Immunosenescence is characterized by paradoxical alterations in adaptive and innate immune responsiveness. Striking increases in the inflammatory status of many individuals with age - even in the absence of overt infection - and the diminished ability to modulate those responses have been implicated causally in the pathogenesis of a variety of aging-associated disorders, and may be involved centrally in all aspects of aging-associated immune dysfunction. In this context, potential changes with age in the anti-inflammatory effects of apoptotic cells have not been considered previously. Our recent studies have demonstrated the profound ability of apoptotic cells to modulate the pro-inflammatory responses of macrophages with which they interact. The modulatory activity of the apoptotic corpse, representing a gain-of-function acquired during the physiological cell death process, is manifest as an immediate-early inhibition of pro-inflammatory cytokine gene transcription within the engulfing macrophage, and is exerted upon binding to the macrophage, independent of subsequent engulfment. Recognition and inflammatory modulation represent key elements of an innate immune response, independent of Toll-like receptor signaling, that discriminates live from effete cells. We hypothesize that the extent of immune modulation exerted by apoptotic cells may be altered in an aging-associated manner, and that these changes underlie and exacerbate the paradoxical and pathological alterations of immunosenescence. The exploratory experiments proposed in this application will test this novel hypothesis by examining, as a function of animal age, the interactions in vivo of macrophages with apoptotic cells, as well as the consequences of those interactions with respect to a variety of innate macrophage immune responses, employing rigorous quantitative approaches. We will evaluate directly whether the abilities of macrophages to interact with and engulf apoptotic cells and consequently to modulate their inflammatory and other immune responses are altered in an aging-associated manner. We will test as well the ability of exogenous apoptotic modulators to attenuate inflammatory responses in vivo as a function of animal age. A fuller understanding of the process of immune modulation exerted physiologically by apoptotic cells has enormous significance for efforts to intervene in cases of deleterious and pathological inflammatory responses that underlie and exacerbate immunosenescence. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AG024234-02
Application #
6938469
Study Section
Special Emphasis Panel (ZRG1-CMAD (01))
Program Officer
Fuldner, Rebecca A
Project Start
2004-09-01
Project End
2006-06-30
Budget Start
2005-08-01
Budget End
2006-06-30
Support Year
2
Fiscal Year
2005
Total Cost
$153,195
Indirect Cost
Name
University of Illinois at Chicago
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
Patel, Vimal A; Feng, Lanfei; Lee, Daniel J et al. (2012) Recognition-dependent signaling events in response to apoptotic targets inhibit epithelial cell viability by multiple mechanisms: implications for non-immune tissue homeostasis. J Biol Chem 287:13761-77
Patel, Vimal A; Lee, Daniel J; Feng, Lanfei et al. (2010) Recognition of apoptotic cells by epithelial cells: conserved versus tissue-specific signaling responses. J Biol Chem 285:1829-40
Patel, Vimal A; Lee, Daniel J; Longacre-Antoni, Angelika et al. (2009) Apoptotic and necrotic cells as sentinels of local tissue stress and inflammation: response pathways initiated in nearby viable cells. Autoimmunity 42:317-21
Cvetanovic, Marija; Mitchell, Justin E; Patel, Vimal et al. (2006) Specific recognition of apoptotic cells reveals a ubiquitous and unconventional innate immunity. J Biol Chem 281:20055-67
Wijewickrama, Gihani T; Albanese, Alexandra; Kim, Young Jun et al. (2006) Unique membrane interaction mode of group IIF phospholipase A2. J Biol Chem 281:32741-54
Mitchell, Justin E; Cvetanovic, Marija; Tibrewal, Nitu et al. (2006) The presumptive phosphatidylserine receptor is dispensable for innate anti-inflammatory recognition and clearance of apoptotic cells. J Biol Chem 281:5718-25
Patel, Vimal A; Longacre, Angelika; Hsiao, Kevin et al. (2006) Apoptotic cells, at all stages of the death process, trigger characteristic signaling events that are divergent from and dominant over those triggered by necrotic cells: Implications for the delayed clearance model of autoimmunity. J Biol Chem 281:4663-70