammation in different organ systems are rapidly emerging, non-resolving inflammation is more complex. Macrophage infiltration of inflammatory sites has a central role in innate and adaptive immune responses, and their activation is central to the outcome of virtually every disease. Inflammatory macrophages originating from the bone marrow (loosely categorized as ‘M1’ type) can convert into healing ‘M2’-like cells indistinguishable from resident tissue macrophages. During normal wound healing, resolution of the inflammatory state is associated with a shift in macrophage polarization from M1 to M2 to favor tissue repair, a process disrupted in non-resolving inflammation. Key questions in understanding non-resolving inflammation are: (i) what are the origins and fates of the different immune cells before, during and after attempts to clear the insult? (ii) What are the signals in local microenvironments perpetuating inflammation? For example, what macrophage-derived signals support malignant cells in cancer and after chemotherapy assaults? (iii) What are the signals given and received by macrophages enabling the switches between resolving and non-resolving inflammation? Answering these questions will point to macrophage-dependent signaling pathways amenable to therapeutic interruption.
We also focus on the interplay between inflammatory myeloid cells and T cells in microenvironments. Specifically, we are dissecting how macrophages exert control over T cell proliferation and phenotype via manipulation of essential amino acid amounts. Consumption of amino acids by activated macrophages and dendritic cells at inflammatory sites can inhibit effector T cell proliferation, promote regulatory T cell activity, and aid the resolution of inflammation. We are using genetic models where molecules suspected of involvement in amino acid sensing are disrupted in T cells (including the mTOR and stress kinase pathways). Our system gives us control over the amino acid metabolizing cell (the macrophage), the sensing cell (the T cell), the time frame and the amino acid composition of the media. When combined with biochemical techniques such as mass spectrometry and tracing of labeled metabolites we can unravel the complex metabolic interplay between different immune cells and translate these findings back to different types of in vivo inflammation.