About

The provided page text does not contain a specific professional biography of Professor Richard Bucala. It primarily describes the research activities, strategic plans, and general achievements of Yale School of Medicine and its faculty, without detailed personal or research focus information about Professor Bucala.

Research topics

• Medicine
• Immunology
• Biology
• Internal medicine
• Pathology
• Cancer research
• Cell biology
• Biochemistry
• Virology

Selected publications

• Dysregulated alveolar type 2 epithelial cell proteostasis promotes fibrogenic macrophage migration inhibitory factor–CD74 signaling

  Science Translational Medicine · 2025-12-03 · 1 citations

  articleCorresponding

  Aberrant proteostasis in alveolar type 2 epithelial cells (AEC2s) contributes to idiopathic pulmonary fibrosis (IPF), but the role of the ubiquitin-proteasome system (UPS) is unclear. Here, we show that UPS disruption in AEC2s amplifies profibrotic signaling to macrophages through macrophage migration inhibitory factor (MIF) family proteins in several models. Modeling UPS disruption with an AEC2-specific cullin 3 ( Cul3 ) deletion produced spontaneous fibrosis in a physiological aging mouse model and exacerbated fibrosis in the bleomycin-induced lung injury model. This was accompanied by expansion of transitional epithelial states and increased MIF and MIF-2 in lung tissue and bronchoalveolar lavage fluid (BALF) in the model. Global or conditional AEC2-specific deletions of Mif or Mif-2 attenuated fibrosis in the bleomycin-treated mouse model, as did conditional deletions of Cd74 , the cognate receptor for MIF and MIF-2, in C-X3-C motif chemokine receptor 1 ( Cx3cr1 )–expressing and platelet factor 4 ( Pf4 )–expressing cells. Pharmacological inhibition of MIF attenuated fibrosis in bleomycin-treated and transforming growth factor–β1 ( TGFB1 ) transgenic mouse models and in ex vivo human precision-cut lung slices treated with fibrotic cocktail. In study participants with IPF, BALF MIF was elevated compared with that in study participants without IPF. In participants with IPF, BALF MIF greater than 4000 picograms per milliliter was associated with increased mortality compared with participants with IPF with lower MIF. Together, these findings define a UPS-sensitive epithelial-macrophage signaling connection and identify MIF-CD74 cross-talk as a potential therapeutic target in fibrotic lung disease.

  PublisherDOI

• Distinctive Macrophage Migration Inhibitory Factor Receptor Patterns and Soluble Biomarkers in Rheumatoid Arthritis: Unveiling Key Associations with Disease Activity

  Journal of Interferon & Cytokine Research · 2025-02-06

  articleOpen access

  We previously reported the peripheral blood cell patterns of expression for the migration inhibitory factor (MIF) canonical (CD74/CD44) and noncanonical receptors (CXCR2, CXCR4, and CXCR7) in rheumatoid arthritis (RA) patients and correlated this with clinical biomarkers and disease activity. This study aimed to evaluate the expression of these receptors alongside the serum levels of CXCL12 and CXCL8 (ligands for CXCR2, CXCR4, and CXCR7), which potentially regulate the action of these receptors and the influence the downstream effects of MIF. Additionally, we evaluated soluble levels of MIF, as well as its soluble cognate receptor (sCD74), in the serum of RA patients and control subjects (CS). Our findings revealed distinctive membrane expression patterns of MIF receptors in active (moderate and high disease activity) and non-active (low activity and remission) RA patients. Furthermore, RA patients exhibited elevated serum sCD74 levels, which correlated with disease activity, and elevated CXCL12 levels, which correlated with rheumatoid factor titers. Regarding serum CXCL8 and MIF levels, we observed higher CXCL8 levels in RA patients compared to CS, while MIF levels did not significantly differ between groups or by disease activity. The circulating sCD74/MIF ratio was elevated in RA patients, particularly in cases of moderate disease activity. Our study also indicated that treatment protocols did not significantly impact circulating MIF levels or the expression of its receptors. This study extends previous findings by supporting a role for sCD74 in downregulating MIF action and in the potential value of the sCD74/MIF ratio as a disease biomarker in RA.

  PublisherOA PDFDOI

• An atypical atherogenic chemokine that promotes advanced atherosclerosis and hepatic lipogenesis

  Nature Communications · 2025-03-07 · 15 citations

  articleOpen access

  Abstract Atherosclerosis is the underlying cause of myocardial infarction and ischemic stroke. It is a lipid-triggered and cytokine/chemokine-driven arterial inflammatory condition. We identify D-dopachrome tautomerase/macrophage migration-inhibitory factor-2 (MIF-2), a paralog of the cytokine MIF, as an atypical chemokine promoting both atherosclerosis and hepatic lipid accumulation. In hyperlipidemic Apoe –/– mice, Mif-2 -deficiency and pharmacological MIF-2-blockade protect against lesion formation and vascular inflammation in early and advanced atherogenesis. MIF-2 promotes leukocyte migration, endothelial arrest, and foam-cell formation, and we identify CXCR4 as a receptor for MIF-2. Mif-2- deficiency in Apoe –/– mice leads to decreased plasma lipid levels and suppressed hepatic lipid accumulation, characterized by reductions in lipogenesis-related pathways, tri-/diacylglycerides, and cholesterol-esters, as revealed by hepatic transcriptomics/lipidomics. Hepatocyte cultures and FLIM-FRET-microscopy suggest that MIF-2 activates SREBP-driven lipogenic genes, mechanistically involving MIF-2-inducible CD74/CXCR4 complexes and PI3K/AKT but not AMPK signaling. MIF-2 is upregulated in unstable carotid plaques from atherosclerotic patients and its plasma concentration correlates with disease severity in patients with coronary artery disease. These findings establish MIF-2 as an atypical chemokine linking vascular inflammation to metabolic dysfunction in atherosclerosis.

  PublisherOA PDFDOI

• Inhibition of MIF with an Allosteric Inhibitor Triggers Cell Cycle Arrest in Acute Myeloid Leukemia

  ACS Omega · 2025-04-22 · 1 citations

  articleOpen access

  to extract mechanistic insights into MIF action. Our findings demonstrate that AML cells utilize an MIF-dependent proliferation mechanism, which upon inhibition triggers a G0/G1 cell cycle arrest of the malignant cells. Complementary analysis of the MIF receptors utilizing neutralizing antibodies and selective small molecule antagonists associates this effect with inhibition of CD74 activation. The collection of data presented herein highlights the important role of MIF in proliferation of AML cells and points to the need of developing small molecule anticancer therapeutics that target MIF signaling.

  PublisherDOI

• Improving immunotherapy responses by dual inhibition of macrophage migration inhibitory factor and PD-1

  JCI Insight · 2025-10-21 · 5 citations

  articleOpen accessSenior author

  Macrophage migration inhibitory factor (MIF) is an upstream regulatory cytokine that is associated with advanced disease and poor outcomes in multiple cancer types, including melanoma. We investigated whether anti-MIF therapy could enhance the antitumor effects of the immune checkpoint inhibitor anti-programmed cell death 1 (anti-PD-1) in 2 murine tumor models. The therapeutic efficacy of anti-MIF, alone or combined with anti-PD-1, was tested in the YUMMER1.7 melanoma and MC38 colorectal cancer models. Tumor growth and survival were assessed in untreated Mif-knockout (KO) and low-expression human MIF allele (CATT5) mice and compared with wild-type (WT) or high-expression MIF allele (CATT7) mice. Tumor-bearing animals underwent cytokine profiling, tumor immunohistochemistry, flow cytometry, and scRNA-Seq. We also correlated functional variant MIF alleles with melanoma incidence and progression in patients. Our results showed that combined anti-MIF and anti-PD-1 significantly reduced tumor growth, improved survival, and promoted tumor regression, accompanied by enhanced TH1 cytokine levels, increased macrophage activation-related cytokines, and increased type 1 conventional dendritic cells. scRNA-Seq analysis revealed an expansion of intratumor Cd74/C1q/Aif1-expressing macrophages, which exhibited an antitumor phenotype, in response to anti-MIF therapy. MIF-KO and CATT5 mice exhibited reduced tumor burdens compared with WT or CATT7 mice alone and in the presence of anti-PD-1. In patients with melanoma, the high-MIF expression genotype (-173C/C) occurred at higher frequencies compared with healthy controls. These findings highlight that the addition of anti-MIF to anti-PD-1 reduces tumor growth, enhances antitumor responses, prolongs survival, and augments key intratumor immune cell populations involved in immune activation against tumors. This approach merits further consideration for clinical trial development.

  PublisherDOI

• POS1390 SINGLE-CELL PROFILING IDENTIFIES PERIPHERAL IMMUNE SIGNATURE OF CORONARY ARTERY DISEASE IN SLE PATIENTS

  Annals of the Rheumatic Diseases · 2024-06-01 · 1 citations

  article
  PublisherDOI

• MIF-CD74 Pathway and Its Effect on Effector T Cell Exhaustion in Alloimmunity

  Journal of the American Society of Nephrology · 2024-10-01

  article
  PublisherDOI

• MIF-Modulated Spinal Proteins Associated with Persistent Bladder Pain: A Proteomics Study

  International Journal of Molecular Sciences · 2024-04-19 · 1 citations

  articleOpen access

  Bladder pain is a prominent symptom in Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS). We studied spinal mechanisms of bladder pain in mice using a model where repeated activation of intravesical Protease Activated Receptor-4 (PAR4) results in persistent bladder hyperalgesia (BHA) with little or no bladder inflammation. Persistent BHA is mediated by spinal macrophage migration inhibitory factor (MIF), and is associated with changes in lumbosacral proteomics. We investigated the contribution of individual spinal MIF receptors to persistent bladder pain as well as the spinal proteomics changes associated with relief of persistent BHA by spinal MIF antagonism. Female mice with persistent BHA received either intrathecal (i.t.) MIF monoclonal antibodies (mAb) or mouse IgG1 (isotype control antibody). MIF antagonism temporarily reversed persistent BHA (peak effect: 2 h), while control IgG1 had no effect. Moreover, i.t. antagonism of the MIF receptors CD74 and C-X-C chemokine receptor type 4 (CXCR4) partially reversed persistent BHA. For proteomics experiments, four separate groups of mice received either repeated intravesical scrambled peptide and sham i.t. injection (control, no pain group) or repeated intravesical PAR4 and: sham i.t.; isotype IgG1 i.t. (15 μg); or MIF mAb (15 μg). L6-S1 spinal segments were excised 2 h post-injection and examined for proteomics changes using LC-MS/MS. Unbiased proteomics analysis identified and relatively quantified 6739 proteins. We selected proteins that showed significant changes compared to control (no pain group) after intravesical PAR4 (sham or IgG i.t. treatment) and showed no significant change after i.t. MIF antagonism. Six proteins decreased during persistent BHA (V-set transmembrane domain-containing protein 2-like confirmed by immunohistochemistry), while two proteins increased. Spinal MIF antagonism reversed protein changes. Therefore, spinal MIF and MIF receptors mediate persistent BHA and changes in specific spinal proteins. These novel MIF-modulated spinal proteins represent possible new targets to disrupt spinal mechanisms that mediate persistent bladder pain.

  PublisherOA PDFDOI

• Macrophage-derived macrophage migration inhibitory factor mediates renal injury in anti-glomerular basement membrane glomerulonephritis

  Frontiers in Immunology · 2024-05-23 · 6 citations

  articleOpen access

  Macrophages are a rich source of macrophage migration inhibitory factor (MIF). It is well established that macrophages and MIF play a pathogenic role in anti-glomerular basement membrane crescentic glomerulonephritis (anti-GBM CGN). However, whether macrophages mediate anti-GBM CGN via MIF-dependent mechanism remains unexplored, which was investigated in this study by specifically deleting MIF from macrophages in MIF f/f−lysM−cre mice. We found that compared to anti-GBM CGN induced in MIF f/f control mice, conditional ablation of MIF in macrophages significantly suppressed anti-GBM CGN by inhibiting glomerular crescent formation and reducing serum creatinine and proteinuria while improving creatine clearance. Mechanistically, selective MIF depletion in macrophages largely inhibited renal macrophage and T cell recruitment, promoted the polarization of macrophage from M1 towards M2 via the CD74/NF-κB/p38MAPK-dependent mechanism. Unexpectedly, selective depletion of macrophage MIF also significantly promoted Treg while inhibiting Th1 and Th17 immune responses. In summary, MIF produced by macrophages plays a pathogenic role in anti-GBM CGN. Targeting macrophage-derived MIF may represent a novel and promising therapeutic approach for the treatment of immune-mediated kidney diseases.

  PublisherOA PDFDOI

• Macrophage migration inhibitory factor as a therapeutic target in neuro-oncology: A review

  Neuro-Oncology Advances · 2024-01-01 · 6 citations

  reviewOpen access

  Primary central nervous system (CNS) tumors affect tens of thousands of patients each year, and there is a significant need for new treatments. Macrophage migration inhibitory factor (MIF) is a cytokine implicated in multiple tumorigenic processes such as cell proliferation, vascularization, and immune evasion and is therefore a promising therapeutic target in primary CNS tumors. There are several MIF-directed treatments available, including small-molecule inhibitors, peptide drugs, and monoclonal antibodies. However, only a small number of these drugs have been tested in preclinical models of primary CNS tumors, and even fewer have been studied in patients. Moreover, the brain has unique therapeutic requirements that further make effective targeting challenging. In this review, we summarize the latest functions of MIF in primary CNS tumor initiation and progression. We also discuss advances in MIF therapeutic development and ongoing preclinical studies and clinical trials. Finally, we discuss potential future MIF therapies and the strategies required for successful clinical translation.

  PublisherDOI

Recent grants

• NIH Grant R01AI051306

  NIH · $1.5M · 2011

• Training Program in Investigative Rheumatology

  NIH · $8.7M · 1976–2026

• NIH Grant R01AI035931

  NIH · $1.4M · 2000

• Aging and Innate Immune Mechanisms in Pulmonary Infection

  NIH · $1.7M · 2015–2020

• NIH Grant R01AR050498

  NIH · $3.6M · 2016

Frequent coauthors

• Lin Leng

  Yale University

  387 shared

• Andreas Meinhardt

  Hudson Institute of Medical Research

  124 shared

• Wise Young

  Rutgers, The State University of New Jersey

  110 shared

• Iman Tadmori

  110 shared

• Changshun Shao

  Changchun University of Science and Technology

  110 shared

• Kai Cao

  University Radiology

  110 shared

• Liang Li

  Guangdong Provincial People's Hospital

  110 shared

• Jianqing Fan

  110 shared

Education

• M.D., Medicine

  Yale University School of Medicine

  1990

• Ph.D., Immunology

  Yale University School of Medicine

  1985

Awards & honors

• American Society for Clinical Investigation
• Association of American Physicians