Proliferating Inflammatory Macrophages Mediate Dysferlinopathy

Vicki Rubin Kelley, PhD

Brigham and Women's Hospital/Harvard Medical School

Dr. Kelley is a Professor of Medicine at Harvard Medical School and Brigham and Women's Hospital (Boston, MA).

Research Projects

Past Projects

To test the hypothesis that dysferlinopathy is mediated by a defect in Mø that precludes a sufficient transition from M1 inflammatory to M2 reparative/regulatory phenotypes.

Dysferlinopathy is a chronic, progressive skeletal muscle wasting disease resulting from loss of function mutations in the gene dysferlin. Macrophages and adipocytes are prominent in the inflamed skeletal muscles of patients with dysferlinopathy. These myeloid cells increase and localize to fat depots within skeletal muscles of mice on a high fat diet. However, it is not clear whether macrophages and adipocytes directly and/or indirectly interact in inflamed muscles. Macrophages are integral to both tissue repair and destruction. Injured skeletal muscle recruits inflammatory (M1) macrophages that transition over time into reparative/regulatory (M2) macrophages to regenerate and heal. During advancing dysferlinopathy in mice, inflammatory M1 are the dominant macrophage phenotype. As muscles in patients with dysferlinopathy do not heal, M1 Mø are likely central to non-resolving inflammation resulting in the loss of muscle fibers and replacement by adipocytes. Colony Stimulating Factor 1 (CSF-1) and IL-34 are the principle cytokines required for macrophage survival and proliferation. Moreover, CSF-1 increases the number of adipocytes in fat depots. Taken together, CSF-1 and/or IL-34 are likely to increase macrophage and adipocytes within muscle, and thereby promote non-resolving inflammation and dysferlinopathy. We will test the hypothesis that intra-muscle CSF-1 and/or IL-34 mediate macrophage and adipocyte interactions driving dysferlinopathy. Detailing macrophage-mediated mechanisms that promote dysferlinopathy will likely lead to novel therapeutic strategies to treat this debilitating muscle disease.