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Remi Diesler, MD






Brigham and Women's Hospital


Harvard Medical School


Rémi Diesler, Melissa Daou, Joelle Chami, Damir Khabibullin, Heng-Jia Liu, Elizabeth P. Henske

Principal Investigator


TSC2-deficiency drives macrophage polarization in lymphangioleiomyomatosis (LAM).


Lymphangioleiomyomatosis (LAM) is an incurable destructive lung disease affecting almost exclusively women. Disease progression occurs most rapidly pre-menopausally and during pregnancy. LAM occurs in women with Tuberous Sclerosis Complex (TSC), an autosomal dominant disease caused by germline loss-of-function mutations in the TSC1 or TSC2, and sporadically in women without TSC. Sporadic LAM is caused by somatic TSC2 mutations. Most women with LAM have benign renal tumors containing abundant macrophages expressing immunosuppressive, M2-like markers. M2-like macrophages are also found in pulmonary LAM. The role of these macrophages in LAM is unknown.

105K cells (Tsc2-null), 105K Tsc2-re-expressing cells (as a control), and murine RAW264.7 macrophages were used. Macrophages were polarized with LPS (M1) or IL-4 (M2). Cell proliferation was assessed by Crystal Violet and mRNA expression by qRT-PCR.

To determine how macrophages impact 105K Tsc2-null cells (a model of LAM cells), 105K cells were treated with concentrated media from M0, M1, or M2-polarized macrophages. The media of M2, but not M1 or M0 macrophages, increased 105K cell proliferation (p = 0.007). Tsc2-expressing control cells did not have an M2-induced proliferative increase, highlighting specificity for Tsc2-deficiency. To determine how Tsc2-null cells impact macrophage polarization, M0 macrophages were treated with concentrated media from 105K Tsc2-null cells. This resulted in a 4-fold increase in the M2 marker CD206/Mrc1, with no effect on M1 markers. Direct co-culture of 105K cells with M0 macrophages resulted in a 20-fold increase of Arginase-1, an M2 marker, in FACS-sorted macrophages, with no change in M1 markers.

These data support the hypothesis that in LAM, TSC2-null cells drive macrophage polarization toward an M2 phenotype. These M2-like macrophages promote LAM proliferation, thereby creating a positive feedback loop that may drive disease progression.

Research Context

Pulmonary lymphangioleiomyomatosis (LAM) occurs almost exclusively in women and can result in lung collapse (pneumothorax), respiratory insufficiency and death. LAM is the result of the infiltration of the lungs by TSC2-deficient LAM cells which express estrogen and progesterone receptors. The origin of LAM cells is unknown, but some evidence suggests that they arise in the uterus. LAM progresses more rapidly in women of childbearing age and is exacerbated by hormonal treatment or pregnancy. Our work aims to decipher the immune mechanisms involved in LAM pathogenesis, including the effects of estrogen and progesterone on these immune mechanisms, and to discover new treatments for this gender-specific, life-threatening condition.