Mary Nakamura, MD

PROF IN RES-HCOMP
Precision Medicine in Rheumatology PREMIER
+1 415 750-2104 ext. 3458

Mary Nakamura received her B.A. from Swarthmore College, her M.D. from Yale and trained in internal medicine at the University of California, San Francisco. She completed her rheumatology training at Johns Hopkins and UCSF. She did her post doctoral work at UCSF under the mentorship of Bill Seaman. She is a basic-translational researcher focused on studies in the field of osteoimmunology. She leads the Rheumatoid Arthritis Clinic at UCSF Parnassus and is a clinical attending at the SF VA HCS.

Research Statement
My research has focused on the study of cells in the innate immune system. We have focused on receptor regulation of NK cells, macrophages and osteoclasts and the roles these cells play in disease pathology and tissue repair. We were one the early investigative groups focusing work in the field of Osteoimmunology, defined as a cross disciplinary field to integrate studies of the immune system and studies of bone and better define the interactions between these systems.

Osteoclasts are the only bone resorbing cell, and are derived from monocyte/macrophage precursors. Our studies demonstrated that innate immune receptors that utilize ITAM or immunoreceptor tyrosine based activation motif signals are critical regulators of osteoclast development and function, during normal bone development and homeostasis and we demonstrated that mice deficient in the ITAM adapter signaling chains DAP12 and FcRgamma are severely osteopetrotic due to defective osteoclast differentiation and function. Our studies suggest that osteoclasts are regulated much like other innate immune cells such as natural killer cells, macrophages and dendritic cells and should be considered an integral part of the innate immune system.

I have chosen to focus work in my laboratory on osteoimmunology since the role of innate immune receptor regulation in the bone is an understudied area, and inflammatory bone loss is of direct importance in rheumatologic diseases. My overall goal is to examine the role of innate immune receptors in autoimmune disease states and bone remodeling, which integrates my research interests with my clinical subspecialty work. Our studies in the role of immune cells in bone repair have led us to collaborative studies examining the role of innate immune cells in other types of tissue repair including traumatic brain injury, ischemic stroke and myocardial infarction.

Our work has primarily been focused in mouse models of disease, but we are also involved in studies of human osteoclasts in vitro and are beginning translational studies with rheumatic disease patients.

Publications: 

ACVR1R206H extends inflammatory responses in human induced pluripotent stem cell-derived macrophages.

Bone

Matsuo K, Lepinski A, Chavez RD, Barruet E, Pereira A, Moody TA, Ton AN, Sharma A, Hellman J, Tomoda K, Nakamura MC, Hsiao EC

2021 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis.

Arthritis care & research

Fraenkel L, Bathon JM, England BR, St Clair EW, Arayssi T, Carandang K, Deane KD, Genovese M, Huston KK, Kerr G, Kremer J, Nakamura MC, Russell LA, Singh JA, Smith BJ, Sparks JA, Venkatachalam S, Weinblatt ME, Al-Gibbawi M, Baker JF, Barbour KE, Barton JL, Cappelli L, Chamseddine F, George M, Johnson SR, Kahale L, Karam BS, Khamis AM, Navarro-Millán I, Mirza R, Schwab P, Singh N, Turgunbaev M, Turner AS, Yaacoub S, Akl EA

2021 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis.

Arthritis & rheumatology (Hoboken, N.J.)

Fraenkel L, Bathon JM, England BR, St Clair EW, Arayssi T, Carandang K, Deane KD, Genovese M, Huston KK, Kerr G, Kremer J, Nakamura MC, Russell LA, Singh JA, Smith BJ, Sparks JA, Venkatachalam S, Weinblatt ME, Al-Gibbawi M, Baker JF, Barbour KE, Barton JL, Cappelli L, Chamseddine F, George M, Johnson SR, Kahale L, Karam BS, Khamis AM, Navarro-Millán I, Mirza R, Schwab P, Singh N, Turgunbaev M, Turner AS, Yaacoub S, Akl EA

Natural killer cells activated through NKG2D mediate lung ischemia-reperfusion injury.

The Journal of clinical investigation

Calabrese DR, Aminian E, Mallavia B, Liu F, Cleary SJ, Aguilar OA, Wang P, Hoover J, Singer JP, Hays SR, Golden JA, Kukreja J, Dugger DT, Nakamura M, Lanier LL, Looney MR, Greenland JR

Lower PDL1/2 and AXL Expression on Lung Myeloid Cells Suggests Inflammatory Bias in Smoking and COPD.

American journal of respiratory cell and molecular biology

Vasudevan S, Vásquez JJ, Chen W, Aguilar-Rodriguez B, Niemi EC, Zeng S, Tamaki W, Nakamura MC, Arjomandi M

Proinflammatory cytokines and ARDS pulmonary edema fluid induce CD40 on human mesenchymal stromal cells-A potential mechanism for immune modulation.

PloS one

Wilfong EM, Croze R, Fang X, Schwede M, Niemi E, López GY, Lee JW, Nakamura MC, Matthay MA

Non-catalytic ubiquitin binding by A20 prevents psoriatic arthritis-like disease and inflammation.

Nature immunology

Razani B, Whang MI, Kim FS, Nakamura MC, Sun X, Advincula R, Turnbaugh JA, Pendse M, Tanbun P, Achacoso P, Turnbaugh PJ, Malynn BA, Ma A

Age-related changes to macrophages are detrimental to fracture healing in mice.

Aging cell

Clark D, Brazina S, Yang F, Hu D, Hsieh CL, Niemi EC, Miclau T, Nakamura MC, Marcucio R

Female-Specific Role of Progranulin to Suppress Bone Formation.

Endocrinology

Wang L, Roth T, Nakamura MC, Nissenson RA

Osteoimmunology: entwined regulation of integrated systems.

Seminars in immunopathology

Nakamura MC

NF-?B/MAPK activation underlies ACVR1-mediated inflammation in human heterotopic ossification.

JCI insight

Barruet E, Morales BM, Cain CJ, Ton AN, Wentworth KL, Chan TV, Moody TA, Haks MC, Ottenhoff TH, Hellman J, Nakamura MC, Hsiao EC

Effects of Aging on Fracture Healing.

Current osteoporosis reports

Clark D, Nakamura M, Miclau T, Marcucio R

A Comprehensive Review of Immunoreceptor Regulation of Osteoclasts.

Clinical reviews in allergy & immunology

Humphrey MB, Nakamura MC

Brain trauma elicits non-canonical macrophage activation states.

Journal of neuroinflammation

Kim CC, Nakamura MC, Hsieh CL

Triggering receptor expressed on myeloid cells 2 (TREM2) deficiency attenuates phagocytic activities of microglia and exacerbates ischemic damage in experimental stroke.

The Journal of neuroscience : the official journal of the Society for Neuroscience

Kawabori M, Kacimi R, Kauppinen T, Calosing C, Kim JY, Hsieh CL, Nakamura MC, Yenari MA

CCR2 deficiency impairs macrophage infiltration and improves cognitive function after traumatic brain injury.

Journal of neurotrauma

Hsieh CL, Niemi EC, Wang SH, Lee CC, Bingham D, Zhang J, Cozen ML, Charo I, Huang EJ, Liu J, Nakamura MC

Bone and the innate immune system.

Current osteoporosis reports

Charles JF, Nakamura MC

CIITA: a master regulator of adaptive immunity shows its innate side in the bone.

Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research

Nakamura MC

Triggering Receptor Expressed on Myeloid Cells-2 Correlates to Hypothermic Neuroprotection in Ischemic Stroke.

Therapeutic hypothermia and temperature management

Kawabori M, Hokari M, Zheng Z, Kim JY, Calosing C, Hsieh CL, Nakamura MC, Yenari MA

Traumatic brain injury induces macrophage subsets in the brain.

European journal of immunology

Hsieh CL, Kim CC, Ryba BE, Niemi EC, Bando JK, Locksley RM, Liu J, Nakamura MC, Seaman WE

Inflammatory arthritis increases mouse osteoclast precursors with myeloid suppressor function.

The Journal of clinical investigation

Charles JF, Hsu LY, Niemi EC, Weiss A, Aliprantis AO, Nakamura MC

PSTPIP2 deficiency in mice causes osteopenia and increased differentiation of multipotent myeloid precursors into osteoclasts.

Blood

Chitu V, Nacu V, Charles JF, Henne WM, McMahon HT, Nandi S, Ketchum H, Harris R, Nakamura MC, Stanley ER

Expression of A20 by dendritic cells preserves immune homeostasis and prevents colitis and spondyloarthritis.

Nature immunology

Hammer GE, Turer EE, Taylor KE, Fang CJ, Advincula R, Oshima S, Barrera J, Huang EJ, Hou B, Malynn BA, Reizis B, DeFranco A, Criswell LA, Nakamura MC, Ma A

Effects of inflammation on bone: an update.

Current opinion in rheumatology

Baker-LePain JC, Nakamura MC, Lane NE

Assessment of bone remodelling in childhood-onset systemic lupus erythematosus.

Rheumatology (Oxford, England)

Baker-LePain JC, Nakamura MC, Shepherd J, von Scheven E

The loss of Cbl-phosphatidylinositol 3-kinase interaction perturbs RANKL-mediated signaling, inhibiting bone resorption and promoting osteoclast survival.

The Journal of biological chemistry

Adapala NS, Barbe MF, Langdon WY, Nakamura MC, Tsygankov AY, Sanjay A

Clinical diagnosis of segmental arterial mediolysis: differentiation from vasculitis and other mimics.

Arthritis care & research

Baker-LePain JC, Stone DH, Mattis AN, Nakamura MC, Fye KH

Multiple roles for CCR2 during fracture healing.

Disease models & mechanisms

Xing Z, Lu C, Hu D, Yu YY, Wang X, Colnot C, Nakamura M, Wu Y, Miclau T, Marcucio RS

Binding and uptake of H-ferritin are mediated by human transferrin receptor-1.

Proceedings of the National Academy of Sciences of the United States of America

Li L, Fang CJ, Ryan JC, Niemi EC, Lebrón JA, Björkman PJ, Arase H, Torti FM, Torti SV, Nakamura MC, Seaman WE

IL-10 suppresses calcium-mediated costimulation of receptor activator NF-kappa B signaling during human osteoclast differentiation by inhibiting TREM-2 expression.

Journal of immunology (Baltimore, Md. : 1950)

Park-Min KH, Ji JD, Antoniv T, Reid AC, Silver RB, Humphrey MB, Nakamura M, Ivashkiv LB

A role for TREM2 ligands in the phagocytosis of apoptotic neuronal cells by microglia.

Journal of neurochemistry

Hsieh CL, Koike M, Spusta SC, Niemi EC, Yenari M, Nakamura MC, Seaman WE

The innate immune response to Salmonella enterica serovar Typhimurium by macrophages is dependent on TREM2-DAP12.

Infection and immunity

Charles JF, Humphrey MB, Zhao X, Quarles E, Nakamura MC, Aderem A, Seaman WE, Smith KD

Osteoclasts - the innate immune cells of the bone.

Autoimmunity

Wu Y, Humphrey MB, Nakamura MC

Cutting edge: inhibition of TLR and FcR responses in macrophages by triggering receptor expressed on myeloid cells (TREM)-2 and DAP12.

Journal of immunology (Baltimore, Md. : 1950)

Hamerman JA, Jarjoura JR, Humphrey MB, Nakamura MC, Seaman WE, Lanier LL

TREM2, a DAP12-associated receptor, regulates osteoclast differentiation and function.

Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research

Humphrey MB, Daws MR, Spusta SC, Niemi EC, Torchia JA, Lanier LL, Seaman WE, Nakamura MC

TIM-2 is expressed on B cells and in liver and kidney and is a receptor for H-ferritin endocytosis.

The Journal of experimental medicine

Chen TT, Li L, Chung DH, Allen CD, Torti SV, Torti FM, Cyster JG, Chen CY, Brodsky FM, Niemi EC, Nakamura MC, Seaman WE, Daws MR

Mice lacking the integrin beta5 subunit have accelerated osteoclast maturation and increased activity in the estrogen-deficient state.

Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research

Lane NE, Yao W, Nakamura MC, Humphrey MB, Kimmel D, Huang X, Sheppard D, Ross FP, Teitelbaum SL

The immunomodulatory adapter proteins DAP12 and Fc receptor gamma-chain (FcRgamma) regulate development of functional osteoclasts through the Syk tyrosine kinase.

Proceedings of the National Academy of Sciences of the United States of America

Mócsai A, Humphrey MB, Van Ziffle JA, Hu Y, Burghardt A, Spusta SC, Majumdar S, Lanier LL, Lowell CA, Nakamura MC

The signaling adapter protein DAP12 regulates multinucleation during osteoclast development.

Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research

Humphrey MB, Ogasawara K, Yao W, Spusta SC, Daws MR, Lane NE, Lanier LL, Nakamura MC

CMRF-35-like molecule-1, a novel mouse myeloid receptor, can inhibit osteoclast formation.

Journal of immunology (Baltimore, Md. : 1950)

Chung DH, Humphrey MB, Nakamura MC, Ginzinger DG, Seaman WE, Daws MR