In metazoan organisms ranging from simple to the complex, the innate immune system is the first line of defense against damage or infection. Vertebrates have the particular challenge of dealing with parasitism and allergen exposure, to which Type 2 responses are critical at mucosal barrier sites. While there is some overlap between innate and adaptive Type 2 effector cell functions, their unique contributions are unclear. Additionally, the broader role of innate immunity in tissue regulation as it relates to the conserved mechanisms of metabolic homeostasis is unexplored.
We targeted the IL-4/13 locus in mice to generate a Th2-specific model of IL-4/13 deficiency (CD4Cre x IL-4/13 fl/fl). Consistent with prior studies, we verified that CD4 T cell-derived IL-4/13 was not required for the clearance of acute Nippostrongylus brasiliensis helminth infection. However, in response to chronic conditions, such as OVA-induced airway inflammation and Schistosoma mansoni infection, conditional knockout mice had an intermediate phenotype. The conditional CD4Cre x IL-4/13 fl/fl model suggests that while innate IL-4/13 can mediate the clearance of acute helminth infection, they may interact with Th2 cells in chronic inflammation.
As IL-4/13 have been implicated as important for adipose tissue macrophage alternative activation in the lean metabolic state, we identified eosinophils as the major IL-4-producing cells in white adipose tissue. In eosinophil-deficient mice, adipose tissue macrophage alternative activation was impaired but could be restored by reconstituting the eosinophil lineage. Additionally, eosinophil-deficient mice, when maintained on a high fat diet, developed increased adiposity and glucose intolerance. Thus, we find that eosinophils play a role in metabolic regulation by sustaining alternatively activated macrophages that promote the lean phenotype.
Our findings confirm that Type 2 innate effector cells are important for the clearance of acute helminth infection, but may be interacting with Th2 cells during chronic infection and airway inflammation. We have also uncovered a surprising observation that eosinophils, a major feature of Type 2 immune responses, sustain macrophage alternative activation in adipose tissue. This suggests that innate cells have evolved functions not only for immunity, but for also for metabolic homeostasis as part of a highly integrated survival strategy.
|Advisor:||Locksley, Richard M.|
|Commitee:||Anderson, Mark S., Lowell, Clifford A.|
|School:||University of California, San Francisco|
|School Location:||United States -- California|
|Source:||DAI-B 71/05, Dissertation Abstracts International|
|Keywords:||Cytokines, Innate effector cells, Metabolic regulation|
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