Our Mission
Basic Research:
To define the role of chemoattractants and their receptors in leukocyte development, immune surveillance, and immune dysregulation (allergy, autoimmunity, and inflammatory disorders).
Public Health and Military Service Member-Targeted Research:
To discover and develop novel therapeutics (small molecules, peptides, monoclonal antibodies) to treat allergy, autoimmune diseases, inflammatory disorders, and cancer.
Chemoattractants and Receptors
Leukocyte chemoattractants are a structurally diverse collection of bioactive molecules that includes lipids (e.g. leukotrienes, sphingosine 1 phosphate, and prostaglandin D2), peptides (e.g. chemerin nonamer and formyl-methionyl-leucyl-phenylalanine (fMLP)), and small proteins of several classes (e.g. chemokines, defensins, “cystatin-like” fold possessing attractants like chemerin, and non-chemokine cytokines (such as stem cell factor)). While all of these molecules are less than 20 kD, individual members can differ ~50-fold in size (e.g. chemerin is ~16,000 Da, while leukotriene B4 (LTB4) is 337 Da). Each attractant binds to one or more receptor of the serpentine, or seven-transmembrane spanning G protein coupled receptor (GPCR) superfamily (although not all receptors necessarily couple to G proteins). Chemoattractants and their receptors are highly regulated both developmentally and during inflammatory and immune responses, and play critical roles in the development and function of the immune (and other) systems. Selective leukocyte homing via chemoattractant:receptor interactions is essential to the overall organization of the immune system and subsequent protection against infectious disease. Importantly, chemoattractants can also play a pathogenic role in exacerbating allergic responses, autoimmune disease, or other inflammatory disorders.
Chemoattractant receptors control the systemic positioning of leukocytes throughout the body by triggering adhesion and extravasation from the blood into tissues and control their intratissue localization via gradient-directed chemotaxis. Selectins and/or integrins concentrated on microvillus tips mediate tethering (step 1) and rolling (step 2) to dampen leukocyte velocity and permit detection of local chemoattractants bound on the vascular endothelium. Activated chemoattractant receptors bound to their cognate ligands signal a conformational unfolding of integrins that rapidly leads to leukocyte adhesion and firm arrest on the vessel wall (step 3). This process is followed by extravasation (step 4). Chemoattractant gradients in the tissue then enable finely tuned leukocyte localization via chemoattractant receptor–mediated chemotaxis. Zabel et al. Ann Rev Pathol 2015.
Orphan Heptahelical Receptors
Orphan receptors are DNA sequences that share significant homology with known leukocyte chemoattractant receptors, yet remain uncharacterized with respect to ligand-binding properties and functions. Leukocyte-expressed orphan receptors represent excellent candidates for additional regulators of immune cell trafficking and function. Identifying ligands for non-signaling orphan serpentine receptors is particularly challenging, since the assays employed in most heptahelical receptor ligand screens depend on functional responses, such as intracellular calcium mobilization or cell migration. We ‘de-orphaned’ three receptors to date: CCR9 (which binds CCL25), CMKLR1 (which binds chemerin), and CCRL2 (which also binds chemerin). We also worked on the initial functional characterization of CXCR7 (which binds CXCL12 and CXCL11).
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Chemoattractant receptor ligand-binding specificity, cellular expression, and disease associations. Disease associations are based on phenotypes in animal disease models and/or receptor expression by ex vivo human cells or tissues. Data points were curated from primary literature reports and selected review articles. Not all chemoattractants and receptors exist in both humans and mice. For example, CXCR1, CXCL7, CXCL8, CXCL11, CCL13, CCL14, CCL15, CCL18, CCL23, CCL24, and CCL26 are present in humans but not in mice, whereas CXCL15, CCL6, CCL9, and CCL12 are present in mice but not in humans. Atypical receptor aliases: ACKR1 (DARC), ACKR2 (D6), ACKR3 (CXCR7), ACKR4 (CCX-CKR). Abbreviations: CysLT, cysteinyl leukotriene; CysLT1, cysteinyl leukotriene receptor 1; COPD, chronic obstructive pulmonary disease; IBD, inflammatory bowel disease; LL37, 37-residue carboxyl-terminal peptide of human cathelicidin; LPA, lysophosphatidic acid; LPA1, lysophosphatidic acid receptor 1; LTB4, leukotriene B4; LXA4, lipoxin A4; PAF, platelet-activating factor; PAFR, platelet-activating factor receptor; PGD2, prostaglandin D2; S1P, sphingosine 1-phosphate; S1P1, sphingosine 1-phosphate receptor 1. Zabel et al. Ann Rev Pathol 2015.
Chemoattractant receptors are heptahelical cell surface proteins with the amino-terminal domain extending into the extracellular space and the carboxyl-terminal domain extending into the cytosol. Here the primary amino acid sequence for the chemerin chemoattractant receptor CMKLR1 is threaded onto seven transmembrane bundles (I–VII) oriented to resemble the recently solved crystal structures of CXCR4 and CXCR1. An extracellular disulfide bond ( purple) likely stabilizes the structure. Most attractant receptors have consensus sequences for extracellular N-linked glycosylation sites (NxS/T) (red ) that can impact receptor expression on the cell surface. The intracellular loop between transmembrane bundles III and IV contains a sequence motif that plays a role in heterotrimeric G protein coupling (DRCISVL, although the more common sequence is DRYLAIV) (red ). The intracellular loops and the carboxyl-terminal domain also have consensus sequences for protein kinase C phosphorylation sites (S/TxR/K) (blue), which play important roles in receptor desensitization mediated by β-arrestins. Zabel et al. Ann Rev Pathol 2015.
For more information on the role of chemoattractant receptors in human disease pathogenesis, I am pleased to provide you complimentary one-time access to my Annual Reviews article as a PDF file (http://arjournals.annualreviews.org/eprint/tCdHiuVIkZjPg6pgxTvD/full/10.1146/annurev-pathol-012513-104640) for your own personal use. Any further/multiple distribution, publication, or commercial usage of this copyrighted material requires submission of a permission request addressed to the Copyright Clearance Center (http://www.copyright.com/).