Dr. Thomas Marichal - Regulation of monocyte-to-macrophage trajectories in the h

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Marichal Thomas Marichal GIGA Institute Liège University, Belgium Regulation of monocyte-to-macrophage trajectories in the healthy and diseased lung The laboratory of Immunophysiology investigates the development and exceptional diversity of lung myeloid cells with the aim to better understand their physio(patho)logical roles and provide robust foundations for the development of new prophylactic or therapeutic approaches for conditions in myeloid cell (dys)functions are involved. In 2009, we have demonstrated that lung Interstitial Macrophages (IM) exhibited a tolerogenic profile and were able to prevent and limit the development of aberrant immune responses against allergens (1). We also found that IM could expand from monocyte precursors upon exposure to bacterial unmethylated CpG-DNA, resulting in robust protection against allergic asthma (2), thus underscoring their role as crucial regulators of lung homeostasis (3). However, until recently, IM had only been characterized as a bulk population in functional studies, and little was known about the tissue-instructive signals, specific transcription factors and differentiation programs which contributed to their identity. In the frame of an ERC Starting Grant, we found that IM encompassed two functionally distinct subsets of monocytederived macrophages localized in particular niches, namely blood vessel-associated Lyve1hiCD206hi IM and nerve-associated Lyve1loCD206lo IM (4, 5). In order to investigate the differentiation trajectories of monocytes to IM, we developed a novel inducible mouse model of lung IM niche depletion and refilling, called the IM-DTR mouse model (6). After IM niche depletion, we found that engrafted classical monocytes could proliferate locally in a Csf1rdependent manner before differentiating into IM, a process that was regulated by MafB, while c-Maf specifically regulated the identity of Lyve1hiCD206hi IM (6). These findings shed new light on the regulation of IM development and made the breakthrough discovery that monocytes can proliferate in vacant niches before differentiating into macrophages. In an ongoing project, References 1. D. Bedoret, H. Wallemacq, T. Marichal, C. Desmet, F. Quesada Calvo, E. Henry, R. Closset, B. Dewals, C. Thielen, P. Gustin, L. de Leval, N. Van Rooijen, A. Le Moine, A. Vanderplasschen, D. Cataldo, P. V. Drion, M. Moser, P. Lekeux, F. Bureau, Lung interstitial macrophages alter dendritic cell functions to prevent airway allergy in mice. J Clin Invest 119, 3723–38 (2009) 2. C. Sabatel, C. Radermecker, L. Fievez, G. Paulissen, S. Chakarov, C. Fernandes, S. Olivier, M. Toussaint, D. Pirottin, X. Xiao, P. Quatresooz, J. C. Sirard, D. Cataldo, L. Gillet, H. Bouabe, C. J. Desmet, F. Ginhoux, T. Marichal, F. Bureau, Exposure to Bacterial CpG DNA Protects from Airway Allergic Inflammation by Expanding Regulatory Lung Interstitial Macrophages. Immunity 46, 457–473 (2017) 3. J. Schyns, F. Bureau, T. Marichal, Lung Interstitial Macrophages: Past, Present, and Future. J Immunol Res 2018, 5160794 (2018) 4. S. Chakarov, H. Y. Lim, L. Tan, S. Y. Lim, P. See, J. Lum, X.-M. Zhang, S. Foo, S. Nakamizo, K. Duan, W. T. Kong, R. Gentek, A. Balachander, D. Carbajo, C. Bleriot, B. Malleret, J. K. C. Tam, S. Baig, M. Shabeer, S.-A. E. S. Toh, A. Schlitzer, A. Larbi, T. Marichal, B. Malissen, J. Chen, M. Poidinger, K. Kabashima, M. Bajenoff, L. G. Ng, V. Angeli, F. Ginhoux, Two distinct interstitial macrophage populations coexist across tissues in specific subtissular niches. Science 363 (2019) 5. J. Schyns, Q. Bai, C. Ruscitti, C. Radermecker, S. De Schepper, S. Chakarov, F. Farnir, D. Pirottin, F. Ginhoux, G. Boeckxstaens, F. Bureau, T. Marichal, Non-classical tissue monocytes and two functionally distinct populations of interstitial macrophages populate the mouse lung. Nat Commun 10, 3964 (2019) 6. D. Vanneste, Q. Bai, S. Hasan, W. Peng, D. Pirottin, J. Schyns, P. Maréchal, C. Ruscitti, M. Meunier, Z. Liu, C. Legrand, L. Fievez, F. Ginhoux, C. Radermecker, F. Bureau, T. Marichal, MafB-restricted local monocyte proliferation precedes lung interstitial macrophage differentiation. Nat Immunol 24, 827–840 (2023). 7. M.