Bone marrow transplantation reveals an essential synergy between neuronal and hemopoietic cell neurokinin production in pulmonary inflammation.
Neurogenic inflammation is believed to originate with the antidromic release of substance P, and of other neurokinins encoded by the preprotachykinin A (PPT-A) gene, from unmyelinated nerve fibers (C-fibers) following noxious stimuli. Consistent with this concept, we show here that selective sensory-fiber denervation with capsaicin and targeted deletion of the PPT-A gene protect murine lungs against both immune complex-mediated and stretch-mediated injuries. Reconstitution of PPT-A gene-deleted mice with WT bone marrow does not abrogate this protection, demonstrating a critical role for PPT-A gene expression by sensory neurons in pulmonary inflammation. Surprisingly, reconstitution of WT mice with PPT-A gene-deficient bone marrow also confers protection against pulmonary injury, revealing that PPT-A gene expression in hemopoietic cells has a previously unanticipated essential role in tissue injury. Taken together, these findings demonstrate a critical synergy between capsaicin-sensitive sensory fibers and hemopoietic cells in neurokinin-mediated inflammation and suggest that such synergy may be the basis for a stereotypical mechanism of response to injury in the respiratory tract.
Chavolla-Calderón
Mara
M
The Edward Mallinckrodt Department of Pediatrics, Washington University School of Medicine, St Louis, Missouri, USA.
Bayer
Meggan K
MK
Fontán
J Julio Pérez
JJ
D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism; D016026:Bone Marrow Transplantation; D002211:Capsaicin / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D017353:Gene Deletion; D005786:Gene Expression Regulation; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D007107:Immune System; D007249:Inflammation; D008024:Ligands; D008168:Lung / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D015288:Neurokinin A / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D011498:Protein Precursors / Q000235:genetics / Q000502:physiology; D012119:Respiration; D013373:Substance P / Q000378:metabolism; D015320:Tachykinins / Q000235:genetics / Q000502:physiology; D013997:Time Factors; D014132:Trachea / Q000378:metabolism
D008024:Ligands; D011498:Protein Precursors; D015320:Tachykinins; C044206:preprotachykinin; D013373:Substance P; D015288:Neurokinin A; D002211:Capsaicin