Nerve growth factor responsive elements modulate immune cell inflammation and are dysregulated in an Alzheimer's...

Inflammation is a crucial regulator of body's defense mechanism primarily modulated by the immune system. Context dependent immune activation (e.g., pathogen) requires acute inflammatory reactions followed by efficient resolution of inflammation. Impaired resolution may lead to chronic inflammation, often associated with several pathological processes, including dementia disorders. At present, the mechanisms of inflammation resolution are poorly understood. High levels of the neurotrophin nerve growth factor (NGF) are evident at the site of inflammation, however the effect of NGF on immune cells is debated, ranging from proinflammatory to anti-inflammatory. Thus, identifying the immune cells which possess NGF responsive receptors is crucial to understand how NGF can modulate immune function of those specific immune cells. Utilizing multi-color flow cytometry, we mapped across various immune cell subtypes including adaptive and innate immunity landscape from unchallenged mouse spleen for the presence of NGF receptors (TrkA and p75). Although NGF receptors were previously reported in some immune cell types, we report comprehensive cell-type dependent expression of NGF receptors on immune cells including dendritic cells, macrophage, natural killer (NK) cell as well as various subsets of lymphocytes (T and B cells). Since NGF is the upstream regulator of cholinergic signaling, we employed single cell RNA sequencing (scRNA-seq) and observed heterogenous neurotrophin-cholinergic landscape among various immune sub-sets, and report discordance between RNA and protein level expression. Interestingly, we found that differential activation methods ex-vivo could increase TrkA and p75 protein levels differently, a crucial regulator of NGF downstream signaling. Furthermore, we report that NGF supplementation reduced inflammatory cytokine production in activated T- and B-cells significantly. Using a mouse model of AD, we show age-dependent alterations in TrkA and p75 in immune cells, indicating altered NGF-immune coupling in AD. In conclusion, this study identifies that immune cells are direct recipient of NGF signaling by expressing its associated receptors and the existence of a novel inflammation regulatory mechanism mediated through NGF-receptors. The NGF responsive elements get hampered in the immune cells in an AD mouse model which may have pathogenic implications in the resolution of chronic inflammatory response. Thus, NGF associated mechanisms constitute novel regulatory potential in immune cells which can be targeted for inflammatory immune disorders.