About

Anna Huttenlocher is a Professor of Medical Microbiology & Immunology and Pediatrics at the University of Wisconsin-Madison. Her research focuses on characterizing the molecular mechanisms that regulate cell migration and understanding their implications for human diseases such as cancer metastasis and inflammation. Her work aims to elucidate how leukocytes migrate into areas of inflammation, how tumor cells invade and metastasize, and how cellular and molecular processes coordinate directional cell movement and adhesion events. Her research contributes to a deeper understanding of fundamental cellular processes and the development of new therapeutic approaches for various medical conditions. Dr. Huttenlocher earned her BA from Oberlin College in 1983 and her MD from Harvard Medical School in 1988. She completed postdoctoral fellowships at UCSF with Caroline Damsky and Zena Werb in 1992, and at the University of Illinois with Rick Horwitz in 1994. Her work has been recognized with numerous awards, including being named a fellow for lifetime achievement by the American Society of Cell Biology in 2017, election to the National Academy of Medicine in 2015, and several other honors acknowledging her contributions to pediatric research, cell biology, and clinical science.

Research topics

• Biology
• Genetics
• Cell biology
• Microbiology
• Immunology
• Materials science
• Medicine
• Biochemistry
• Chemistry
• Cancer research

Selected publications

• Leukocyte-epithelial physical contacts mediate interstitial migration in vivo

  Research Square · 2026-02-05

  preprintOpen access1st authorCorresponding
  PublisherOA PDFDOI

• The paracrine factor myeloid derived growth factor regulates the inflammatory fate and motility of human induced pluripotent stem cell–derived neutrophils

  The Journal of Immunology · 2026-02-01

  articleSenior author

  Neutrophils are necessary for host defense but also contribute to tissue damage. Understanding the molecular mechanisms that govern human neutrophil development and fate is critical for developing interventions for treating and preventing human disease. Human induced pluripotent stem cell (iPSC)-derived neutrophils (iNeutrophils) are genetically tractable and provide a robust source of neutrophils to dissect molecular regulation and for potential use in infusion therapies. Here, we show that deletion of the paracrine factor myeloid-derived growth factor (MYDGF) in human iPSCs results in the development of iNeutrophils with improved zymosan-induced reactive oxygen species generation and antimicrobial functions. MYDGF-deficient iNeutrophils showed improved transendothelial migration to microbes in organotypic models and motility in confined microchannels. We identify MYDGF as a new endogenous inhibitor of cytosolic calcium dynamics that suppresses neutrophil inflammatory activity. Our findings show that MYDGF mediates neutrophil-to-neutrophil communication during migration through a paracrine mechanism. Since MYDGF-deficient iNeutrophils show improved effector and antimicrobial function, these cells may improve future therapeutic use of iNeutrophils for infusion therapies. Finally, soluble MYDGF provides an attractive strategy to limit chronic neutrophil-mediated inflammation and tissue damage.

  PublisherDOI

• Multi-omic analysis reveals nitric oxide dependent remodeling in classically activated macrophages and identifies negative regulation mediated by AKR1A1

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-01-01 · 1 citations

  articleOpen access

  ABSTRACT Nitric oxide (NO•) is an important signaling molecule in many biological processes, including immune response. During response to classical activation stimuli lipopolysaccharide (LPS) and interferon-γ (IFNγ), macrophages generate NO• via inducible nitric oxide synthase (iNOS). To comprehensively define the effects of NO•, we applied a multi-omic strategy integrating proteomics and transcriptomics to profile murine macrophages across conditions with or without LPS/IFNγ-activation, with or without iNOS expression or exogenous NO• donor treatment. The results revealed NO• has broad, yet selected and controlled, regulatory effects, playing a key role in coordinating the systematic remodeling during macrophage classical activation. Among the proteins that are most suppressed in a NO•-dependent manner, electron transport chain (ETC) is the most enriched. NO• drives complex-specific remodeling of ETC, causing selected downregulation of complex I, II, and IV, through a different combination of transcriptional and post-transcriptional mechanisms for each complex. Functionally, we found NO• is required, but not sufficient, for the strong suppression of cellular respiration upon macrophage activation. Among the most consistently upregulated proteins are many enzymes involved in redox defense. AKR1A1 was identified as a top hit. We found Akr1a1 induction requires both NO• and LPS/IFNγ stimulation. The S-nitroso-CoA reductase activity of AKR1A1 mitigates NO•-driven inhibition of pyruvate dehydrogenase complex by limiting the inhibitory modifications targeting its lipoyl cofactor. Knocking out Akr1a1 causes accelerated remodeling of TCA cycle, dysregulated immunoregulatory metabolite level, and altered functional gene expression and cytokine production at later stage of immune response. Thus, the NO•-dependent upregulation of AKR1A1 forms a negative regulatory loop to fine-tune NO•-mediated metabolic and functional remodeling during immune response. Together, this work provided a systems-level map of NO•-dependent regulation, revealed the crosstalk between NO• and immune signaling, and demonstrated mechanisms providing redox adaptation and precise control of NO•’s effects.

  PublisherDOI

• Multi-omic analysis reveals nitric oxide dependent remodeling in classically activated macrophages and identifies negative regulation mediated by AKR1A1

  Redox Biology · 2026-04-22

  articleOpen access

  Nitric oxide (NO•) is an important regulatory molecule in many biological processes, including immune response. During response to classical activation stimuli lipopolysaccharide (LPS) and interferon-γ (IFNγ), macrophages generate NO• via inducible nitric oxide synthase (iNOS). To comprehensively characterize the effects of NO•, we applied a multi-omic strategy integrating proteomics and transcriptomics to profile murine macrophages across conditions with or without LPS/IFNγ-activation, with or without iNOS expression or exogenous NO• donor treatment. The results showed NO• has broad, yet selected and controlled, regulatory effects, playing a key role in coordinating the systematic remodeling during macrophage classical activation. Among the proteins that are most suppressed in a NO•-dependent manner, electron transport chain (ETC) is the most enriched. NO• drives complex-specific remodeling of ETC, causing selected downregulation of complex I, II, and IV, through a different combination of transcriptional and post-transcriptional mechanisms for each complex. Among the most consistently NO•-dependent upregulated proteins are many enzymes involved in redox defense, and AKR1A1 was identified as a top hit. We found Akr1a1 induction requires both NO• and LPS/IFNγ stimulation. The S-nitroso-CoA reductase activity of AKR1A1 mitigates NO•-driven inhibition of pyruvate dehydrogenase complex by limiting the inhibitory modifications targeting its lipoyl cofactor. Knocking out Akr1a1 causes accelerated remodeling of TCA cycle, dysregulated immunoregulatory metabolite level, and altered functional gene expression and cytokine production at later stage of immune response. Thus, the NO•-dependent upregulation of AKR1A1 forms a negative regulatory loop to fine-tune NO•-mediated metabolic and functional remodeling during immune response. Together, this work provided a systems-level map of NO•-dependent regulation, revealed the crosstalk between NO• and immune signaling, and demonstrated mechanisms providing adaptation and precise control of NO•'s effects.

  PublisherDOI

• Evidence that xylazine disrupts skin homeostasis by acting on epithelial cells through the kappa opioid receptor

  Disease Models & Mechanisms · 2026-03-01 · 2 citations

  articleOpen accessSenior author

  The veterinary sedative and alpha-2 adrenergic receptor (α2AR) agonist xylazine, found in the illicit opioid supply, is associated with cutaneous wounds in humans. Here, we developed a larval zebrafish model of xylazine-induced tissue damage to investigate the mechanisms by which xylazine affects the skin. Xylazine treatment caused keratinocyte extrusion, tissue-wide skin contraction and disruption of basal keratinocyte cell-cell interactions in zebrafish larvae. Notably, other α2AR agonists did not recapitulate most of these effects. Xylazine was recently described as a kappa opioid receptor (κOR) agonist, and we found that both xylazine and a separate κOR agonist acted directly on epithelial cells to drive cellular contraction and disrupt tissue homeostasis. Our model suggests that xylazine disrupts skin homeostasis through a direct mechanism involving epithelial cells and κOR, which may be of importance for the treatment of these wounds.

  PublisherOA PDFDOI

• Larval zebrafish burn wound infection model reveals conserved innate immune responses against diverse pathogenic fungi

  mBio · 2025-04-08 · 2 citations

  articleOpen access

  ABSTRACT Secondary fungal infections represent a major complication following thermal injuries. However, the mechanisms of fungal colonization of burn tissue and how the host subsequently responds to fungi within this niche remain unclear. We have previously reported a zebrafish model of thermal injury that recapitulates many of the features of human burn wounds. Here, we characterize host-fungal interaction dynamics within the burn wound niche using two of the most common fungal pathogens isolated from burn injuries, Aspergillus fumigatus and Candida albicans . Both A. fumigatus and C. albicans colonize burned tissue in zebrafish larvae and induce a largely conserved innate immune response following colonization. Using drug-induced cell-depletion strategies and transgenic zebrafish lines with impaired innate immune function, we found that macrophages control fungal burden, whereas neutrophils primarily control invasive hyphal growth at the early stages of infection. However, we also found that loss of either immune cell can be compensated by the other at the later stages of infection and that fish with both macrophage and neutrophil deficiencies show more invasive hyphal growth that is sustained throughout the infection process, suggesting redundancy in their antifungal activities. Finally, we demonstrate that C. albicans strains with increased β(1,3)-glucan exposure are cleared faster from the burn wound, demonstrating a need for shielding this immunogenic cell wall epitope for the successful fungal colonization of burn tissue. Together, our findings support the use of zebrafish larvae as a model to study host-fungal interaction dynamics within burn wounds. IMPORTANCE Secondary fungal infections within burn wound injuries are a significant problem that delays wound healing and increases the risk of patient mortality. Currently, little is known about how fungi colonize and infect burn tissue or how the host responds to pathogen presence. In this report, we expand upon an existing thermal injury model using zebrafish larvae to begin elucidating both the host immune response to fungal burn colonization and fungal mechanisms for persistence within burn tissue. We found that both Aspergillus fumigatus and Candida albicans , common fungal burn wound isolates, successfully colonize burn tissue and are effectively cleared in immunocompetent zebrafish by both macrophages and neutrophils. We also find that C. albicans mutants harboring mutations that impact their ability to evade host immune system recognition are cleared more readily from burn tissue. Collectively, our work highlights the efficacy of using zebrafish to study host-fungal interaction dynamics within burn wounds.

  PublisherDOI

• Zebrafish larval GPR132b differentially influences wound repair and infection control

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-07-22 · 1 citations

  preprintOpen accessSenior authorCorresponding

  Abstract GPR132 (G2A), a lipid- and pH-sensing GPCR, has been implicated in both pro- and anti-inflammatory signaling, but its in vivo function in wound repair and infection control remains unknown. Here, we investigated the role of GPR132b, a zebrafish homolog of G2A, in regulating innate immune responses. Using CRISPR-Cas9, we generated gpr132b mutants and found that they exhibit enhanced wound healing following sterile injury but increased susceptibility to Listeria monocytogenes infection, indicating that GPR132b modulates a trade-off between wound repair and antimicrobial defense. The enhanced regrowth phenotype was associated with increased macrophage accumulation at the wound site and reduced basal expression of the pro-inflammatory cytokine tnf-α . Macrophage depletion suppressed the enhanced regrowth phenotype, suggesting a functional role for macrophages in GPR132b-mediated repair. Pharmacological inhibition of cyclooxygenase (COX) and 12-lipoxygenase (12-LOX) pathways mimicked the gpr132b mutant phenotype in wild-type larvae, indicating that GPR132b likely responds to lipid-derived signals. Together, our findings reveal that GPR132b acts as a c ontext-dependent regulator of innate immunity, impairing efficient tissue repair in sterile conditions while supporting pathogen resistance during infection. Our results underscore the importance of GPCR-mediated signaling in orchestrating effective responses to tissue injury and infection.

  PublisherOA PDFDOI

• Chemical and Mechanical Regulation of Leukocyte Migration

  Cold Spring Harbor Perspectives in Biology · 2025-09-22 · 1 citations

  articleOpen accessSenior author

  Directed leukocyte motility is essential for immunity and host defense. Dysregulated leukocyte migration is implicated in clinical immunodeficiency and hyperinflammatory conditions. Leukocytes sense both chemical and physical cues within the environment to regulate internal migration machinery and thus coordinate the immune response and its resolution. In response to environmental cues, leukocytes cater migration strategies to both exert forces on surrounding tissues and alter the chemical environment through self-generated gradients. Here, we synthesize recent advances in our understanding of how chemical and physical cues within the tissue environment regulate leukocyte motility, with implications to develop therapeutic strategies to modulate the immune response in human disease.

  PublisherOA PDFDOI

• Mitochondrial metabolism is rapidly re-activated in mature neutrophils to support stimulation-induced response

  Frontiers in Immunology · 2025-04-28 · 11 citations

  articleOpen access

  Introduction: Neutrophils are highly abundant innate immune cells that are constantly produced from myeloid progenitors in the bone marrow. Differentiated neutrophils can perform an arsenal of effector functions critical for host defense. This study aims to quantitatively understand neutrophil mitochondrial metabolism throughout differentiation and activation, and to elucidate the impact of mitochondrial metabolism on neutrophil functions. Methods: To study metabolic remodeling throughout neutrophil differentiation, murine ER-Hoxb8 myeloid progenitor-derived neutrophils and human induced pluripotent stem cell-derived neutrophils were assessed as models. To study the metabolic remodeling upon neutrophil activation, differentiated ER-Hoxb8 neutrophils and primary human neutrophils were activated with various stimuli, including ionomycin, monosodium urate crystals, and phorbol 12-myristate 13-acetate. Characterization of cellular metabolism by isotopic tracing, extracellular flux analysis, metabolomics, and fluorescence-lifetime imaging microscopy revealed dynamic changes in mitochondrial metabolism. Results: As neutrophils mature, mitochondrial metabolism decreases drastically, energy production is offloaded from oxidative phosphorylation, and glucose oxidation through the TCA cycle is substantially reduced. Nonetheless, mature neutrophils retain the capacity for mitochondrial metabolism. Upon stimulation with certain stimuli, TCA cycle is rapidly activated. Mitochondrial pyruvate carrier inhibitors reduce this re-activation of the TCA cycle and inhibit the release of neutrophil extracellular traps. Treatment with these inhibitors also impacts neutrophil redox status, migration, and apoptosis without significantly changing overall bioenergetics. Conclusions: Together, these results demonstrate that mitochondrial metabolism is dynamically remodeled and plays a significant role in neutrophils. Furthermore, these findings point to the therapeutic potential of mitochondrial pyruvate carrier inhibitors in a range of conditions where dysregulated neutrophil response drives inflammation and contributes to pathology.

  PublisherOA PDFDOI

• 759 Label-free imaging reveals <i>in situ</i> metabolic changes in zebrafish scale T cells during migration

  Regular and Young Investigator Award Abstracts · 2025-11-01

  articleOpen access

  Figure 1 OMI captures metabolic and morphological changes in zebrafish scale T cells in response to metabolic perturbations from NaCN and 2-DG.(A) T cell NAD(P)H a1 in NaCN was recorded for 5 minutes.(B) T cell NAD(P)H a1 and (C) circularity in PBS and 2-DG were compared.(D) T cell circularity was recorded for 12 minutes and statistical differences are relative to the 1-min time point

  PublisherOA PDFDOI

Recent grants

• NIH Grant R01GM102924

  NIH · $2.5M · 2016

• NIH Grant R56AI094923

  NIH · $410k · 2014

• Integrated Training For Physician-Scientists

  NIH · $10.5M · 1998–2021

• Cancer Center Administration

  NIH · $99.8M · 1997–2028

• NIH Grant K08CA076631

  NIH · $324k · 2001

Frequent coauthors

• David J. Beebe

  University of Wisconsin Carbone Cancer Center

  69 shared

• David A. Bennin

  University of Wisconsin–Madison

  44 shared

• Karen Onel

  26 shared

• Kevin W. Eliceiri

  University of Wisconsin–Madison

  25 shared

• Nancy P. Keller

  University of Wisconsin–Madison

  25 shared

• Erwin Berthier

  University of Washington

  23 shared

• Robert P. Sundel

  Boston Children's Museum

  22 shared

• Melissa C. Skala

  Morgridge Institute for Research

  21 shared

Labs

• Huttenlocher LabPI

  New Member

Education

• B.A.

  Oberlin College

  1983

• M.D.

  Harvard Medical School

  1988

• Other

  UCSF (Caroline Damsky and Zena Werb)

  1992

• Other

  University of Illinois (Rick Horwitz)

  1994

Awards & honors

• 2017, American Society of Cell Biology, fellow for lifetime…
• 2015, National Academy of Medicine
• 2011, UW-Madison WARF Kellett Mid-Career Awardee
• 2009, Elected to American Pediatric Society
• 2009, APS Norman J Siegel New Member Outstanding Science Awa…