Although mast cell functions classically relate to allergic responses1–3, recent studies indicate that these cells contribute to other common diseases such as multiple sclerosis, rheumatoid arthritis, atherosclerosis, aortic aneurysm, and cancer4–8. This study presents evidence that mast cells contribute importantly to diet-induced obesity and diabetes. White adipose tissues (WAT) from obese humans and mice contain more mast cells than WAT from their lean counterparts. Genetically determined mast cell deficiency and pharmacological stabilization of mast cells in mice reduce body weight gain and levels of inflammatory cytokines, chemokines, and proteases in serum and WAT, in concert with improved glucose homeostasis and energy expenditure. Mechanistic studies reveal that mast cells contribute to WAT and muscle angiogenesis and associated cell apoptosis and cathepsin activity. Adoptive transfer of cytokine-deficient mast cells established that these cells contribute to mice adipose tissue cysteine protease cathepsin expression, apoptosis, and angiogenesis, thereby promoting diet-induced obesity and glucose intolerance by production of IL6 and IFN-γ. Mast cell stabilizing agents in clinical use reduced obesity and diabetes in mice, suggesting the potential of developing novel therapies for these common human metabolic disorders.

Mammalian Toll-like receptors (TLRs) 3, 7, 8 and 9 initiate immune responses to infection by recognizing microbial nucleic acids1, 2; however, these responses come at the cost of potential autoimmunity due to inappropriate recognition of self nucleic acid3. The localization of TLR9 and TLR7 to intracellular compartments appears to play a role in facilitating responses to viral nucleic acids while maintaining tolerance to self nucleic acid, yet the cell biology regulating the trafficking and localization of these receptors remains poorly understood4-6. Here, we define the route by which TLR9 and TLR7 exit the endoplasmic reticulum (ER) and traffic to endolysosomes. Surprisingly, the ectodomains of TLR9 and TLR7 are cleaved in the endolysosome, such that no full-length protein is detectable in the compartment where ligand is recognized. Remarkably, though both the full-length and cleaved forms of TLR9 are capable of binding ligand, only the processed form recruits MyD88 upon activation, arguing that this truncated receptor, rather than the full-length form, is functional. Furthermore, conditions that prevent receptor proteolysis, including forced TLR9 surface localization, render the receptor non-functional. We propose that ectodomain cleavage represents a strategy to restrict receptor activation to endolysosomal compartments and prevent TLRs from responding to self nucleic acid.

Pycnodysostosis, an autosomal recessive osteochondrodysplasia characterized by osteosclerosis and short stature, maps to chromosome 1q21. Cathepsin K, a cysteine protease gene that is highly expressed in osteoclasts, localized to the pycnodysostosis region. Nonsense, missense, and stop codon mutations in the gene encoding cathepsin K were identified in patients. Transient expression of complementary DNA containing the stop codon mutation resulted in messenger RNA but no immunologically detectable protein. Thus, pycnodysostosis results from gene defects in a lysosomal protease with highest expression in osteoclasts. These findings suggest that cathepsin K is a major protease in bone resorption, providing a possible rationale for the treatment of disorders such as osteoporosis and certain forms of arthritis.