There is a growing recognition that innate immune cells play a critical role in initiating and sustaining autoimmune and inflammatory disorders. The Lyn tyrosine kinase is one of the primary inhibitory enzymes that regulate innate immune cell signaling. Lyn functions by phosphorylating inhibitory receptors that recruit tyrosine phosphatases to down modulate cellular activation. In the absence of Lyn kinase, mice develop spontaneous autoimmunity resembling human systemic lupus erythematous (SLE). In preliminary studies, we have found that loss of Lyn kinase in dendritic cells (DCs) alone is sufficient to cause a severe autoimmune/inflammatory disease, with strong tissue inflammation and reduced survival, compared to the global lyn-/- mice. This disease is completely dependent on MyD88-signaling, since generation of mice lacking MyD88 and Lyn in DCs alone lack the inflammation and autoimmunity. These observations provide a clear example that mutations resulting in loss of inhibitory signaling in DCs can result in breakdown of immune tolerance in lymphocytes, leading to autoimmunity. This proposal consists of 4 specific aims.
Our first aim i s to define the molecular mechanisms by which inhibition of tyrosine kinase pathways impacts MyD88 signaling in DCs. We hypothesize that the cross talk between these pathways occurs via the CARD9/Malt1/Bcl10 complex, which we will investigate biochemically and genetically. We will use a chemical genetic approach to define the molecular substrates of Lyn in DCs.
Aim #2 will expand on our preliminary observations, done with Dr. Lynch (UCSF) that loss of Lyn in DCs results in dysbiosis of gut microbiota, allowing for outgrowth of species that may drive systemic inflammation by altering the intestinal barrier function. We will expand on these observations in a series of microbiota profiling experiments, by use of bacterial supplementation methods, and by directly examining intestinal barrier function in the various Lyn-deficient strains.
Aim #3 will expand on preliminary data suggesting that an undefined Lyn-mediated signaling pathway in non- hematopoietic cells may have an immunomodulatory effect on the disease process in lyn-/- mice. Lyn related inhibitory signaling in non-hematopoietic cells is very poorly studied. We will focus on follicular retricular cells using biochemical and genetic means (including generating mutant mice lacking Lyn in these cells specifically).
Aim #4 will expand on preliminary studies done with Dr. Locksley (UCSF) showing that group 2 innate lymphocytes (ILC2s) are expanded and activated in lyn-/- mice.
This aim will address whether altered signaling in ILC2 cells alone can lead to spontaneous disease phenotypes (by generating novel ILC2-specific lyn mutants) and whether these cells may contribute to autoimmune disease. Since changes in Lyn kinase related signaling pathways have been observed in human SLE patients and Lyn is now a therapeutic target in diabetes treatments (therapeutic trials) understanding the inhibitory signaling pathways regulated by this kinase in innate cells will have direct impact on human autoimmune and inflammatory conditions.
Autoimmune diseases such as human lupus erythematous (and related disorders) are generally considered to arise from defects in lymphocytes leading to production of antibodies that recognize self- proteins. We have found that genetic defects in innate immune cells, which are involved in protection from bacterial, fungal and other infections, can also cause autoimmune disease. The goal of this project is to determine the mechanisms by which defects in innate immune cells cause autoimmune and inflammatory disease.
|McCreedy, D A; Lee, S; Sontag, C J et al. (2018) Early Targeting of L-Selectin on Leukocytes Promotes Recovery after Spinal Cord Injury, Implicating Novel Mechanisms of Pathogenesis. eNeuro 5:|
|Rosales, Carlos; Lowell, Clifford A; Schnoor, Michael et al. (2017) Neutrophils: Their Role in Innate and Adaptive Immunity 2017. J Immunol Res 2017:9748345|
|Costa, Sara; Marini, Olivia; Bevilacqua, Dalila et al. (2017) Role of MyD88 signaling in the imiquimod-induced mouse model of psoriasis: focus on innate myeloid cells. J Leukoc Biol 102:791-803|
|Zikherman, Julie; Lowell, Clifford A (2017) B cell autoimmunity at the extremes. Nat Immunol 18:1065-1066|
|Abram, Clare L; Lowell, Clifford A (2017) Shp1 function in myeloid cells. J Leukoc Biol 102:657-675|
|Chen, Jun; Zhong, Ming-Chao; Guo, Huaijian et al. (2017) SLAMF7 is critical for phagocytosis of haematopoietic tumour cells via Mac-1 integrin. Nature 544:493-497|
|Sinha, Meenal; Lowell, Clifford A (2017) Efficiency and Specificity of Gene Deletion in Lung Epithelial Doxycycline-Inducible Cre Mice. Am J Respir Cell Mol Biol 57:248-257|
|Roubinian, Nareg H; Looney, Mark R; Keating, Sheila et al. (2017) Differentiating pulmonary transfusion reactions using recipient and transfusion factors. Transfusion 57:1684-1690|
|Clemens, Regina A; Chong, Joshua; Grimes, Derayvia et al. (2017) STIM1 and STIM2 cooperatively regulate mouse neutrophil store-operated calcium entry and cytokine production. Blood 130:1565-1577|
|Poh, Ashleigh R; Love, Christopher G; Masson, Frederick et al. (2017) Inhibition of Hematopoietic Cell Kinase Activity Suppresses Myeloid Cell-Mediated Colon Cancer Progression. Cancer Cell 31:563-575.e5|
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