Cigarette smoke exposure sets up a pro-inflammatory circuit in the lung that induces the hyper-activation of myelin-specific T helper cells

Sanchez, N. A.; Haughian, A.; Cordeiro, B.; Paneda, E.; Heaney, T. A.; Pitkethly, M.; Rojas, J. G. V.; Pullen, E.; Latreille, E.; Lee, W.; Stampfli, M.; Robbins, C.; Dunn, S. E.

doi:10.1101/2025.08.06.668725

bioRxiv · 10.1101/2025.08.06.668725

Cigarette smoke exposure sets up a pro-inflammatory circuit in the lung that induces the hyper-activation of myelin-specific T helper cells

Sanchez, N. A.·Haughian, A.·Cordeiro, B.·Paneda, E.·Heaney, T. A.·Pitkethly, M.·Rojas, J. G. V.·Pullen, E.·Latreille, E.·Lee, W.·Stampfli, M.·Robbins, C.·Dunn, S. E.

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Abstract

Cigarette smoke (CS) exposure increases the risk of multiple sclerosis; however, the mechanisms are unclear. To investigate this, we exposed C57BL6/J mice to CS or ambient air (AA) for 8 weeks using a protocol modelling human chronic CS exposure and studied the impact of these exposures on the development of experimental autoimmune encephalomyelitis (EAE). We found that CS increased the incidence of neurological signs in 2D2 myelin oligodendrocyte glycoprotein (MOG) T cell receptor transgenic mice, whereas in active EAE induced by MOG peptide and Complete Freunds adjuvant, CS delayed the onset of disease. In both cases, the effects of CS tended to be greater in the males who also developed greater leukocyte infiltration and expression of IL-12p40 and other cytokines. To gain insights into the paradoxical effects of CS in these EAE models, we transferred congenically-marked pMOG-reactive T helper cells into AA- or CS-exposed mice and examined the phenotype of these cells in the lungs, spleen, and spinal cord. We found that CS-exposed lungs acted as a sink for the pMOG-reactive T cells, in that more of these T cells homed to the lungs instead of the spinal cord. However, these CS-educated pMOG Th cells exhibited a hyperactivated Th phenotype with greater expression of activation markers, IL-17, and GM-CSF, a cytokine that is essential for EAE development. Intranasal treatment with anti-IL-12p40 negated these effects of CS on the expression of pro-inflammatory cytokines by pMOG Th cells. These studies suggest that CS sets up a pro-inflammatory circuit in the lung that amplifies the encephalitogenic properties of myelin-specific T effector cells. HighlightsO_LICS exposure enhances the development of spontaneous neuroimmunity. C_LIO_LIMyelin-reactive T helper 1 responses are enhanced by CS exposure. C_LIO_LICS-exposed lung attracts myelin-specific T helper cells to this site. C_LIO_LICS enhances myelin-specific Th1/Th17 cytokine production and GM-CSF through lung IL-12p40 C_LI

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Sanchez, N. A., Haughian, A., Cordeiro, B., Paneda, E., Heaney, T. A., Pitkethly, M., Rojas, J. G. V., Pullen, E., Latreille, E., Lee, W., Stampfli, M., Robbins, C., Dunn, S. E.. 2025-08-09. Cigarette smoke exposure sets up a pro-inflammatory circuit in the lung that induces the hyper-activation of myelin-specific T helper cells. https://doi.org/10.1101/2025.08.06.668725

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