Immunometabolic regulation of inflammaging by nerve-associated macrophages

About This Grant

PROJECT SUMMARY: The sympathetic nervous system (SNS) along with innate immune system are the first lines of defense in sensing danger and protection of tissues from internal and external threats. The emergence of chronic inflammation is considered a hallmark feature of the aging process that is directly linked to a decline in tissue function. This project is based on our findings that a unique subset of macrophages reside on the sympathetic nerve (SN) fibers called the Nerve-associated macrophages (NAMs). These Nerve-associated macrophages are integral components of SNS as these regulate nerve integrity and express machinery that regulates the neurotransmitter release and degradation. We propose that NAMs are homeostatic cells required for host protection against multiple threats by integrating neural and innate immune sensing. Our prior work has demonstrated that NAMs regulate bioavailability of SNS derived norepinephrine and hence controls adipose tissue function and metabolism. We have defined NAMs as F4/80+CD11b+CD169+CD11c-CD38-Folr2-CD163- and found that they decline with aging. Given NAMs highly expresses CD169, using Cre-based labelling we localized and characterized their unique morphology, behavior by intra-vital microscopy and found that they may control nerve remodeling and catecholamine signaling. In an effort to understand their function, we depleted CD169 enriched NAMs using CD169DTR Tg mice and found that absence of NAMs increased inflammation. These new findings raised several important questions directly related to aging biology – primary among them are: (a) whether there is functional heterogeneity of NAMs? (b) does accumulation of damage with age in NAMs impairs their repair capacity of nerves? (c) does aberrant NAM activation causes loss of innervation in aging? (d) Are NAMs a neuro-immune buffer that controls SNS response via degradation of catecholamines? Based on our original findings, the central hypothesis of this proposal is that the NAM- sympathetic nervous system interactions drive immunometabolic control of inflammation. Corollary: Targeting aberrant NAM driven inflammation and inhibition of catecholamine degradation will enhance healthspan.