The Nicotinic Receptor Alphα7 Impacts the Mouse Lung Response to LPS through Multiple Mechanisms

The nicotinic acetylcholine receptor alpha7 (alpha 7) is expressed by neuronal and non-neuronal cells throughout the body. We examined the mechanisms of the lung inflammatory response to intranasal (i.n.) lipopolysaccharide (LPS) regulated by alpha 7. This was done in mice using homologous recombination to introduce a point mutation in the alpha 7 receptor that replaces the glutamate residue 260 that lines the pore with alanine (alpha 7(E260A)), which has been implicated in controlling the exceptional calcium ion conductance of this receptor. The alpha 7(E260A) mice exhibit normal inflammatory cell recruitment to the blood in response to i.n. LPS administration. This differs from the alpha 7knock-out (alpha 7(KO)) in which upstream signaling to initiate the recruitment to the blood following i.n. LPS is significantly impaired. While hematopoietic cells are recruited to the bloodstream in the alpha 7(E260A) mouse, they fail to be recruited efficiently into both the interstitium and alveolar spaces of the lung. Bone marrow reconstitution experiments demonstrate that the responsiveness of both CD45(+) and CD45(-) cells of the alpha 7(E260A) mouse are impaired. The expression of several pro-inflammatory cytokine and chemokine RNAs including TNF alpha, IL-1 alpha, Ccl2 and Cxcl10 are decreased in the alpha 7(E260A) mouse. However, there is a substantial increase in IL-13 expression by CD45(-) lung interstitial cells in the alpha 7(E260A) mouse. Our results support the conclusion that alpha 7 functional pleiotropy contributes to modulating the tissue response to an inflammatory insult through impacting upon a variety of mechanisms reflecting the individual cell composition of the lung.