Jonathan P. Arm

Associate Professor
Division of Rheumatology, Immunology and Allergy
Brigham and Women's Hospital
Smith Research Building, Room 638B
One Jimmy Fund Way
Boston, MA 02115
Tel: 617-525-1305
Fax: 617-525-1310
e-mail:jarm@rics.bwh.harvard.edu

Dr. Arm's research interests are the role of phospholipase A2 in innate immune responses; and a novel family of immunoregulatory receptors, the human leukocyte immunoglobulin-like receptors (LIRs).

Phospholipase A2 and innate immune responses Ð Phospholipase A2 (PLA2) releases arachidonic acid from the sn-2 position of cell membrane phospholipids for metabolism by 5-lipoxygenase to leukotrienes (LT) or by one of the isoforms of cyclooxygenase (COX) to prostaglandins. Leukotrienes and prostaglandins have been implicated in diverse physiological processes, including inflammation and carcinogenesis. The present focus of our research is the role of individual PLA2 enzymes in providing arachidonic acid for eicosanoid generation and in regulating the innate immune response. Mammalian PLA2 enzymes fall into four broad categories; group IV cytosolic PLA2 (cPLA2); at least ten low molecular weight secretory enzymes (sPLA2); Ca2+-independent PLA2; and the selective acetyl hydrolases of platelet activating-factor. The differing structure, Ca2+ requirements, pH optima, substrate specificity, and tissue distribution of PLA2 enzymes suggest that, rather than being redundant, they serve specific cellular functions. Using mast cells from mice in which the gene for the 85 kDa cPLA2-a has been disrupted we have shown that cPLA2-a is essential for immediate LTC4 and PGD2 generation in response to signaling through c-kit and the high affinity Fc receptor for IgE. cPLA2-a is also essential for delayed phase COX-2-dependent PGD2 generation. To address the role of the low molecular weight group V sPLA2 we generated mice with targeted disruption of the gene encoding this enzyme. Our findings indicate that group V sPLA2 is not required for eicosanoid generation by mast cells, but it augments the essential function of cPLA2-a in regulating eicosanoid generation by mouse peritoneal macrophages in response to zymosan, a phagocytic stimulus. Of interest, group V sPLA2 translocates to the phagosome in response to zymosan stimulation, and resident peritoneal macrophages from group V sPLA2-null mice have ~50% attenuation of zymosan phagocytosis that appears to be independent of the role of group V sPLA2 in regulating eicosanoid generation. Current studies are focused on the mechanisms by which group V sPLA2 regulates phagocytosis, its implications for host defense, and the broader role of group V sPLA2 in innate immunity.

The Leukocyte Immunoglobulin-Like Receptors. The human leukocyte immunoglobulin-like receptors (LIRs) are type I integral membrane proteins, highly homologous in their extracellular domains, that are encoded by thirteen different genes on chromosome 19q13.4. They are either inhibitory receptors, in which the cytoplasmic domain contains two to four immunoreceptor tyrosine-based inhibition motifs (ITIMs), or activating receptors, in which the transmembrane domain contains a charged arginine residue that associates with the common Fc receptor gamma chain, followed by a short cytoplasmic domain that lacks ITIMs. We have characterized the expression of individual LIRs on human eosinophils, basophils, neutrophils, and in vitro culture-derived mast cells. We have demonstrated granule exocytosis, leukotriene C4 generation, and regulated release of preformed interleukin-12 by vesicular transport from human eosinophils in response to signaling through LIR-7, an activating LIR. Cross-linking of LIR7 on human basophils elicits exocytosis, leukotriene C4 generation, and, in contrast to the eosinophil, the release of interleukin 4 by gene induction. We have demonstrated the expression of inhibitory LIR-2 and activating LIR-7 in rheumatoid synovium, but not in normal synovium or synovium derived from patients with osteoarthritis. Our present research is based on the hypothesis that LIRs modulate the inflammatory response in disease and that LIRs provide a novel therapeutic target in inflammation.

Our ongoing studies are focused on investigating the regulated expression and function of individual LIRs in asthma and allergic disease.

Papers & Publications:

Kikawada E, Bonventre JV, Arm JP. Group V secretory PLA2 regulates TLR2-dependent eicosanoid generation in mouse mast cells through amplification of ERK and cPLA2a activation. Blood 2007; Prepublished online March 16, 2007; DOI 10.1182/blood-2006-10-052258.

Diaz BL, Satake Y, Kikawada E, Balestrieri B, Arm JP. Group V secretory phospholipase A2 amplifies the induction of cyclooxygenase 2 and delayed prostaglandin D2 generation in mouse bone marrow culture-derived mast cells in a strain-dependent manner. Biochim Biophys Acta – Molecular and Cell Biology of Lipids. 2006; 1761:1489-1497.

Balestrieri B, Hsu VW, Gilbert H, Leslie CC, Han WK, Bonventre JV, Arm JP. Group V secretory phospholipase A2 translocates to the phagosome after zymosan stimulation of mouse peritoneal macrophages and regulates phagocytosis. J Biol Chem 2006; 281:6691-8.

Sloane D, Tedla N, Awoniyi M, MacGlashan DW, Jr., Borges L, Austen KF, Arm JP. Leukocyte immunoglobulin-like receptors; novel innate receptors for human basophil activation and inhibition. Blood 2004; 104:2832-9.

Satake Y, Diaz BL, Balestrieri B, Lam BK, Kanaoka Y, Grusby MJ, Arm JP. Role of group V phospholipase A2 in zymosan-induced eicosanoid generation and vascular permeability revealed by targeted gene disruption. J Biol Chem 2004: 279:16488-94